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Antihistamines and birth defects: a systematic review of the literature

Introduction: Approximately 10 - 15% of women reportedly take an antihistamine during pregnancy for the relief of nausea and vomiting, allergy and asthma symptoms, or indigestion. Antihistamines include histamine H1-receptor and H2-receptor antagonists.

Areas covered: This is a systematic evaluation of the peer-reviewed epidemiologic literature published through February 2014 on the association between prenatal exposure to antihistamines and birth defects. Papers addressing histamine H1- or H2-receptor antagonists are included. Papers addressing pyridoxine plus doxylamine (Bendectin in the United States, Debendox in the United Kingdom, Diclectin in Canada, Lenotan and Merbental in other countries) prior to the year 2001 were excluded post hoc because of several previously published meta-analyses and commentaries on this medication.

Expert opinion: The literature on the safety of antihistamine use during pregnancy with respect to birth defects is generally reassuring though the positive findings from a few large studies warrant corroboration in other populations. The findings in the literature are considered in light of three critical methodological issues: i) selection of appropriate study population; ii) ascertainment of antihistamine exposures; and iii) ascertainment of birth defect outcomes. Selected antihistamines have been very well studied (e.g., loratadine); others, especially H2-receptor antagonists, require additional study before an assessment of safety with respect to birth defect risk could be made.

Keywords: antihistamines; birth defects; pregnancy; prenatal exposure.

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Antihistamines and Birth Defects: A Systematic Review of the Literature

Associated data, introduction.

Approximately 10-15% of women reportedly take an antihistamine during pregnancy for the relief of nausea and vomiting, allergy and asthma symptoms, or indigestion. Antihistamines include histamine H 1 -receptor and H 2 -receptor antagonists.

Areas covered

This is a systematic evaluation of the peer-reviewed epidemiologic literature published through February 2014 on the association between prenatal exposure to antihistamines and birth defects. Papers addressing histamine H 1 - or H 2 -receptor antagonists are included. Papers addressing pyridoxine plus doxylamine (Bendectin in the United States, Debendox in the United Kingdom, Diclectin in Canada, Lenotan and Merbental in other countries) prior to the year 2001 were excluded post-hoc because of several previously published meta-analyses and commentaries on this medication.

Expert opinion

The literature on the safety of antihistamine use during pregnancy with respect to birth defects is generally reassuring though the positive findings from a few large studies warrant corroboration in other populations. The findings in the literature are considered in light of three critical methodological issues: (1) selection of appropriate study population; (2) ascertainment of antihistamine exposures; and (3) ascertainment of birth defects outcomes. Selected antihistamines have been very well-studied (e.g. loratadine); others, especially H 2- receptor antagonists, require additional study before an assessment of safety with respect to birth defects risk could be made.

Antihistamines, available in both prescription and over-the-counter formulations, are commonly used during early pregnancy for the treatment of nausea and vomiting, symptoms of asthma and allergies, and relief of indigestion 1 , 2 . Collectively, antihistamine use is reported by 10-15% of pregnant women 2 , 3 ; a recent analysis of pooled data from two large national studies showed that several individual antihistamine components (i.e. promethazine, diphenhydramine, loratadine, cetirizine, doxylamine, chlorpheniramine, and fexofenadine) are each used by 1-4% of pregnant women during the first trimester 1 . First generation H 1 -receptor antagonists (e.g. diphenhydramine [Benadryl®], dimenhydrinate [Dramamine], doxylamine plus pyridoxine (vitamin B6) [Bendectin in the United States, Debendox in the United Kingdom, Diclectin in Canada, Lenotan and Merbental in other countries] can cross the blood-brain barrier with resulting sedative and anticholinergic side effects and are frequently used to treat allergic reactions and nausea and vomiting of pregnancy (NVP). Second generation H 1 -receptor antagonists (e.g. loratadine [Claritin], cetirizine [Zyrtec], fexofenadine [Allegra]) lack those side effects and are primarily used to treat symptoms of asthma and allergies. H 2 -receptor antagonists (e.g. ranitidine [Zantac], cimetidine [Tagamet], famotidine [Pepcid], nizatidine [Axid]) used to treat indigestion, are less commonly used during pregnancy, though recent data indicate that approximately 1 in 100 pregnant women take ranitidine during the first trimester 1 .

The most controversial antihistamine ever in widespread use in the United States, the combination of doxylamine plus pyridoxine (originally a three-component drug which also included dicyclomine [an antispasmodic]), was reformulated to the more commonly-used two-component version in 1976 after a double-blind evaluation demonstrated that dicyclomine did not contribute to the drug's effectiveness (reported in Brent, 2003) 4 . Sold in the United States from 1957-1983, an estimated 30-35% of pregnant women used doxylamine plus pyridoxine for the treatment of NVP during the height of its popularity the 1970s 4 . However, because of concerns about fetal safety, doxylamine plus pyridoxine has been the topic of at least 27 original research peer-reviewed publications 5 , three published meta-analyses 5 - 7 , and at least 30 commentaries, editorials, and letters to the editor ( 4 , 8 - 11 ). The meta-analysis by McKeigue and colleagues based on 16 cohort and 11 case-control studies reported a pooled relative risk showing no association between any birth defect and first trimester exposure to doxylamine plus pyridoxine (0.95; 95% confidence interval (CI) 0.88-1.04). Separate analyses were conducted on types of birth defects including neural tube defects, oral clefts, congenital heart defects (CHD), and limb reductions, with relative risks ranging from 0.81 to 1.12, all of which had confidence intervals that contained the null value of 1.0 5 . However in the face of numerous lawsuits stating that the drug caused birth defects, including a class action case with over 1,000 plaintiffs, 4 its manufacturer stopped marketing doxylamine plus pyridoxine in the United States in 1983. As of April 2013, however, the US Food and Drug Administration has granted approval for a marketing a formulation of doxylamine plus pyridoxine for the treatment of NVP in women who do not respond to conservative management.

This review evaluates the peer-reviewed epidemiologic literature on the association between prenatal exposure to antihistamine medications and birth defects. It is limited in scope to only structural birth defects; other potential adverse pregnancy outcomes such as fetal loss, preterm delivery, or low birth weight, or longer-term neurodevelopmental outcomes, are not included in this review. Papers addressing either histamine H 1 - or H 2 -receptor antagonists (or both antihistamine subtypes) are included. The findings in the literature are considered in light of three critical methodological issues: (1) selection of appropriate study population; (2) ascertainment of antihistamine exposures; and (3) ascertainment of birth defects outcomes.

2.1 Data sources and search terms

The authors conducted a search of the peer-reviewed literature using PubMed (National Center for Biotechnology Information, United States National Library of Medicine) with a filter for human studies in the English language published through February 4, 2014. Two distinct search strings were used, the results of which were combined and de-duplicated in a single EndNote X7 (Thomson Reuters, 1998-2013) library:

Search string (2) was used to ensure that papers which had a primary focus on NVP, but reported analyses for antihistamine use were captured. Papers that only reported on the associations with NVP did not meet inclusion criteria and would be excluded. Two co-authors each initially screened one-half of the article titles and abstracts for relevance; two additional coauthors then independently re-screened the article titles and abstracts. If both co-authors who reviewed a title and/or abstract agreed that the article could be excluded, then it was excluded without further review. If one of the two co-authors determined that the screened title and/or abstract needed a review of the full text, either because it appeared to meet inclusion criteria or it could not be determined whether it met inclusion criteria, the full text was retrieved and reviewed. The reference lists of the selected articles were also searched for additional papers that were not ascertained through the PubMed search (see flowchart, Figure 1 ). Through personal communication with the author, one additional article that was electronically published in September, 2013 but was not indexed in PubMed until March 2014 was also included in the review (in flowchart box entitled “Articles identified through other sources”).

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Flowchart for inclusion of articles in systematic review

2.2 Inclusion criteria

A study was included in this review if it:

Studies that focused exclusively on doxylamine plus pyridoxine use and were published during the 1980s and 1990s (through the year 2000) were excluded post-hoc , as it was determined that re-reviewing this literature was unnecessary in light of the several previously published meta-analyses and commentaries on this medication. In addition, if other studies included doxylamine plus pyridoxine as one of several antihistamines under investigation, the results of the other antihistamines are included in this review and the doxylamine plus pyridoxine results are not discussed, though the table notes for Tables 1 and and2 2 indicate the papers with published results for doxylamine plus pyridoxine use. Recent papers (since January 2001) that included doxylamine plus pyridoxine exposures are abstracted and included in this review because these are subsequent to the last published meta-analysis.

Cohort studies investigating association between antihistamines and birth defects included in systematic review (n=31)

CI, confidence interval; CL/P, cleft lip with or without cleft palate; CPO, cleft palate only; LMP, last menstrual period; NTD, neural tube defects; NTS, nonteratogenic substances; NVP, nausea and vomiting of pregnancy; OAN, other antinauseant; OAH, other antihistamines; OR, odds ratio; RR, risk ratio; TIS, Teratogen Information Service

Case-control studies investigating association between antihistamines and birth defects included in systematic review (n=23)

CHD, congenital heart defect; CI, confidence interval; CL/P, cleft lip with or without cleft palate; CPO, cleft palate only; GP, general practitioner; HCCSCA, Hungarian Case-Control Surveillance of Congenital Abnormalities; HCAR, Hungarian Congenital Abnormalities Registry; NBDPS, National Birth Defects Prevention Study; NTD, neural tube defects; NVP, nausea and vomiting of pregnancy; OAH, other antihistamines; OR, odds ratio; PR, prevalence ratio; PUD, peptic ulcer disease; RR, risk ratio

Included studies were not required to report a measure of association (i.e. odds ratio, prevalence ratio, risk ratio) or the results of statistical testing. For selected studies in which adequate data were available but a measure of association was not reported in the original publication, we calculated a measure of association. When distinct publications included overlapping data, it was noted in the text and notes for Tables 1 and and2 2 .

Out of the 7,670 articles identified through PubMed and 45 identified through other sources, 54 papers met the inclusion criteria for this review ( Figure 1 ). Thirty-one are cohort studies ( Table 1 ); 23 are case-control studies ( Table 2 ).

3.1 Histamine H 1 -receptor antagonists: Findings from cohort studies

A total of 24 cohort studies reported findings with respect to histamine H 1 -receptor antagonists ( Table 1 ). Eight of these 24 cohort studies were based on data from a Teratogen Information Service (TIS). Briefly, TIS locations in the United States and in several countries provide evidence-based information to mothers, health care professionals, and the general public about medications and other exposures during pregnancy and while breastfeeding. This typically occurs when physicians or women call the service concerned about a chemical or medication exposure. During the call, information on pregnancy exposures is collected. For TIS conducting studies of pregnancy outcomes, within a year of delivery, a follow-up survey is sent to the women to gather information on the outcome of the pregnancy. In some services, the outcome of the pregnancy is verified with a health care provider. Additional data sources are sometimes linked to the information gathered during the initial telephone call or in the follow-up interview. Many of the studies using TIS data derive an “unexposed” group from women calling about exposures deemed to be “non-teratogenic”, such as dental examinations, x-ray exposures, and use of medications such as acetaminophen.

One cohort study analyzed antihistamines in the aggregate only 12 though reported frequencies of selected birth defects by specific medication exposures. Källén explored a wide array of first and second generation H 1 -receptor antagonists in relation to several pregnancy outcomes, but reported estimates of association by indication only (not specific antihistamines), and analyzed medications used to treat NVP separately from those used to treat allergies. Among the reported analyses of aggregated outcomes such as all birth defects, selected birth defects, all CHDs, specified CHDs, and all birth defects except CHDs, there were no significantly elevated associations with either antihistamines used to treat NVP or those used to treat allergies 12 .

3.1.1 First generation H 1 -receptor antagonists

3.1.1.1 cyclizine or meclizine.

Seven cohort studies investigated the association between cyclizine or meclizine exposure and birth defects 13 - 19 . A Northern California Kaiser Permanente cohort study of 4,277 pregnancies between 1960-1964 included detailed maternal interviews to ascertain medication use in addition to validation from the prenatal record 18 . There were 315 pregnancies exposed to meclizine or cyclizine in the first trimester compared with 3,902 unexposed to any antinauseant medication. The prevalence of birth defects was comparable in the two groups (3.2% in the meclizine/cyclizine group and 3.8% in the unexposed comparison group) 18 . In a follow-up study of the same population including several additional years of data, Milkovich and van den Berg found no difference in the prevalence of birth defects among women exposed to meclizine or cyclizine compared with a group of women with unmedicated NVP 16 .

Based on data from over 25,000 pregnancies in Sydney, Australia from 1956-1961, McBride reported a prevalence of cleft palate of 4.4 per 1,000 among 1,125 women who took cyclizine during pregnancy, compared with a baseline prevalence of 0.78 per 1,000 among 24,208 unexposed pregnancies. However, in a sub-analysis comparing the cyclizine-exposed group to a group with untreated NVP (i.e. controlling for indication), the difference in the two groups was no longer noteworthy (4.4 per 1,000 compared with 3.6 per 1,000) 15 .

Using data from the United States Collaborative Perinatal Project (CPP), Shapiro and colleagues 17 analyzed data for 1,014 pregnant women who took meclizine in the first four lunar months of pregnancy compared with 49,268 unexposed pregnancies. A wide array of birth defects were investigated; eye and ear defects were the only significant associations identified (standardized relative risk: 2.79; 95% CI: 1.12-5.73). However, further investigation of subtypes of eye and ear defects did not reveal a relationship between meclizine and any specific birth defect 17 .

Three analyses of Swedish data explored meclizine in relation to birth defects 13 , 14 , 19 . The earliest included 5,753 women, 778 of whom used an antiemetic (i.e. promethazine, prochlorperazine [an antiemetic with no antihistaminic properties], diphenhydramine, or meclizine) during pregnancy. Meclizine exposure was not associated with an increased risk of any of the birth defects under study 14 . In a more recent analysis of Swedish surveillance data that focused only on meclizine, the frequency of birth defects was 3.2% among 16,536 meclizine exposed pregnancies; the association was slightly protective (odds ratio (OR): 0.91; 95% CI: 0.83-0.99) when compared with an unexposed group 19 . Lastly, in a 2005 study by Asker and colleagues, there was no reported association between birth defects and cyclizine, and again a protective effect was noted for meclizine (cyclizine OR: 1.08; 95% CI: 0.86-1.35; meclizine OR: 0.89; 95% CI 0.82-0.96). In this Swedish population, meclizine was the most commonly used antihistamine (there were over 18,000 meclizine-exposed pregnancies compared with less than 2,000 pregnancies exposed to any other antihistamine) 13 .

3.1.1.2 Doxylamine plus pyridoxine

Two relatively recent papers have investigated doxylamine plus pyridoxine 20 , 21 . Using data obtained from the Canadian TIS (the “Motherisk Program”) from 2001-2003, Boskovic and colleagues compared women with no NVP with two groups of women with NVP – the first group of women took a standard dose of doxylamine plus pyridoxine and the second group took a “supradose”. Among the group without NVP, there were no birth defects reported; the frequency of birth defects was 2/122 (1.6%) among the women on the standard dose and 0/124 among women on the supradose 21 . Askenazi-Hoffnung and colleagues compared doxylamine plus pyridoxine to metoclopramide for the treatment of NVP using data from an Israel TIS. There were no birth defects among the 29 women exposed to doxylamine plus pyridoxine and one among the 29 women exposed to metoclopramide 20 .

3.1.1.3 Hydroxyzine

There were two cohort studies that examined the association between hydroxyzine exposure and birth defects 22 , 23 . In a 1971 study conducted in Turkey, hydroxyzine (n=100) or placebo (n=50) was administered during the first two months of pregnancy 23 . Among the 150 pregnancies enrolled, 115 had information on fetal outcomes. There was one birth defect in the hydroxyzine group; and none in the placebo group. Hydroxyzine was also investigated by Einarson and colleagues using data from Motherisk Program 22 . Among 43 women with first trimester hydroxyzine exposure, 2 infants were born with major birth defects; in the comparison population of 120 women exposed to non-teratogens, there were none.

3.1.1.4 Other first generation H 1 -receptor antagonists – brompheniramine, chlorpheniramine, dimenhydrinate, diphenhydramine, promethazine, triprolidine

In a matched analysis using data from a German population based cohort study from 1964-1976, the association between first trimester use of “miscellaneous antiemetics” (including meclizine, dimenhydrinate, and chlopheniramine) and birth defects was 0.92 (90% CI: 0.42-2.00) based on 11 birth defects among 628 exposed pregnancies and 12 birth defects among 628 unexposed pregnancies 24 .

Two analyses of data from the Seattle-based Group Health Cooperative of Puget Sound analyzed a wide range of first trimester antihistamine use in relation to risk for birth defects 25 , 26 . Based on data from 1977-1979, Jick and colleagues compared the prevalence of birth defects among women exposed to selected antihistamines in the first trimester of pregnancy to a baseline risk of birth defects of 11.7 per 1,000. The prevalence among those exposed to triprolidine (6/384; 15.6 per 1,000) and diphenhydramine (1/361; 2.8 per 1,000) were not statistically significantly different from the baseline 26 . In an update of this analysis using data from 1980-1982, Aselton and colleagues reported a baseline birth defects prevalence of 16.1 per 1,000. Among women with first trimester exposures to diphenhydramine, triprolidine, chlorpheniramine, brompheniramine or promethazine, the prevalence of birth defects was not statistically significantly different from the baseline 25 . Schatz and colleagues, using data from the Kaiser-Permanente Prospective Study of Asthma During Pregnancy, reported a prevalence of birth defects of 5.5% among unexposed pregnancies and 3.7% among pregnancies exposed to chlorpheniramine, tripelennamine, or other antihistamines (not otherwise specified) in the first trimester 27 .

Bsat and colleagues published a prospective evaluation of three outpatient regimens for NVP: promethazine, prochlorperazine (an antiemetic with no antihistaminic properties), and pyridoxine plus metoclopramide. There were no birth defects noted among the 52 women exposed to promethazine; one birth defect was reported among the women exposed to prochlorperazine 28 .

Kullander and Kallen's analysis of a Swedish prospective cohort found no association between first trimester exposure to diphenhydramine and birth defects. The one association reported in that paper was between promethazine exposure and congenital dysplasia of the hip (based on 11 observed cases; 4 were expected) 14 . Asker and colleagues’ later analysis of Swedish surveillance data found no association with promethazine (OR: 0.91; 95% CI: 0.75-1.11) 13 .

3.1.2 Second generation H 1 -receptor antagonists

Eight cohort studies in this review investigated the association between one or more second generation H 1 -receptor antagonists and birth defects 22 , 29 - 35

3.1.2.1 Cetirizine

Two cohort studies have investigated the association between cetirizine use during pregnancy and birth defects 22 , 35 . Einarson and colleagues, using data from the Motherisk Program, observed no pregnancies affected by a major birth defect among the 33 exposed to cetirizine in the first trimester 22 ; no birth defects were reported in the non-teratogen comparison group as well. An analysis of the Berlin TIS data documented three pregnancies affected by birth defects among the 177 exposed to cetirizine in the first trimester (1.7%) compared with 24/1,521 (1.6%) in the non-teratogen comparison group (OR: 1.07; 95% CI: 0.21-3.59) 35 .

3.1.2.2 Loratadine

Four cohort studies have investigated the association between loratadine use during pregnancy and birth defects 29 - 31 , 33 . The first investigation to report an association between loratadine and hypospadias was by Källén and Olausson using data from the Swedish Medical Birth Registry 30 . In a cohort of over 540,000 women with deliveries from 1995-2001, 2,780 infants were exposed to loratadine in early pregnancy. The observed prevalence of hypospadias was 5.4 per 1,000 among the loratadine-exposed pregnancies, significantly higher than the expected prevalence of 1 in 500 (OR: 2.27; 95% CI: 1.33-3.87) 30 . Five years later, after linkage with additional national registries, the same authors published a follow-up study and proposed that the 2001 “signal” had been a chance finding. In the revised analysis, which included three additional years of data (2002-2004), the prevalence of hypospadias among the loratadine-exposed pregnancies was 1.04 per 1,000 during 2002-2004, dramatically lower than during 1995-2001. When analyzing the full time period, the association was attenuated from what had been previously published (RR: 1.61; 95% CI: 1.04-2.34) 31 . Two papers published in 2003 based on TIS data also investigated the fetal safety of loratadine 29 , 33 . Using data form the Israel TIS, Diav-Citrin and colleagues reported one birth defect among 126 first trimester loratadine-exposed pregnancies (0.8%), compared with 7/146 (4.8%) pregnancies exposed to “other antihistamines”, and 25/844 (3.0%) pregnancies exposed to non-teratogens. Moretti and colleagues pooled data across four TIS (Canada [Motherisk], Israel, Italy, Brazil) in their analysis of loratadine use and birth defects. Among those exposed to loratadine, 5/143 (3.5%) had a major birth defect, compared with 6/150 (4.0%) in the comparison group of women exposed to non-teratogens; these prevalence estimates were not significantly different 33 .

3.1.2.3 Terfenadine and astemizole

Three cohort studies, all based on TIS data, investigated terfenadine and/or astemizole use during pregnancy in relation to birth defects 29 , 32 , 34 . Using data from the Motherisk Program and the Italy TIS, Loebstein and colleagues reported no cases of birth defects among 65 women with first trimester exposure to terfenadine compared with 2 birth defects among 111 exposed to a non-teratogen (RR: 0.57; 95% CI: 0.06-5.39) 32 . A second analysis from the Motherisk Program (in collaboration with the Pregnancy Healthline in Philadelphia) focused on astemizole. 34 . Among 114 women exposed to astemizole there were 2 reported cases of major birth defects (1.8%); there were 2 reported among the 114 women in the non-teratogen comparison group as well 34 . Although not the primary exposure of interest in a study by Diav-Citrin and colleagues using Israel TIS data (exposure of interest was loratadine, see above), the authors reported the prevalence of major birth defects for specific antihistamines included in their “other antihistamines” analytic group. The frequencies of birth defects among women exposed to astemizole (3/50; 6%) or terfenadine (2/27; 7.4%) during pregnancy were not significantly different from the comparison group 29 .

3.2 Histamine H 1 -receptor antagonists: Findings from case-control studies

A total of 21 case-control studies that met inclusion criteria for this review reported findings with respect to histamine H 1 -receptor antagonists ( Table 2 ). Four studies analyzed antihistamines in the aggregate only 36 - 39 , the remainder reported aggregated analyses in addition to analyses of specific antihistamines.

In a paper focused on risk factors for infant craniostenosis (more commonly referred to as craniosynostosis), Källén and Robert-Gnansia 36 compared prenatal use of medications among the mothers of 398 infants born with craniostenosis between 1995-2002 with the nearly 730,000 Swedish births during the same time period. Twenty-two case mothers had documentation in their prenatal record of first trimester exposure to an antihistamine compared with an expected frequency of 15.6 based on the larger population data (observed/expected ratio: 1.4; 95% CI: 0.9-2.1).

Two manuscripts based on data from the Slone Epidemiology Center Birth Defects Study (Slone BDS) also known as the Pregnancy Health Interview Study 37 , 38 reported on the associations between any antihistamine use and gastroschisis; the more recent paper also reported on the association with small intestinal atresias 38 . In data from 1976-1990, there were 76 gastroschisis cases, among whom 10 (13.2%) were exposed to antihistamines (excluding antiemetics) and 2,142 controls affected by other, non-related birth defects, among whom 173 (8.1%) were exposed to antihistamines leading to an adjusted OR of 1.3 (95% CI: 0.5-3.1) 37 ; in more recent Slone BDS data (1995-1999) based on 206 gastroschisis cases, the association was closer to the null (OR: 0.6; 95% CI: 0.3-1.2). There was also no association with small intestinal atresia (OR: 0.9; 95% CI: 0.4-1.8) (based on 126 small intestinal atresia cases) 38 .

Boneva and colleagues, using data from metropolitan Atlanta from 1982-1983, analyzed antihistamine use for the treatment of severe first trimester NVP among 998 mothers of infants with a CHD and 3,029 mothers of infants born without any major birth defect. The analysis focused on Bendectin use (not reported in this review) and antihistamines in general. Comparing women with the most severe level of NVP to those with no NVP, the association between CHD and using any antinausea medication was protective with a relative risk estimate of 0.74 (95% CI: 0.56-0.97). Considering specific CHD subtypes, all associations among women with NVP, comparing those who took medications with those who did not, were below the null (but not statistically significant), with the exception of tetralogy of Fallot, which was greater than 1.0 (OR: 2.19; 95% CI: 0.39-22.32), based on 8 cases, 6 of whom took medication to treat NVP, compared with 2 who did not take medication 39 .

3.2.1. First generation H 1 -receptor antagonists

3.2.1.1 antihistamines other than doxylamine plus pyridoxine.

The authors of 1982 and 1984 reports on the association between doxylamine plus pyridoxine exposure and pyloric stenosis 40 , 41 re-analyzed their data to explore the role of antihistamines excluding doxylamine plus pyridoxine antihistamines, and reported findings in letters to the editor in 1985 42 , 43 . Based on data from the mothers of 71 cases with pyloric stenosis (5 exposed) and 3,002 control mothers (40 exposed), Eskenazi and Bracken reported a 5-fold increase in risk (OR: 5.61; 95% CI: 2.14-14.67) for use of antihistamines excluding doxylamine plus pyridoxine 41 . Aselton and Jick, using the Puget Sound Group Health Cooperative data from the mothers of 12 cases of pyloric stenosis and 32 matched control mothers, reported an elevated but not statistically significant association (matched OR: 4.1; 95% CI: 0.8-21.7).

3.2.2.2 Other first generation H 1 -receptor antagonists

The oldest case-control study included in this review was a letter to the editor published in The Lancet in 1961 reporting on the frequency of first trimester use of meclizine, dimenhydrinate, and cyclizine among mothers of 266 infants with birth defects, and mothers of two groups of control infants (n=266 in each control group) 44 . Considering the three antihistamines combined, there were no differences across the three groups in the prevalence of medication use (11.3% of cases; 11.7% of control group 1; 12.0% of control group 2). A 1973 report using data from 1964-1972 from the Finnish Register of Congenital Malformations 45 investigated whether exposure to a combination drug, imipramine (a tricyclic antidepressant) plus chloropyramine (an antihistamine) was more common among mothers of 2,784 birth defect cases than among mothers of 2,784 matched controls. Three case mothers were exposed to imipramine/chloropyramine; no control mothers were exposed. The following year Saxén, in a letter to the editor of The Lancet , reported on the association between antihistamine intake and oral clefts (cleft palate only [CPO], cleft lip with or without cleft palate [CL/P]), using data from the Finnish Register. There was no association between cyclizine use and oral clefts, yet there was a significant difference between the frequency of diphenhydramine use among mothers of CPO cases (8/232; 3.4%) and mothers of controls (6/590; 1.0%) 46 . Concern about oral clefts continued; in 1983, Golding and colleagues reported on data from the United Kingdom based on 196 oral cleft cases and 407 matched controls. Exposure to several antihistamines during the first 69 days of pregnancy was considered; only promethazine (and doxylamine plus pyridoxine) had a sufficient prevalence of exposure for analysis. The frequency of promethazine use was not significantly different among mothers of oral clefts cases and controls 47 .

In 1971, Nelson and Forfar reported on a Scottish case-control study with 175 cases with major defects, 283 cases with minor defects, and 911 controls in which mothers were interviewed before hospital discharge about medication use during pregnancy. An attempt was made to validate maternal report of medication use by following up with the pharmacy that filled the prescription. Two of the 175 (1.1%) case mothers were exposed to an antihistamine (i.e. promethazine, diphenhydramine, triprolidine, mepyramine, diphenylpyraline, chlorpheniramine, chlorcyclizine, and trimeprazine) during the first trimester; 26 of the 911 (2.9%) control mothers were exposed and no individual antihistamine was more commonly used in the first trimester among case mothers than control mothers 48 .

The Hungarian Case Control Surveillance of Congenital Anomalies (HCCSCA) has been used to examine the risks associated with several antihistamines. The HCCSCA uses national birth defects surveillance data, the Hungarian Congenital Abnormality Registry (HCAR). Notification of cases with birth defects to HCAR is mandatory for physicians in Hungary; cases among live births, fetal deaths or terminations of pregnancy are reported. Medication data for cases and controls were gathered in one of two ways: (1) prenatal care “logbooks” and other medical records (gathered prospectively); or (2) responses to maternal questionnaires (self-reported, gathered retrospectively). In an investigation of 23 subtypes of major birth defects, dimenhydrinate was found to be inversely associated with risk for obstructive defects of the urinary tract (prevalence ratio (PR): 0.2; 95% CI: 0.1-0.7) 49 . In a similarly structured analysis, medically recorded promethazine use (excluding promethazine use that was only self-reported by mothers and not validated with documentation of use in the medial record) in the first trimester of pregnancy was also inversely associated with obstructive urinary tract defects, as well as hypospadias, undescended testes, clubfoot, and the aggregation of all defects in the analysis (OR: 0.8; 95% CI: 0.7-0.9) 50 . In a 2003 paper, Czeizel and colleagues 51 limited their analysis of the association between oral clefts and antihistamine exposure to women with hyperemesis gravidarum, a severe form of NVP often resulting in hospitalization 52 . They found no association between dimenhydrinate use and CL/P (OR: 1.20; 95% CI: 0.66-2.19) but a positive association between the medication and CPO (OR: 2.47; 95% CI: 1.10-5.54). The prevalence of dimenhydrinate use among mothers of two oral cleft subtypes was substantially different, with 25-30% of CL/P case and control mothers reporting use of the medication, but nearly 50% of the mothers of CPO cases reporting use 51 .

Using data from the National Birth Defects Prevention Study (NBDPS), Gilboa and colleagues 3 and Anderka and colleagues 53 conducted analyses of the association between first trimester antihistamine use and selected birth defects. Gilboa and colleagues, using data from 1997-2003, conducted frequentist and Bayesian analyses of the association between self-reported first trimester use of 10 specific first generation antihistamines (i.e. clemastine, dimenhydrinate, diphenhydramine, doxylamine, hydroxyzine, meclizine, pheniramines [chlorpheniramine and brompheniramine], promethazine, triprolidine, and antihistamine “not otherwise specified”) or any antihistamine, and 26 isolated major birth defects 3 . Three second generation antihistamines were also investigated (i.e. cetirizine, fexofenadine, and loratadine) (see below in Second generation H 1 -receptor antagonists ). Only one association had a magnitude greater than 3.0 – the association between prenatal meclizine exposure and cleft palate (Bayesian posterior OR: 6.2; 95% Posterior Interval: 1.8-21.3) – based on 5 exposed cases and 4 exposed controls. The authors identified several modest, but elevated associations with diphenhydramine, and doxylamine. Many of these were not previously identified in the literature and could represent chance findings. The authors conducted several sensitivity analyses to explore the robustness of these findings to residual confounding by indication, but the results were largely unchanged.

Anderka and colleagues’ analysis focused on the subpopulation of mothers of cases and controls with NVP, and four birth defect subtypes - CL/P, CPO, neural tube defects (NTD), and hypospadias using data from 1997-2004. Among NBDPS controls, the prevalence of NVP was nearly 70%; among those with NVP, approximately 15% reported treatment. The associations between NVP itself and the four birth defect subtypes included in the analyses were either protective or null, with OR estimates ranging from 0.84 to 1.00. The reported associations with antihistamine antiemetics (including promethazine as an itemized subgroup) and the other antihistamines (including diphenhydramine, cetirizine, and doxylamine as itemized subgroups) ranged from 0.9 to 1.4, all with confidence intervals including the null value of 1.0. The only exception was an elevated, but not statistically significant OR of the association between NTD and doxylamine plus pyridoxine of 1.84 (95% CI: 0.71-4.78).

In the most recent paper included in this review, Li and colleagues, using data from the Slone Birth Defects Study (BDS) (gastroschisis cases overlapped somewhat with those analyzed by Werler and colleagues 38 ), divided their study into a priori (hypothesis testing) and exploratory (hypothesis generating) analyses 54 . The 16 a priori analyses, selected based on previous reports in the literature, were: loratadine and hypospadias (see below in Second generation H 1 -receptor antagonists ); diphenhydramine and CPO, CL/P, NTD, spina bifida, limb reduction defects, and gastroschisis; chlorpheniramine and eye defects, ear defects, spina bifida, and CL/P; and doxylamine and oral clefts, pyloric stenosis, hypoplastic left heart syndrome, spina bifida, and NTD. None of the a priori analyses demonstrated a significantly elevated association. In their exploratory analyses, there were a few elevated associations: diphenhydramine and transposition of the great arteries (OR: 2.3; 95% CI: 1.1-5.0), right ventricular outflow tract obstruction defects (OR: 1.6; 95% CI: 1.0-2.7), renal collecting system anomalies (OR: 1.5; 95% CI: 1.0-2.2); chlorpheniramine and NTD (OR: 2.6; 95% CI: 1.1-6.1), tetralogy of Fallot (OR: 3.1; 95% CI: 1.2-8.4), hypoplastic left heart syndrome (OR: 4.9; 95% CI: 1.6-14.9) and anomalies of the great veins (OR: 3.3; 95% CI: 1.1-10.0); and doxylamine and renal collecting system anomalies (OR: 2.7; 95% CI: 1.3-5.6) 54 . These were all novel associations, and like the novel associations reported by Gilboa and colleagues, could represent chance findings and are in need of replication in other datasets.

3.2.3 Second generation H 1 -receptor antagonists

Gilboa and colleagues published the only case-control study investigating exposure to cetirizine and fexofenadine; there were no elevated associations observed for either antihistamine 3 . Loratadine, however has been much more thoroughly studied, and has been of particular interest in the literature, in part due to the 2002 Swedish study (discussed above) that suggested an association with hypospadias 12 . Several case-control studies have since explored this association – one using data from the Slone BDS 54 , two using data from the NBDPS 3 , 55 , and three using data from Denmark 56 - 58 . Li and colleagues considered the hypospadias – loratadine association as one of their a priori hypotheses (based on previous suggestions in the literature). Based on self-reported medication use data from the mothers of 632 cases with hypospadias and 3,448 mothers of controls, there was no association found between first trimester loratadine use and hypospadias (OR: 0.8; 95% CI: 0.4-1.7) 54 . Li and colleagues investigated the association between loratadine and 20 other major birth defects in their “exploratory” analyses; all of the adjusted OR were between 0.5 and 1.7 with 95% confidence intervals all including the null value of 1.0 54 . A 2004 Morbidity and Mortality Weekly Report reported the results of an NBDPS analysis of maternal loratadine use from one month before pregnancy through the end of the first trimester among 563 male infants with 2 nd or 3 rd degree hypospadias (cases with first degree hypospadias are excluded from the NBDPS) and 1,444 male control infants 55 . The analysis also included a larger group of nonsedating antihistamines (which included loratadine) and sedating antihistamines (not otherwise specified). All associations with hypospadias were null; loratadine OR: 0.96; 95% CI: 0.41-2.22, nonsedating antihistamines OR: 0.95; 95% CI: 0.48-1.89, sedating antihistamines OR: 1.02; 95% CI: 0.68-1.53 55 . Gilboa and colleagues, using two additional years of data from NBDPS and exploring a wide array of birth defects, did not observe an elevated risk with loratadine for hypospadias or any other major birth defect, with the exception of transverse limb deficiencies (OR: 2.16; 95% CI: 1.08-4.30) 3 . Two reports from Denmark published in 2006 reported on analyses of the association between first trimester loratadine use and hypospadias using case-control data 57 , 58 . One was based on data from four Danish counties where 227 cases of hypospadias and 10 matched controls per case (n=2,270) were identified using linked national hospital discharge and birth registry datasets from 1989-2002. Medication use during pregnancy was identified through further linkage with pharmacy records. One case and eight control mothers were exposed to loratadine in the period from 30 days before conception through the end of the first trimester; there was no elevated risk of hypospadias associated with this exposure (OR: 1.4; 95% CI: 0.0-10.5) 58 . The second Danish report was based on a case-control study nested within the Danish National Birth Cohort, in which 203 cases of hypospadias and 2,030 matched controls were identified. During maternal interview, one case and 25 control mothers self-reported use of loratadine from one month before pregnancy through the end of the first trimester. Similar to the results from the record-linkage based analysis, there was no association with hypospadias (OR: 0.9; 95% CI: 0.1-6.9) 57 . Lastly, in 2008, in a nationwide record-linkage analysis using data from 1996-2004, 1,575 cases of hypospadias were identified, 7 (0.4%) of whom had prenatal loratadine exposure. Among 14,660 matched controls, 88 (0.6%) were exposed to loratadine. No association was observed (prevalence ratio [PR]: 0.6; 95% CI: 0.3-1.4) 56 .

3.3 Histamine H 2 -receptor antagonists: Findings from cohort and case-control studies

The body of literature investigating the association between histamine H 2 -receptor antagonists and birth defects is substantially smaller than that for H 1 -receptor antagonists, with seven cohort studies 59 - 65 and three case-control studies 53 , 66 , 67 meeting inclusion criteria for this review. Colin Jones and colleagues reported on 12-month post-marketing surveillance in Scotland of 9,809 users of cimetidine and a comparison population of 9,140 non-users. Over the surveillance, there were 20 pregnancies exposed to cimetidine and 22 unexposed pregnancies; among cimetidine users there was one birth defect reported – a case of Down syndrome. There were no birth defects among the non-users 59 .

Two studies used data from a TIS – the first based on data from the Motherisk Program 62 and the second based on pooled data from 18 members of the European Network of Teratogen Information Service (ENTIS) 60 . In the analysis of Motherisk data, there were 185 pregnancies exposed to histamine H 2 -receptor antagonists (i.e. ranitidine [the most common], cimetidine, famotidine, nizatidine), 142 of them were first trimester exposed and resulted in a live birth. Three birth defects occurred among these pregnancies (2.1%) compared with 5 birth defects among 143 pregnancies in the comparison group (3.5%). The difference between the prevalence of birth defects among these two groups was not statistically significant (p=0.55) 62 . The analysis of pooled ENTIS data (n=553 exposed to H 2 -receptor antagonists; n=1,390 in comparison group exposed to “non-teratogenic” substances) had similar findings with a prevalence of birth defects of 2.7% among the exposed pregnancies and 3.5% among those unexposed to H 2 -receptor antagonists 60 . In another analysis of the Motherisk data (combined with data from Italy and France TIS), first trimester exposure to H 2 -receptor antagonists (not otherwise specified; n=113; n=98 with live births) was compared with exposure to non-teratogens (n=113; n=66 with live births) 65 . The prevalence of birth defects among those with live births was similar in the exposed and unexposed groups: H 2 -receptor antagonists: 3.1%; non-teratogens: 3.0%.

In a 1998 publication of data from the Swedish Medical Birth Registry, Källén reported on the association between acid-suppressing drugs (e.g. proton pump inhibitors, H 2 -receptor antagonists) and birth defects. The baseline birth defects prevalence was 3.9%; among users of H -receptor antagonists, the prevalence was 2.4% (6/255) (OR: 0.46; 95% CI: 0.17-1.20) 61 Ruigómez and colleagues reported on two cohorts of cimetidine- and ranitidine-exposed pregnancies – one from Italy and one from the United Kingdom 64 . In the United Kingdom cohort, prevalence of birth defects among cimetidine-exposed pregnancies was 4.0% (9/227) and among ranitidine-exposed pregnancies was 7.4% (17/229), compared with the baseline prevalence of 5.7% among the unexposed population. In the Italy cohort, 2/10 (20%) cimetidine-exposed pregnancies and 3/101 (3.0%) rantidine-exposed pregnancies were compared with the unexposed baseline of 2.9%. Measures of association for each medication were calculated from pooled data: cimetidine (RR (95% CI)): 1.3 (0.7-2.6); ranitidine: 1.5 (0.9-2.6) 64 . In the most recently published cohort analysis, Matok and colleagues used data from the largest health maintenance organization in Israel to examine the safety of H 2 -receptor antagonists during pregnancy 63 . The associations between any major birth defect and first trimester exposure to any H 2 -receptor antagonist (n=1,148 exposed pregnancies) or famotidine (n=878 exposed pregnancies) were both null (OR: 1.03; 95% CI: 0.80-1.32 for any H 2 -receptor antagonist and OR: 1.21; 95% CI: 0.92-1.58 for famotidine). No measure of association was calculated for ranitidine because there were fewer than seven birth defects noted (n=276 exposed pregnancies) 63 .

Anderka and colleagues, using NBDPS data, reported on H 2 -receptor antagonists as a group, and where sample size permitted, ranitidine. There was no association found between H 2 -receptor antagonists and CL/P (OR: 0.57; 95% CI: 0.19-1.67), CPO (OR: 1.04; 95% CI: 0.39-2.75), or hypospadias (OR: 1.07; 95% CI: 0.41-2.83). There was an elevated, though not statistically significant association with NTD (OR: 1.80; 95% CI: 0.80-4.05), though when restricted to ranitidine exposure only, the association did not persist (OR: 1.28; 95% CI: 0.43-3.82) 53 .

Data from the HCCSCA have been used in two recent case control analyses exploring H 2 -receptor antagonists and birth defects. In the first study, Ács and colleagues explored the association among mothers with severe chronic dyspepsia. Severe chronic dyspepsia affected 148 case mothers and 214 control mothers; 9.5% (14/148) case mothers and 12.6% (27/214) control mothers took an H 2 -receptor antagonist (i.e. cimetidine or ranitidine, not specified in the paper) (OR: 0.7; 95% CI: 0.4-1.4) 66 . In the second study, Bánhidy and colleagues, using data from HCCSCA restricted their analyses of the association between cimetidine exposure and major birth defects to mothers with definitive peptic ulcer disease (PUD). There were 20 mothers of cases (6 exposed) and 58 mothers of matched controls (7 exposed); the association was elevated (OR: 3.1; 95% CI: 0.9-10.8) 67 .

In summary, the majority of findings reported in this body of literature demonstrate a lack of association between prenatal antihistamine exposure and birth defects. Among the 31 cohort studies included in this review, two identified any statistically significant positive associations between antihistamines and birth defects ( Table 3 ). Among the 23 case-control studies included in this review, seven identified any statistically significant positive associations ( Table 3 ). Supplemental online tables are provided that detail the frequencies of antihistamine exposure – birth defect outcome combinations. Although this lack of reported associations is reassuring, and suggests that antihistamines are unlikely to be strong risk factors for the major birth defects considered in the literature, a few large studies did identify associations that might warrant follow-up and corroboration in other study populations 3 , 54 . Considering the populations included in this review, the vast majority of the 54 studies are from the U.S., Canada, or Scandinavia. Given this, there is likely a lack of heterogeneity in the reviewed literature with respect to race-ethnicity and population diversity. The inclusion criterion of an English-language publication likely contributed to this.

Summary of significant positive associations among 54 studies included in systematic review of antihistamines and birth defects

It is important to note, however, that these might be chance findings only, given the large number of comparisons conducted. The most thoroughly studied “signal” in the recent literature, that of the association between loratadine and hypospadias, first identified in data from the Swedish Medical Birth Registry 30 , has not been confirmed in a subsequent case-control nor cohort analysis 3 , 31 , 54 - 58 . This, too, is reassuring and confirms the need for continued research using different designs and study populations. However, other antihistamines, especially H 2 -receptor antagonists (e.g. ranitidine, cimetidine, famotidine, nizatidine) have much less literature on which an assessment of safety can be based and further study to understand the potential fetal effects of H 2 -receptor antagonists is needed.

Expert Opinion

The findings in this literature should be considered in light of three critical methodological issues: (1) selection of appropriate study population; (2) ascertainment of antihistamine exposures; and (3) ascertainment of birth defects outcomes.

5.1 Selection of appropriate study population

The distinction between population-based studies and studies based on a convenience sample is important. The population-based case-control studies included in this review 3 , 39 , 49 , 53 , 55 , 66 , 67 have the advantage of deriving cases from surveillance systems that, in general, attempt to capture all major birth defects cases occurring in a population. Most of the significant findings were reported in case-control studies which are typically better able to assess individual types of birth defects rather than being limited to an assessment of all birth defects as an aggregate group. Given the rarity of major birth defects in the population (approximately 3% overall 68 ; specific birth defects are less common) population-based cohort studies for birth defects are less frequent in the literature; however, cohort studies in both Sweden 14 , 19 , 30 , 31 and the United States 17 , 69 have been conducted making important contributions to the literature. The Swedish cohorts were built from extensive linkages of national registries; while the Collaborative Perinatal Project gathered data through maternal interviews of pregnant women enrolled at medical centers around the United States 70 , 71 . Cohorts derived from health maintenance organizations are designed to simulate population-based cohorts 18 , 25 - 27 , 63 and in some situations do capture the vast majority of the population in a given geographic area. These cohorts have access to rich clinical information as well as prescription claims. Cohorts based on a convenience sample, however, such as those derived from the TIS around the United States and internationally, while likely having acceptable internal validity, have questionable external generalizability. The TIS serve a critically important role – providing counsel to concerned women and providers about chemical and medication exposures during pregnancy and might provide important initial signals of teratogenicity. However, TIS study cohorts are comprised exclusively of individuals who choose to inquire about an exposure with a TIS 20 - 22 , 29 , 32 , 33 , 35 , 60 , 65 . Those who inquire about an exposure are likely to be qualitatively different from those who do not; those who do not inquire cannot, by definition, be in a TIS cohort. In addition, the TIS studies, by necessity, must select a comparison group of women exposed to “something” – since this is the entirety of their cohort. The studies tend to choose a comparison group of women exposed to “nonteratogenic agents” that is consisting of women exposed to dental x-rays or acetaminophen (see Table 2 ).

5.2 Ascertainment and analysis of antihistamine exposures

A second important issue to consider is the ascertainment and analysis of antihistamine exposures. Medication exposure during pregnancy is typically ascertained in one of two ways: (1) self-report by the mother, either prospectively or retrospectively and reported either in prenatal care records or during a maternal interview for the purposes of the study; or (2) linkage with pharmacy records or pharmaceutical claims. Both approaches are represented in the 54 papers included in this review though self-report by the mother was the most common; over 30 studies used the approach either alone or in combination with one of the other approaches. Given that many of the antihistamines of interest are currently sold over-the-counter, self-reported exposure assessment is a critical tool. In addition, given concerns about the safety of medication use (including antihistamine use) during pregnancy 72 , it is not uncommon for women to fill a prescription, but decide not to take it during pregnancy 73 . However, retrospective self-reporting has limitations – the most concerning is the potential for biased or inaccurate recall 74 . The Slone BDS and NBDPS attempt to limit inaccurate recall by asking about specific indications of medications, categories of medications, and specific medications, including both generic and brand names. Study participants in the BDS are also provided with picture booklets of medications as well as a calendar to highlighting key dates and events to aid recall 2 , 37 , 38 , 54 . Earlier BDS analyses also used a “malformed control” group 2 , 37 , 38 ; this design was chosen under the assumption that mothers of control infants born with birth defects other than the birth defect of interest might have less biased recall than mothers of control infants born without any major birth defects. In addition, NBDPS has approximately a 70% response rate among cases and controls; analyses have suggested that NBDPS participants are representative of the populations from which they were selected 75 . However if mothers of cases and controls have differential participation with respect to pregnancy exposures, study findings could be subject to selection bias.

In the analytic phase of a study, steps can be taken to enhance the accuracy of the exposure data. One of the most common approaches in studies of birth defects is to limit the medication exposure to the first trimester (sometimes also including the 30 days prior to conception to account for the fact that women who are prescribed a medication prior to conception may take it during after conception as well). Since the primary period of susceptibility to human teratogens is the first eight weeks of pregnancy (approximately 10 weeks when counting from the date of last menstrual period) 76 , a focus on medication exposure during the first trimester (since medication exposure data are often too imprecise to accurately focus on specific weeks) is appropriate. While most studies limited the period of exposure to the first trimester, a handful explored the association with exposure any time during pregnancy 13 , 60 , potentially leading to an underestimate of the association with birth defects. In another analytic approach, the Slone BDS has developed and utilized an exposure classification algorithm based on the certainty of recall to help categorize individuals as “likely” or “possibly” exposed to a medication 77 . Furthermore, the investigators of several case-control studies 39 , 51 , 53 , 66 , 67 have restricted analyses to individuals with a particular indication for medication use (e.g. NVP, peptic ulcer disease and severe dyspepsia in the papers noted above) as a method of minimizing confounding by indication 78 . This is an advantage in this body of literature, especially since a lack of NVP is considered a risk factor for a poor pregnancy outcome. In addition, because women often take multiple medications during pregnancy 79 analyses can exclude women who took medications during pregnancy known to be teratogenic or adjust for other medication use.

5.3 Ascertainment of birth defects outcomes

Among the studies included in this review, the data sources for the ascertainment of birth defects varied widely with respect to data quality and specificity. In studies using birth defects data derived from state or national surveillance programs, the quality and accuracy of the data were likely to be high 3 , 12 , 19 , 30 , 31 , 39 , 46 , 49 , 51 , 53 , 55 - 58 , 61 . In datasets developed exclusively through linkages between national birth registry data and hospital discharge data with cases of birth defects identified by International Classification of Diseases (ICD) coding, the quality might be somewhat lower than data that are actively abstracted from medical records, however, the statistical power that comes with larger sample sizes as well as the ability to create small, relatively homogeneous categories of birth defects is beneficial. Additionally, in some studies 39 , 54 , 55 rigorous clinical review of every case 80 - 82 was undertaken to verify reported diagnoses and determine whether the case met the study's inclusion criteria. Similarly, a few studies in the review are based on data from health maintenance organizations 18 , 25 - 27 , 42 , 63 with medical records forming the foundation of the birth defects ascertainment and in some of these studies, additional clinical review of potential cases was also undertaken.

In contrast, in other studies, such as those based on the TIS included in this review 20 - 22 , 29 , 32 , 33 , 35 , 60 , 65 , the pregnancy outcome data were self-reported by mother who initially called the TIS, up to a year or more after their initial inquiry. This delay could lead to a substantial loss to follow-up, if mothers could not be located in order to report on the pregnancy outcome. While the reported pregnancy outcome was verified with the child's pediatrician in some of the included studies, this was not universally done across all TIS-based analyses.

A final methodological issue pertaining to birth defects outcome ascertainment is follow-up – the time period after birth during which birth defects could be identified and reported. In most state and national surveillance systems, this period of time is at least one year, accounting for the fact that not all birth defects are identified prenatally or immediately after birth. Some studies ascertained birth defects over a shorter period of time, for example, at delivery 23 or before age 5 months 37 , 38 , 54 . In the BDS, the 5-month cut-off was intentional, to help ensure the conduct of maternal interviews no later than 6 months after delivery.

Despite these methodological issues, the body of literature on the risk of birth defects from antihistamine use in early pregnancy remains reassuring, particularly for the first generation H 1 -receptor antagonists. There is still a need for larger studies with clinical verification of birth defect subtypes, validation of maternal recall of medication exposures, and appropriate selection of study populations to follow-up on some of the signals found in previous studies, as well as a need to enrich the body of literature on H 2 -receptor antagonists, which are currently relatively understudied.

Finally, as stated earlier, this review was limited in scope to only structural birth defects; other potential adverse pregnancy outcomes such as fetal loss, preterm delivery, or low birth weight, or longer-term neurodevelopmental outcomes were not included. To have a complete understanding of the safety of medication for use during pregnancy, an understanding of the full spectrum of adverse outcomes associated with that medication is required. At this time the body of literature investigating other adverse pregnancy or developmental outcomes associated with prenatal use of antihistamines is much smaller than that focused on birth defects.

Article Highlights

Supplementary Material

Supplemental table, acknowledgement.

The authors would like to acknowledge the contribution of Emory Rollins School of Public Health graduate student, Valerie Godoshian, for her invaluable assistance with searching reference lists and editing the manuscript tables.

Disclaimer: The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.

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Etiology and clinical presentation of birth defects: population based study

Objective To assess causation and clinical presentation of major birth defects.

Design Population based case cohort.

Setting Cases of birth defects in children born 2005-09 to resident women, ascertained through Utah’s population based surveillance system. All records underwent clinical re-review.

Participants 5504 cases among 270 878 births (prevalence 2.03%), excluding mild isolated conditions (such as muscular ventricular septal defects, distal hypospadias).

Main outcome measures The primary outcomes were the proportion of birth defects with a known etiology (chromosomal, genetic, human teratogen, twinning) or unknown etiology, by morphology (isolated, multiple, minors only), and by pathogenesis (sequence, developmental field defect, or known pattern of birth defects).

Results Definite cause was assigned in 20.2% (n=1114) of cases: chromosomal or genetic conditions accounted for 94.4% (n=1052), teratogens for 4.1% (n=46, mostly poorly controlled pregestational diabetes), and twinning for 1.4% (n=16, conjoined or acardiac). The 79.8% (n=4390) remaining were classified as unknown etiology; of these 88.2% (n=3874) were isolated birth defects. Family history (similarly affected first degree relative) was documented in 4.8% (n=266). In this cohort, 92.1% (5067/5504) were live born infants (isolated and non-isolated birth defects): 75.3% (4147/5504) were classified as having an isolated birth defect (unknown or known etiology).

Conclusions These findings underscore the gaps in our knowledge regarding the causes of birth defects. For the causes that are known, such as smoking or diabetes, assigning causation in individual cases remains challenging. Nevertheless, the ongoing impact of these exposures on fetal development highlights the urgency and benefits of population based preventive interventions. For the causes that are still unknown, better strategies are needed. These can include greater integration of the key elements of etiology, morphology, and pathogenesis into epidemiologic studies; greater collaboration between researchers (such as developmental biologists), clinicians (such as medical geneticists), and epidemiologists; and better ways to objectively measure fetal exposures (beyond maternal self reports) and closer (prenatally) to the critical period of organogenesis.

Introduction

Birth defects are inborn errors of development. Broadly defined, they include any structural or functional anomaly with measureable effects on physical, intellectual, and social wellbeing. 1 Birth defects represent a considerable and increasing clinical and public health challenge because of their worldwide impact on population health.

Major birth defects are common, costly, and critical. Collectively, they occur in one in 33 births, 2 which in 2006 translated into an estimated 7.9 million babies worldwide. 3 In the US alone, the cost of care during a single year (2004) was estimated at $2.6bn (£2bn, €2.4bn). 4 This estimate does not account for the considerable indirect and lifelong personal and societal costs. Finally, many birth defects critically affect survival. In the US, birth defects are the leading cause of infant mortality 5 and in 2013 were associated with 4778 deaths, one in every five deaths in the first year of life.

The temporal trends are even more concerning. The occurrence of birth defects, with few localized exceptions (such as neural tube defects in countries that implemented folic acid fortification), has not decreased for many decades. Birth defects might indeed increase worldwide, with the alarming increase of known risk factors such as maternal diabetes and obesity. New threats such as the Zika epidemic are emerging. Unless progress is made in identifying and preventing the root causes of birth defects, these conditions will continue to have draining effects on the survival and health of individuals, families, and countries.

Progress in detecting and characterizing risk factors for birth defects has come mainly from epidemiologic studies. In fact, such studies have produced many associations between risk factors and groups of birth defects. Translating these associations to actual causes, however, has been difficult. As a first step in filling this gap, we evaluated the clinical and etiologic profile of birth defects in a well characterized population based case cohort through systematic review by clinicians, using a multidimensional assessment tool that incorporates etiology, morphology, and pathogenesis.

Study population

The data source for this study was Utah’s statewide population based public health surveillance system (Utah Birth Defect Network, UBDN), housed at the Utah Department of Health. There is no patient involvement or contact as part of this surveillance system. The network monitors birth defects among all pregnancy outcomes (live births, stillbirths, pregnancy terminations) among Utah residents. If a termination occurred, existing medical records were ascertained and reviewed to determine eligibility. To identify potential cases, the program uses multiple reporting sources, both prenatal and postnatal. All reporting sources are mandated to regularly submit any potential diagnosis in infants aged up to 24 months and are legally protected to report if a diagnosis is made after 24 months. The detailed clinical information for each case is based on the abstracted prenatal and postnatal clinical records by trained data abstractors. The presence of a prenatal diagnosis without autopsy or postnatal confirmation is not sufficient for inclusion in the system, with few exceptions, the main one being anencephaly if well described by a perinatologist. For example, hydronephrosis based on only prenatal diagnosis was not eligible for inclusion unless it was confirmed postnatally. Some birth defects have not ever been eligible for inclusion in the surveillance system because it is more challenging to identify and ascertain all cases or they are not considered a birth defect—for example, isolated muscular ventricular septal defects, patent foramen ovale, patent ductus arteriosus, talipes equinovarus, congenital hip dysplasia/dislocation, congenital pulmonary airway malformation, and cryptorchidism. Cases of fetal alcohol syndrome were included only if a major birth defect was diagnosed. Further details of the system’s case ascertainment and medical record abstraction have been published elsewhere. 6 7

Clinical case review

A team of clinicians with training in medical genetics (LDB, JCC, JLBB) reviewed case records, including inpatient and outpatient records, laboratory reports (such as genomic microarray), diagnostic evaluations (such as ultrasound images and echocardiograms), operative notes, and autopsy reports. Once a case was deemed eligible, the clinician generated a list of the major and minor defects and the timing of first diagnosis (prenatal or postnatal). Each defect was coded with the World Health Organization international classification of diseases (version 9) with British Paediatric Association extensions (ICD-9 BPA). In addition, the clinician provided three additional classifications for each case: known etiology (yes, no); isolated versus multiple (unrelated) birth defect versus syndromic (that is, known etiology: genetic or environmental); and whether the case was familial (yes, no). A case was considered familial if a first degree relative (parent or sib) had a concordant phenotype.

Multidimensional etiologic classification

To systematically capture the clinical presentation and etiology in the study cohort we developed and implemented a multidimensional classification with three axes: etiology (known, unknown), morphology (isolated, multiple majors, minors only), and pathogenesis (sequence, developmental field, or pattern). Table 1 ⇓ summarizes the system and definitions. Briefly:

Classification groups and definitions for etiologic classification of all cases of birth defects in Utah, 2005-09

View inline

Known etiology was assigned based on specific and conservative criteria and could be either genetic, environmental (teratogenic), or due to twinning:

Genetic—cases were classified as having a known genetic etiology if there was documentation of abnormal chromosomal number (trisomy) or structure (insertion, deletion) or a single gene condition (such as Noonan syndrome)

Environmental—this required documentation of exposure to a recognized human teratogen 8 (for example, medication, such as valproic acid, or pregestational diabetes with abnormal hemoglobin A 1c concentration during the periconceptional period or early pregnancy). Among mothers noted to have diabetes (pregestational or gestational), we reviewed their timing of diagnosis before or during pregnancy, medication use for control of blood sugar, and if listed, the hemoglobin A 1c testing date and concentration. Women listed as having gestational diabetes with a diagnosis in the first trimester were reclassified as having pregestational diabetes if their hemoglobin A 1c was >5.6. To assign diabetes as a cause, the mother had to have evidence of poorly controlled pregestational diabetes and an infant with selected birth defects that, based on the published literature, were indicative of diabetic embryopathy 9 10 11 : heterotaxy, holoprosencephaly, multiple vertebral defects, bilateral renal defects, or caudal dysgenesis. Conversely, pregestational diabetes in cases of isolated defects such as anencephaly or a congenital heart defect, or a major with minor defect was not considered as a known cause for those particular infants

Twinning—abnormalities in twinning included either acardiac or conjoined twins.

Morphology: a case with a single major birth defect (with or without a minor birth defect) was considered isolated. This definition includes isolated sequences. Infants without a major birth defect were included if they had a chromosomal anomaly (such as trisomy 21 with no reported major birth defect, normal echocardiogram, and none of the selected list of objective minor defects) or eligible genetic condition (such as skeletal dysplasia). Only a selected list of minor defects was classified and analyzed; these were selected because they can be considered as objective findings with limited variation in reporting and classification (table 1 ⇑ ). This list included mainly discontinuous traits such as preauricular tags or single umbilical artery, rather than continuous traits such as hypertelorism, which require careful measurements and chart based decision criteria

Pathogenesis: three groups were created and defined by mechanism based on embryology, not ICD-9 BPA codes (sequence, developmental field defect, or known pattern of birth defects, table 1 ⇑ ). An example of a “known pattern” is the VATER/VACTERL association. This association was operationally defined as the presence of three or more VACTERL defects (vertebral defects, anal atresia, cardiac anomaly, esophageal atresia or tracheoesophageal (TE) fistula, renal malformation, radial limb malformation) with at least one being either esophageal atresia/TE fistula or anal atresia. 12 To further promote consistency, the same clinical geneticist (JCC) reviewed and classified all cases of potential VACTERL association

Implementation of multidimensional classification

For this study, the clinicians together developed a systematic process for the re-review of all cases. In general, each case was reviewed by one clinician, and the accuracy of the classification was further enhanced by assigning certain phenotypes to the clinician with the greatest expertise in that specialty. We re-reviewed the complete population based resident cohort for five consecutive birth years (1 January 2005 to 31 December 2009). We elected to assess this five year birth cohort because some genetic tests can be ordered well after infancy, changing the classification status. Case classification can also change as knowledge progresses. For example, cases of CHARGE association (coloboma, heart defect, choanal atresia, growth/developmental retardation, genital and ear abnormalities) were changed from “multiple congenital anomaly” to “syndrome/genetic” after mutations in the CHD7 gene were established as a cause in 2004 13 —in this situation, cases that met the established clinical criteria for CHARGE (with or without CHD7 mutation testing) were reclassified as “genetic.” The classification was supported by an Access database module that captured both the classifications and comments from the clinical reviewers.

The cohort included 6547 confirmed cases. We excluded 834 cases of isolated birth defect: twin related (n=2); pelviectasis or hydronephrosis without evidence of obstruction (n=47); small (<4 mm) secundum atrial septal defects (n=200); and distal (first degree) or megameatus type hypospadias (n=585). We also excluded spontaneous abortions occurring at <20 weeks’ gestation (n=209). After exclusions, the final study cohort included 5504 cases.

Statistical analyses were done with SAS Enterprise Guide version 6.1 software (SAS Institute, Cary, NC, 2013).

Patient involvement

No patients were involved in setting the research question or the outcome measures, nor were they involved in the design and implementation of the study. There are no plans to involve patients in the dissemination of results.

The population based study cohort included 5504 infants with major birth defects among 270 878 total births (live births and stillbirths), giving a prevalence of 2.03%. In this cohort, 92.1% (5067/5504) of cases (isolated and non-isolated) occurred in liveborn infants: 75.3% (4147/5504) had an isolated defect (unknown and known etiology combined) (table 2, ⇓ fig 1 ⇓ ). A positive family history (having a similarly affected first degree relative) was documented in 4.8% cases overall (266/5504). Compared with the underlying birth cohort (births in Utah, 2005-09), the affected cohort included more boys (57.7%, P<0.001), even after we excluded cases known to be sex limited anomalies (such as hypospadias, 47,XXY/XYY/XXX, 45,X).

Number of cases of birth defects, percentage, and prevalence (per 1000 births) stratified by morphology (isolated and non-isolated) and pregnancy outcome in Utah, 2005-09

Fig 1 Known and unknown etiology of birth defects

Unknown etiology

Overall, 79.8% of cases (n=4390) were classified as unknown etiology (table 3 ⇓ ), 3.6% were known to be familial (isolated 3.7%; multiple 2.7%). Boys were over-represented in both isolated (59.5%, P<0.001) and multiple (55.4%, P=0.02) case groups.

Etiologic classification of birth defects stratified by morphology and pregnancy outcome in Utah, 2005-09. Figures are numbers (percentage)

Among the unknown etiology case group, 344 (7.8% of 4390) were further classified as a sequence (n=242, 70.3%), a developmental field defect (n=71, 20.6%), or a known pattern (n=31, 9.0%) (table 4 ⇓ ). Isolated defects accounted for most cases classified as a sequence (n=187, 77.3%) or developmental field defect (n=50, 70.4%), whereas cases classified as a pattern were more likely to have multiple birth defects (n=30, 96.8%). Eighteen of 20 infants with birth defects consistent with VATER/VACTERL association (known pattern) were classified as unknown etiology.

Pathogenesis of 344 cases of birth defects with unknown etiology, stratified by morphology and pregnancy outcome in Utah, 2005-09. Figures are numbers (percentage)

Known etiology

A fifth (20.2%, n=1114) of cases were assigned a known etiology (table 3 ⇑ ). As shown in figure 2 ⇓ , 90.4% of the cases with a known etiology were represented by the three common trisomies (21, 18, 13), Turner syndrome, structural chromosomal abnormalities, and single gene disorders.

Fig 2 Number and cumulative percent of cases of birth defects with a known etiology, Utah 2005-09. TBSS=tract based spatial statistics

For the known etiology case group, 57 (5.1% of 1114) were further classified as a sequence (n=35, 61.4%), a developmental field defect (n=13, 22.8%), or a known pattern (n=10, 17.5%) (data not shown). Of the remaining two cases with VATER/VACTERL association (known pattern), one case occurred with pregestational diabetes (teratogen) and another with partial trisomy (7q11.21 duplication) (chromosomal-structure).

In this five year population based birth defect case cohort, systematic clinical review identified known etiology in only one in five—specific etiology could not be conclusively assigned in most (79.8%) cases. We considered the etiology known if there was conclusive evidence of one of four factors: chromosomal abnormalities (structure or number), genetic conditions, twinning, or an established human teratogen. Methods to determine if an environmental exposure is a human teratogen were recently reviewed and applied to the birth defects associated with the Zika virus. 14

Based on current science, our study revises and updates the historical findings from two well known hospital based studies of infants with birth defects. 15 16 The overall conclusion remains that a specific cause cannot yet be determined for most birth defects, underscoring the current gaps in knowledge and the challenge of primary prevention.

Comparison with other studies

We focused on major birth defects (excluding some common defects), for a prevalence of 2%. If we extrapolate from this conservative estimate, we estimate that each year a minimum of 78 000 infants are born in the US with a serious birth defect. In 63 000, there would be no identifiable etiology. These figures are intended as minimum estimates. With different criteria for inclusion, investigators have reported a prevalence of 2.24% among infants with a birth defect diagnosed before discharge from the maternity ward or before the age of 5 days at Boston Hospital for Women 16 and 5.5% 17 from the Texas Birth Defects Monitoring Program.

Our estimate of a known etiology in just over 20% is conservative. As genetic technology advances and more discoveries made on the genetic causes of birth defects, the proportion with a known cause will increase. For example, estimates of the genetic contribution to congenital heart disease (the most common birth defect) has increased, based on recent data suggesting that copy number variants and de novo mutations together could account for 15% of all cases. 18 19 20 Also, for some well known risk factors, attribution of an exposure to a birth defect in an individual case remains challenging. The epidemiologic metric of attributable fraction (that is, the proportion of birth defects attributable to the exposure when cause is known) is applicable to populations, not individual cases. In this study, it was not possible to determine if a woman’s history of smoking directly resulted in her infant’s oral facial cleft as the modest odds ratio of about 1.3 predicts that many children do not have an oral cleft because of that exposure. For pregestational diabetes, however, we used data on the estimates and attributable fraction of 70% for isolated and 90% for multiple defects 10 to select certain birth defects as related to diabetes.

Determination of etiology is critically important to focus research efforts for reduction of risk or prevention of occurrence (such as preconception folic acid supplementation and neural tube defects). Few studies have tried to directly assess the proportion of birth defects with or without a known etiology. Higurashi and colleagues re-examined infants each month for the first year to identify those with malformation syndromes not diagnosed at birth but did not mention the proportion without a known etiology. 21 Two hospital based cohorts used different methods (such as inclusion criteria and diagnosis within days after birth) to generate estimates of those infants without a known etiology. 15 16 Nelson and Holmes estimated 43.2% of their infants with birth defects born in a single hospital did not have a known etiology. 16 Infants were included if they received a diagnosis on or before the fifth day of life. Notably, cases considered to be familial (14.5%) or “multifactorial” (23%) were considered to be of known etiology; however, definitions were not provided and the inclusion especially of the “multifactorial” conditions is debatable. In contrast, in our study, we defined familial cases only as infants with an affected first degree relative (4.8% overall, 3.6% unknown etiology). Moreover, because of the difficulty in defining and proving multifactorial inheritance, we did not have such a category. Of note, if we add the cases classified by Nelson and Holmes 16 as multifactorial inheritance (23%) and familial (14.5%) to those that they classified originally as unknown (43.2%), the total adds to 80.7%, similar to our finding.

The causes of birth defects currently without known etiology are probably complex and could include interactions between the genetic profiles of parents and embryo and the environmental milieu during preconception and early gestation. For some birth defects, some progress has been made over the past decades, such as the contribution of microdeletions (such as deletion 22q11 in cases of heart defects and cleft palate 22 23 24 25 ) and novel single gene mutations (such as CHD7 mutations in CHARGE syndrome 13 ). While these genetic causes are relatively straightforward, however, it is likely that further research will discover more complex networks accounting for genetic and environmental contributions to birth defects etiology. Accumulating evidence is uncovering developmental networks that when disrupted can cause birth defect syndromes. 26 Some of these networks could also be influenced by environmental exposures, such as the midline patterning network related to the sonic hedgehog gene, which directly involves cholesterol metabolism. For example, the risk for holoprosencephaly could be increased not only by mutations in sonic hedgehog but potentially also by environmental influences (yet undiscovered) that alter the embryonic cholesterol biosynthesis, perhaps interacting with sonic hedgehog variants. 26

Birth defects know no geographic boundary and occur in every country of the world. Because many countries do not have the capacity to monitor birth defects that occur among all pregnancy outcomes, it is difficult to estimate their true worldwide prevalence and global burden. Based on the findings of this study, however, if we count only those infants live born with an isolated birth defect, 25% of the cases will be missed. The resulting underestimation of the burden of disease can have serious policy implications and hinder the investments in research and interventions to better prevent and treat these major threats to childhood survival and lifelong health.

Research to understand birth defect etiology requires a well defined and clinically characterized case group. Cases with known etiology must be carefully identified and excluded to maximize the chance of discovery. 27 While commonly used birth defect classification schemes (such as ICD-9 or ICD-10) are valuable for general purposes such as studies on morbidity and mortality, they are not ideal in the evaluation of etiologies or trends 28 and could overestimate prevalence. 29 30 31 32 These coding systems are typically organized by anatomy or function rather than cause or embryologic process. Few studies have applied classifications specific to birth defects to population based cohorts. One of these, the National Birth Defects Prevention Study, has leveraged the collaboration of clinical geneticists and epidemiologists to pursue discovery of modifiable causes of birth defects. 33 34 35 Continued progress will require the combined effort and a multidisciplinary approach that incorporates not only the clinical evaluation by dysmorphologists/clinical geneticists and the methodological expertise of epidemiologists but also includes experts in developmental biology, pharmacology, infectious diseases, immunology, and bioinformatics, in addition to a more objective assessment of periconceptional exposures that improve on the typical maternal self reports. Finally, it would be helpful to integrate etiology, morphology, and pathogenesis assessment into the basic framework of epidemiologic studies. Such integration will improve precision and assist researchers to focus research initiatives and investigate common pathways among birth defects.

Limitations

This study has potential limitations. The birth prevalence of 2.03% reported in this study is lower than the 2.24-5.5% reported elsewhere. 2 16 17 Such lower prevalence estimates could relate to the eligibility criteria of the Utah surveillance system, which exclude some common mostly milder conditions that are variably defined and ascertained (such as muscular ventricular septal defects, clubfoot, cryptorchidism). Also, because cases were classified based on data abstracted from mother and infant medical records, there is a possibility that critical information for appropriate classification was unavailable at the time of medical record abstraction. In addition, we could have underestimated the proportion caused by a teratogen if an exposure (such as maternal pregestational diabetes) was not noted in the medical record or not queried by the physician of record. The information in these medical records comes from different specialists, often including perinatologists, genetic counselors, neonatologists, and/or pediatric geneticists. Whereas some level of etiologic under-ascertainment cannot be excluded, it is unlikely that an established environmental cause of birth defects would be missed by everyone involved in the care of the mother and the child. For a genetic investigation, the laboratory evaluation (such as karyotype, microarray) was determined by the clinician(s) caring for the infant and was tailored to the clinical presentation. We would expect some variation within the practice of medicine.

Conclusion and public health implications

Understanding the etiology of birth defects should be both a public health and research priority. Our findings underscore the large gaps in current knowledge of the causes of birth defects. These gaps in turn represent opportunities for both basic and translational researchers. Such research can be particularly powerful and efficient if done in collaboration with population based birth defect surveillance programs enhanced with clinical expertise and meaningful case classification. 36 Advances in the knowledge of the causal pathway leading to birth defects can be the basis for better primary prevention interventions, resulting in longer and better lives. For clinicians and parents, it is important to understand what can be done today to prevent birth defects, in particular the role of preconception care focusing on optimal women’s health (including screening/treating chronic illnesses, attaining folic acid sufficiency, etc). In addition, investigation of potential causes of a birth defect at the time of diagnosis (such as whether a genetic condition is present) can help to better plan management and appropriately counsel families, including the relief of anxiety related to unfounded information and guilt.

What is already known on this topic

Birth defects are common, costly, and critical

Two hospital based studies have tried to directly assess the proportion of birth defects with or without a known etiology

What this study adds

In this population based birth defect case cohort, the cause was established in only one in every five infants

The inability to understand etiology in four of five cases highlights the urgent need for better basic and translational research as a basis for primary prevention and care

In addition, many birth defects are associated with fetal loss: estimates of the global burden of birth defects that consider only liveborn infants with isolated conditions will underestimate this burden by at least 25%, and even more for selected conditions

Contributors: MLF, JCC, JLBB, and LDB conceived and designed the project. SK and MLF cleaned and conducted the analysis for the project. All authors interpreted the data, drafted the manuscript, and assisted with manuscript revisions. MLF is guarantor.

Funding: This publication was supported by a cooperative agreement (No U01DD000490) from the Centers for Disease Control and Prevention. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the Centers for Disease Control and Prevention. Data were provided by the Utah Birth Defect Network, a program within the Utah Department of Health. This project is supported by the Health Resources and Services Administration (HRSA) of the US Department of Health and Human Services (HHS) under grant No B04MC25374. This information or content and conclusions are those of the author and should not be construed as the official position or policy of, nor should any endorsements be inferred by HRSA, the US Government, or the Utah Department of Health.

Competing interests: All authors have completed the ICMJE uniform disclosure form and declare no support from any organization for the submitted work, no financial relationships with any organizations that might have an interest in the submitted work in the previous three years, and no other relationships or activities that could appear to have influenced the submitted work.

Ethical approval: Not required.

Data sharing: No additional data available.

Transparency: The lead author (the manuscript’s guarantor) affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/ .

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Evaluation of the risk of birth defects related to the use of assisted reproductive technology: an updated systematic review.

birth defects systematic review of the literature

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1.1. fertility and infertility problem, 1.2. characteristics of assisted reproduction techniques, 1.3. prenatal diagnostic, 4. discussion, 5. conclusions, author contributions, institutional review board statement, informed consent statement, data availability statement, acknowledgments, conflicts of interest.

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Serafin, D.; Grabarek, B.O.; Boroń, D.; Madej, A.; Cnota, W.; Czuba, B. Evaluation of the Risk of Birth Defects Related to the Use of Assisted Reproductive Technology: An Updated Systematic Review. Int. J. Environ. Res. Public Health 2022 , 19 , 4914. https://doi.org/10.3390/ijerph19084914

Serafin D, Grabarek BO, Boroń D, Madej A, Cnota W, Czuba B. Evaluation of the Risk of Birth Defects Related to the Use of Assisted Reproductive Technology: An Updated Systematic Review. International Journal of Environmental Research and Public Health . 2022; 19(8):4914. https://doi.org/10.3390/ijerph19084914

Serafin, Dawid, Beniamin Oskar Grabarek, Dariusz Boroń, Andrzej Madej, Wojciech Cnota, and Bartosz Czuba. 2022. "Evaluation of the Risk of Birth Defects Related to the Use of Assisted Reproductive Technology: An Updated Systematic Review" International Journal of Environmental Research and Public Health 19, no. 8: 4914. https://doi.org/10.3390/ijerph19084914

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Research Paper Volume 12, Issue 24 pp 25373—25394

Effect of paternal age on offspring birth defects: a systematic review and meta-analysis, yiwei fang 1 , , yongfeng wang 1 , , meilin peng 1 , , jia xu 1 , , zunpan fan 1 , , chunyan liu 1 , , kai zhao 1 , , huiping zhang 1 , ,.

1 Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

Received: June 24, 2020 Accepted: September 20, 2020 Published: November 20, 2020

Cite this article, how to cite.

Fang Y , Wang Y , Peng M , Xu J , Fan Z , Liu C , Zhao K , Zhang H , . Effect of paternal age on offspring birth defects: a systematic review and meta-analysis. Aging (Albany NY). 2020 Nov 20; 12:25373-25394. https://doi.org/10.18632/aging.104141

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Click to copy this citation from the text box above or download the citation: Citation | Citation & Abstract

Copyright: © 2020 Fang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Objective: This systematic review and meta-analysis was aimed at determining whether paternal age is a risk factor for offspring birth defects.

Results: A total of 38 and 11 studies were included in the systematic review and meta-analysis, respectively. Compared with reference, fathers aged 25 to 29, young fathers (< 20 years) could increase the risk of urogenital abnormalities (OR: 1.50, 95 % CI: 1.03–2.19) and chromosome disorders (OR: 1.38, 95 % CI: 1.12–1.52) in their offsprings; old fathers (≥ 40 years) could increase the risk of cardiovascular abnormalities (OR: 1.10, 95 % CI: 1.01–1.20), facial deformities (OR: 1.08, 95 % CI: 1.00–1.17), urogenital abnormalities (OR: 1.28, 95 % CI: 1.07–1.52), and chromosome disorders (OR: 1.30, 95 % CI: 1.12–1.52).

Conclusions: Our study indicated that paternal age is associated with a moderate increase in the incidence of urogenital and cardiovascular abnormalities, facial deformities, and chromosome disorders.

Methods: PubMed, Web of Science, the Cochrane Library, and Embase were searched for relevant literatures from 1960 to February 2020. The systematic review follows PRISMA guidelines. Relevant meta-analyses were performed.

Introduction

Previous study has shown that the overall prevalence of birth defects in live births ranges from 3–5 % [ 1 ]. Birth defects are a major cause of perinatal mortality, accounting for more than 20 % of infant deaths [ 2 , 3 ]. Moreover, birth defects are one of the strongest known risk factors for childhood cancers [ 4 ], causing serious effects in children’s health; such defects are also associated with high risks of preterm birth (PTB), low birth weight (LBW), and infant death [ 5 ]. Thus, birth defects do not only increase medical burden but also place an economic burden on families and society [ 6 ].

According to Medical Subject Headings (MeSH) of the PubMed database, classification of urogenital abnormalities, digestive system abnormalities, nervous system malformations, cardiovascular abnormalities, facial deformities, musculoskeletal abnormalities, and chromosome disorders are shown in Supplementary Table 1 .

In accordance with a consensus, young fathers are aged 20 years and below, whereas older fathers are older than 40 years [ 7 ]. In developed regions, such as Europe and the USA, the proportion of late marriage and childbirth is increasing [ 7 , 8 ], whereas early marriage and early childbearing are on the ascendancy in developing countries [ 9 , 10 ]. Some studies have assessed the relationship between paternal age and birth defects in offspring, but no substantive conclusion, even contradictory has been drawn [ 10 – 12 ]. In previous years, a few systematic reviews and meta-analyses have evaluated the relationship between paternal age (especially advanced paternal age) and birth defects, including congenital heart disease, cleft lip and palate, neural tube defects, gastroschisis, and trisomy 21 syndrome. However, these studies did not include other birth defects, such as hydranencephaly of common nervous system malformations and trisomy 13 and trisomy 18 syndromes of common chromosome disorders. Moreover, systematic reviews and meta-analyses about urogenital abnormalities and digestive system abnormalities seem limited [ 11 , 13 , 14 ]. Therefore, a further systematic review and meta-analysis of birth defects is needed to fill the gap [ 15 – 17 ].

This systematic review and meta-analysis focused on the influence of paternal age, particularly of old (> 40 years old) and young fathers (< 20 years old), on offspring birth defects in each system and chromosomal abnormalities. This meta-analysis is the first of its kind that focuses on the effect of paternal age on urogenital and digestive system abnormalities; the results of this work contributes to a comprehensive understanding of the risk factors for birth defects and its effective prevention.

Study selection and characteristics

We identified a total of 3581 articles published between 1962 and 2020 after duplicates were removed. A total of 3412 articles were directly excluded after reading the titles and abstracts, and 131 articles were excluded after reading the full text for the following reasons: insufficient data (92), non-English (22), no access to the full paper (8), and others (9) ( Figure 1 ). Lastly, a total of 38 and 11 studies were included in the systematic evaluation and meta-analysis, respectively. Figure 1 , Table 1 and Supplementary Table 2 respectively show the process of literature inclusion and summarize the characteristics of the included literature.

PRISMA flow diagram for a systematic review and meta-analysis. A total of 3581 articles were identified after duplicates removed. Out of the 3581 articles, 3412 articles were directly excluded after reading the titles and abstracts, and 131 articles were excluded for some reasons after reading the full text. Finally, 38 and 11 studies were included in the systematic evaluation and meta-analysis, respectively.

Figure 1. PRISMA flow diagram for a systematic review and meta-analysis. A total of 3581 articles were identified after duplicates removed. Out of the 3581 articles, 3412 articles were directly excluded after reading the titles and abstracts, and 131 articles were excluded for some reasons after reading the full text. Finally, 38 and 11 studies were included in the systematic evaluation and meta-analysis, respectively.

Table 1. Summary results of the systematic review of the association between young and old father and birth defects.

Of the 38 studies, 18 were case-control studies, and the rest were cohort studies. In accordance with the NOS, the quality of research was evaluated. The following were obtained: 27 high-quality studies (NOS scores ≥ 7), nine medium-quality studies (NOS scores of 5–6), and two low-quality studies (NOS scores ≤ 4). Twenty-six studies adjusted or controlled for maternal age, and 12 did not.

The number of reported cases is as follows: more than 1,000 in 14 studies; 101-1,000 in 19 studies, and not more than 100 in five studies. The number of studies conducted by region is as follows: 15 in North America (12 in the USA), 15 in Europe (five in Norway and four in Denmark), six in Asia (three in China), two in South America, and only one in Africa. One study was conducted simultaneously in the United States and the Czech Republic. Twenty-seven studies began before 2000, and nine studies were conducted after 2000; 31 studies lasted longer than 3 years, and five studies lasted less than 3 years. The longest study lasted for more than 40 years, whereas the shortest study lasted for less than one year. Two studies did not report the time of study execution.

Regarding the assessment of exposure factors (paternal age), 32 studies clarified the paternal age. However, different studies used various methods for categorizing paternal age; the most common categorization of paternal age was 39 years. In the present study, we defined fathers younger than 20 years as young fathers, older than 40 years as old fathers, and 25 – 29 years as the reference group.

Meta-analytic results for birth defects in each system

Urogenital abnormalities.

We identified six studies [ 14 , 15 , 18 – 21 ] that reported a total of 5217 cases about urogenital abnormalities in the systematic review; four were cohort studies, whereas two were case-control studies. On the basis of the NOS scoring criteria, five high-quality and one medium-quality studies were identified. In the meta-analysis, only two studies [ 14 , 19 ] could be included. Young and old fathers increased the risk of offspring urogenital abnormalities (OR: 1.50, 95 % CI: 1.03 – 2.19; OR: 1.28, 95 % CI: 1.07 – 1.52, respectively). Among the studies, no heterogeneity was found in these two subgroups (I 2 = 0.0 %, 0.0 %, respectively) ( Figure 2 ). The results of the funnel plots and Egger’s test (P = 0.369) revealed no significant publication bias.

Forest plot presenting the effect of young and old father on urogenital abnormalities in their offspring: Only two studies could be included in the meta-analysis. Both young and old father increased the risk of urogenital abnormalities in offspring (OR 1.50, 95%CI 1.03-2.19; OR 1.28, 95%CI 1.07-1.52, respectively). There was no heterogeneity in these two subgroups (I2=0.0%, 0.0%, respectively) amongst the studies.

Figure 2. Forest plot presenting the effect of young and old father on urogenital abnormalities in their offspring: Only two studies could be included in the meta-analysis. Both young and old father increased the risk of urogenital abnormalities in offspring (OR 1.50, 95%CI 1.03-2.19; OR 1.28, 95%CI 1.07-1.52, respectively). There was no heterogeneity in these two subgroups (I 2 =0.0%, 0.0%, respectively) amongst the studies.

Digestive system abnormalities

Five studies [ 14 , 15 , 19 , 20 , 22 ] reporting a total of 5823 cases analyzed the association between paternal age and digestive system abnormalities in offspring. Of these studies, four were cohort studies, and one was a case-control study. In addition, all the studies were of high quality and adjusted for maternal age. Three studies [ 14 , 19 , 22 ] were included in the meta-analysis. The pooled ORs in the subgroup of young and old fathers were 1.13 (95 % CI: 0.98 – 1.30) and 0.90 (95 % CI 0.79 – 1.02), respectively. Among the studies, no heterogeneity was found in these two subgroups (I 2 = 0.0 %, 0.0 %, respectively) ( Figure 3 ). The results of the funnel plots and Egger’s test (P = 0.244) revealed no significant publication bias.

Forest plot presenting the effect of young and old father on digestive system abnormalities in their offspring: Three studies were included in the meta-analysis. The pooled OR in subgroup of young fathers and old fathers was 1.13(95%CI 0.98-1.30) and 0.90(95%CI 0.79-1.02), respectively. There was no heterogeneity in these two subgroups (I2=0.0%, 0.0%, respectively) amongst the studies.

Figure 3. Forest plot presenting the effect of young and old father on digestive system abnormalities in their offspring: Three studies were included in the meta-analysis. The pooled OR in subgroup of young fathers and old fathers was 1.13(95%CI 0.98-1.30) and 0.90(95%CI 0.79-1.02), respectively. There was no heterogeneity in these two subgroups (I 2 =0.0%, 0.0%, respectively) amongst the studies.

Nervous system malformations

Nine papers [ 14 , 15 , 19 – 25 ] reporting a total of 8191 cases of nervous system malformations were included in the systematic review; seven were cohort studies, and two were case-control studies. In accordance with the NOS scoring criteria, eight high-quality and one medium-quality studies were identified. Five studies [ 14 , 19 , 22 – 24 ] were included in the meta-analysis. The pooled ORs in the subgroup of young and old fathers were 1.23 (95 % CI: 0.94 – 1.60) and 1.12 (95 % CI: 0.97 – 1.30), respectively. Among the studies, minimal heterogeneities were found in the two subgroups (I 2 = 36.5 %, 33.5 %, respectively) ( Supplementary Figure 1 ). The results of the funnel plots and Egger’s test (P = 0.071) revealed no significant publication bias.

Cardiovascular abnormalities

Five cohort studies and six case-control studies [ 15 , 19 , 21 , 22 , 26 – 32 ] reported the association between paternal age and cardiovascular abnormalities; nine high-quality and two medium-quality studies were identified. The total number of cases of cardiovascular system malformations was 32,190. A meta-analysis of the data based on four studies [ 19 , 22 , 30 , 31 ] showed that compared with fathers aged 25 – 29, younger fathers ( 2 = 2.1%, 37.6%, respectively) ( Supplementary Figure 2 ). The results of the funnel plots and Egger’s test (P = 0.128) revealed no publication bias.

Facial deformities

Thirteen papers [ 12 , 14 , 15 , 19 – 22 , 33 – 38 ], including nine cohort studies and four case-control studies, concentrated on paternal age as a risk factor for facial deformities in offspring; eleven were of high quality, one was of medium quality, and one was of low quality. A total of 18807 cases of facial deformities (most of the cleft lip or palate) were explored in thirteen studies. Older fathers (≥ 40 years) slightly increase the risk of facial deformities in their children, whereas younger fathers ( 2 = 0.0 %, 0.0 %, respectively) [ 14 , 19 , 22 , 33 ] ( Supplementary Figure 3 ). The results of the funnel plots and Egger’s test (P = 0.186) revealed no significant publication bias.

Musculoskeletal Abnormalities

Thirteen papers [ 14 , 15 , 19 – 22 , 39 – 45 ], including nine cohort studies and four case-control studies, concentrated on paternal age as a risk factor for musculoskeletal abnormalities in offspring; ten were of high quality, two were of medium quality, and one was of low quality. A total of 27546 cases of musculoskeletal abnormalities in fourteen studies were included in the systematic review. We included four studies [ 14 , 19 , 22 , 44 ] in the meta-analysis, and the results showed that compared with fathers aged 25 – 29, younger ( Supplementary Figure 4 ). Among the studies, medium heterogeneity was found in the two subgroups (I 2 = 53.7 % and 41.4 %, respectively). The funnel plots and Egger’s test (P = 0.004) revealed a significant publication bias. We detected publication bias in the subgroup of young and old fathers. The Egger’s test found no publication bias in the subgroup of young fathers (P = 0.586) but found such bias in the subgroup of old fathers (P = 0.002). In addition, after correcting publication bias in the subgroup of old fathers via the nonparametric trim-and-fill method, the pooled OR was still not statistically significant (OR: 1.039, 95 % CI: 0.841 – 1.284). The funnel plots after correcting the publication bias in the subgroup of old fathers is shown in Supplementary Figure 5 .

Chromosome disorders

Ten papers [ 14 , 15 , 17 , 22 , 46 – 51 ], including five cohort studies and five case-control studies, were identified. Among them, eight papers were of high quality, and two were of medium quality. A total of 18108 cases of chromosome disorders, such as Trisomy 21, Trisomy 13, and Trisomy 18, were accessed in this systematic review. We conducted meta-analysis on four studies [ 14 , 22 , 46 , 50 ] and revealed a moderately high risk of chromosome disorders in newborns of young and old fathers (OR: 1.38, 95 % CI: 1.01 – 1.89; OR: 1.30, 95 % CI: 1.12 – 1.52, respectively) in comparison with the reference fathers (25 – 29 years) ( Supplementary Figure 6 ). Among the studies, medium heterogeneity was found in the two subgroups (I 2 = 52.6 % and 62.1% for young and old fathers, respectively). The funnel plots and Egger’s test (P = 0.376) revealed no significant publication bias.

Previously, a few works involving meta-analysis evaluated the association between paternal age and birth defects; however, most of them explored birth defects in general, without sorting the defects by systems. Based on the results of our meta-analysis, young fathers ( Table 2 summarizes the main findings of the meta-analysis.

Table 2. Summary results of the meta-analyses of the association between young and old father and birth defects.

As for cardiovascular abnormalities, a previous study suggested that older fathers were not a risk factor (OR: 1.15, 95 % CI: 0.96 – 1.36); this finding is consistent with our results [ 52 ]. However, the other study was in line with our results in cardiovascular abnormalities (OR: 1.27, 95 % CI: 1.14 – 1.42) [ 53 ]. Our meta-analysis controlled for the confounding of maternal age, and we included not only congenital heart defects but also vascular malformations. This might indicate that the difference is due to additional vascular malformations. Conversely, their meta-analysis did not set an age reference group for fathers, whereas our reference group was 25 – 29 years. Two meta-analyses were consistent with our findings that advanced paternal age did not increase the risk of facial deformities; however, these studies focused on orofacial clefts only [ 52 , 54 ]. Our finding that paternal age was not a risk factor was similar to that of Oldereid [ 52 ] (OR: 0.98, 95 % CI: 0.72 – 1.32) in nervous system malformations but different with Jia [ 55 ]; the latter reported that younger paternal age (< 20) significantly increased the risk of neural tube defects compared with 25 – 29 years (OR: 1.41 (1.10–1.81)). However, our study encompasses not only neural tube defects but also other neurological diseases, such as hydrocephalus.

The exact mechanism by which young and old paternal age increase the risks of birth defects in offspring is unclear. However, the decline in sperm quality in older men has been demonstrated by several studies, even resulting in infertility. Androgen levels drop significantly in older fathers, and some significant abnormalities in sperm parameters, including the decrease in the total number of Sertoli cells, have been identified in human and animal models [ 56 – 59 ]. Aging could result in testicular histomorphology abnormalities [ 60 ], which are the underlying mechanisms of infertility and adverse pregnancy outcomes in older men. Sperms are also associated with an increased abnormal chromosome segregation during meiosis, which may lead to chromosomal defects, including trisomy 21 in progeny [ 61 – 63 ]. Studies have shown that an increase in the number of genetic mutations carried by offspring is related to the age at which the parents conceived [ 64 ]. As the father grows older, the number of mutations in the father’s genome increases, leading to an increase in the incidence of congenital malformations in offspring [ 11 , 65 ].

Older paternal age may be harmful to the offspring’s health in terms of genetic mutations, telomere length, and epigenetics [ 66 ]. Several lines of evidence suggest that epigenetic changes occur in the sperm of older fathers, particularly defects in DNA methylation [ 67 – 69 ]. As fathers age, they are exposed to various environmental risk factors, which are involved in the formation and maintenance of epigenetic patterns; these epigenetic modifications have serious consequences for offspring, often contributing to the early onset of diseases [ 70 , 71 ]. Common environmental risk factors include physical factors (such as radiation and high temperature), chemical factors (such as alcohol, aromatic compounds, heavy metals), and biological factors (such as viruses and bacteria). Older fathers have less antioxidant capacity, and environmental risk factors which may lead to new mutations and DNA damage in some key DNAs related to fetal development [ 72 – 74 ]. Interestingly, a study found that young and old fathers increase the risks of new dominant autosomal mutations, leading to various birth defects in their offspring [ 75 ].

A few studies have found that young fathers increase the risk of adverse pregnancy outcomes; unfortunately, fewer studies have focused on the mechanisms. Steiner found that younger fathers have a higher risk of chromosomal aneuploidy in their offspring [ 76 ]. Interestingly, Steiner assumed if a 35-year-old woman receives the sperm of a 20-year-old man, her offspring almost doubled their risks of aneuploidy compared with the sperm of a 40-year-old man; meanwhile, the odds of a dominant de novo mutation increased. Moreover, a recent study maintains that young fathers could contribute a substantial load of point mutations to their offspring [ 77 ]. Chromosomal aneuploidy and point mutations may partially explain that young fathers increase the risk of some birth defects in newborns, but other factors might be involved, too. The early-bearing population may be at low socioeconomic status [ 78 ]. Consequently, factors, including the nutrition of the father or the pregnant woman, and the family's health care affect the health of the fetus in many ways. This phenomenon may be due to unplanned pregnancies among young people, who probably do not take prenatal supplements (such as folic acid) and may be continuously exposed to environmental risk factors (such as smoking) [ 79 – 83 ]. Young fathers may take in additional acrylamide because of special dietary habits and high-temperature food [ 84 ]. The metabolites of acrylamide have strong genotoxicity [ 84 ], which can indirectly lead to the alkylation of protamine, DNA breakage, and chromosome aberration [ 85 , 86 ]. Some substances in the semen of young fathers may alter the normal structure and function of sperm, leading to birth defects. Uric acid is highly concentrated in young male semen [ 87 ]; such high concentration has been shown to adversely affect sperm morphology and functions [ 88 ]. This may be a potential mechanism despite the lack of relevant clinical data validation. Young fathers under stress may contribute to poor birth outcomes, as pre-pregnancy stress may lead to changes in epigenetics [ 89 , 90 ]. In short, although the exact mechanism is unclear, birth defects caused by young and older fathers may be attributed to some interactions between environmental and genetic factors.

Our findings showed that paternal age, particularly that of young or old fathers is associated with an increased risk of birth defects, indicating that men’s childbearing age should not be too early or too late. Moreover, the implementation of strategic interventions and appropriate preventive measures to reduce the risks of birth defects in offspring are of paramount importance. We found that epidemiological studies in developing countries (especially in Africa, Latin America, and Asia) are relatively few, and future research needs to happen in these regions. Furthermore, some birth defects, such as those of the respiratory, endocrine, and skin systems, have been poorly studied. This requires further study to fill this gap. Future research may also focus on the mechanisms by which paternal age leads to birth defects in offspring for improved prevention and intervention.

Strengths and limitations

We investigated the influences of old and young paternal age on offspring in this systematic review and meta-analysis. This study neither summarized all birth defects into one category nor analyzed a single birth defect; instead, the study divided them into seven categories according to body regions or systems. The analysis from a systematic perspective is unable to lower the heterogeneity among studies but also incorporate papers about birth defects as many as possible. Moreover, we included some literature published recently in the systematic evaluation. The number of cases of birth defects included in our study was large, with each study sample covering over 5,000 cases, among which the number of cases of cardiovascular abnormalities and musculoskeletal abnormalities exceeded 30,000 cases. Studies that did not control for the confounding of maternal age were excluded, and all high-quality studies (NOS score ≥ 7) were included in the quantitative synthesis, thus improving the reliability of the results to a certain extent. Lastly, this work is the first meta-analysis on the effect of paternal age on urogenital abnormalities in offspring. This can guide clinicians to use some methods before or after delivery, such as ultrasound examination, to check these potential defects in offspring.

However, this systematic review and meta-analysis also have some limitations. Although, tens of studies were retrieved, only a few studies could involve quantitative synthesis as some studies did not control for confounding factors, such as maternal age or different stratification methods of father’s age. Again, most of the estimates and 95 % CI are close to 1.00. For the limitation of the number of articles, we could not perform the subgroup analysis of the countries, years, and specific "isolated" malformations of the study. Although most of the birth defects were included in this meta-analysis, some unusual birth defects, such as respiratory birth defects, were not available. In addition, different studies may have some differences in the definition and classification of birth defects. Some research may only study live births, whereas some studies include birth defects during stillbirth and thus may reduce the accuracy of the results to some extent. The marked etiologic and pathogenic heterogeneity involved in organ systems and body region malformations in this meta-analysis might constitute a major bias regarding the etiologic effect of paternal age. The results showed that heterogeneity was almost minimal (most of I 2 Table 2 ). However, this heterogeneity may not be important because the systematic review and meta-analysis are based exclusively on observational studies and not on intervention trials. We do not circumscribe the meta-analysis to those specific "isolated" malformations but classified them by body regions because the number of studies on specific birth defects is limited.

Conclusions

The results of this systematic review and meta-analysis showed that young fathers (< 20 years) could increase risks of urogenital abnormalities and chromosome disorders in their offspring. On the other hand, old fathers (≥ 40 years) could increase risks of cardiovascular abnormalities, facial deformities, urogenital abnormalities, and chromosome disorders in their offspring. In general, younger fathers had less effect on birth defects compared with older ones. Albeit of a moderate effect, we have yet to understand the plausible effects of young or old paternal age in the onset of congenital defects in their offspring. To determine whether paternal age have an adverse effect on specific "isolated" malformations in offsprings, more high-quality prospective cohort studies are needed to be conducted in the future.

Materials and Methods

This study strictly followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria. The protocol has been registered with PROSPERO (CRD42020180376).

Search strategy and selection criteria

We systematically searched original research on Pubmed, Web of Science, the Cochrane Library, and Embase online databases from 1960 to February 2020; references to selected articles were also searched. The retrieval process on PubMed database is as follows: (“Paternal Age”[Mesh] OR (((“male age” OR “man age”) OR “men age”) OR “father age”)) AND (“Congenital Abnormalities”[Mesh] OR ((((((“congenital abnormality” OR “congenital disorder”) OR “congenital disorders”) OR “congenital malformation”) OR “congenital malformations”) OR “birth defect”) OR “birth defects”)). All terms were searched through a combination of the field “Title / Abstract,” but no filters were used to retrieve the literature.

Inclusion criteria

Observational epidemiologic studies, including cohort and case-control studies published in English; examined the association between paternal age and birth defects in infants; reported ORs and 95 % confidence intervals (CIs) or had raw data available. For multiple publications using the same database, we chose the study that contains the most comprehensive information.

Exclusion criteria

Studies that were not adjusted or controlled for maternal age, had unclassified birth defects, had no available full text or complete data, and involved animal experiments.

Outcome measures

This study mainly focuses on urogenital abnormalities, digestive system abnormalities, nervous system malformations, cardiovascular abnormalities, facial deformities, musculoskeletal abnormalities, and chromosome disorders. All these defects have been mentioned in the introduction. Supplementary Table 3 shows the selected birth defects of each study included in the meta-analysis.

Data extraction and quality assessment

Studies that met the inclusion criteria were independently reviewed by two authors (Y.F. and J.X.), and discrepancies between the authors were resolved through a consensus with a third author (Z.F.). The following information were extracted in a standardized format: first author and year of publication, study period and location, study design, sample size (case/population or case/control), types of birth defects, paternal age categorization, ORs (95 % CI), and adjusted factors.

The methodological quality of the study was evaluated independently by two evaluators (Y.F. and J.X.) in accordance with the Newcastle–Ottawa Quality Assessment Scale (NOS) [ 91 ]. NOS has been widely used to evaluate the quality of cohort and case-control studies and strongly recommended by Cochrane. We defined a score of 7–9 as high quality, 5–6 as medium quality, and 0–4 as low quality. The conflicting results were resolved through a discussion between two authors.

Statistical analysis

To improve reliability, we only included the studies of the reference group with fathers aged 25–29 years into the quantitative meta-analysis. Moreover, studies included in the meta-analysis should be at least adjusted or controlled for maternal age. We quantitatively synthesized the ORs (95 % CI) of each study and compared birth defects in the offspring of young ( 40 years old) with those of fathers aged 25–29 years old. The results in this study only report random-effect models due to the potential heterogeneity of the study. Funnel plots and Egger’s test were used to assess publication bias, and a nonparametric trim-and-fill method was conducted to correct publication bias. Stata12.0 was used for statistical analysis, and p < 0.05 was considered statistically significant.

Supplementary Materials

Supplementary Figures

Supplementary table 1, supplementary table 2, supplementary table 3.

Author Contributions

H. Z. and K. Z. designed this study. Y. F. and Y. W. performed the literature search and study selection. Y. F., J. X. and Z. F. extracted the data and assessed the quality of studies. Y. F. and M. P. conducted the statistical analysis. Y. F. drafted the article. All authors contributed to the final version of the manuscript.

Acknowledgments

We very grateful to Joseph Lasong for the improving the language and “Xiaoyaojun Study Hall” for sharing the methodological knowledge of meta-analysis.

Conflicts of Interest

The authors have no conflicts of interest.

This work was funded by National Key R&D Program of China (2018YFC1004300, 2018YFC1004304), National Natural Foundation of China (Grant numbers: 81701539).

Corresponding Authors

Kai Zhao [email protected]

Huiping Zhang [email protected] https://orcid.org/0000-0002-5728-6658

Table of Contents

Evaluation of the association between maternal folic acid supplementation and the risk of congenital heart disease: a systematic review and meta-analysis

Nutrition Journal volume 21 , Article number: 20 ( 2022 ) Cite this article

Metrics details

Folic acid (FA), as a synthetic form of folate, has been widely used for dietary supplementation in pregnant women. The preventive effect of FA supplementation on the occurrence and recurrence of fetal neural tube defects (NTD) has been confirmed. Incidence of congenital heart diseases (CHD), however, has been parallelly increasing worldwide. The present study aimed to evaluate whether FA supplementation is associated with a decreased risk of CHD.

We searched the literature using PubMed, Web of Science and Google Scholar, for the peer-reviewed studies which reported CHD and FA and followed with a meta-analysis. The study-specific relative risks were used as summary statistics for the association between maternal FA supplementation and CHD risk. Cochran's Q and I 2 statistics were used to test for the heterogeneity.

Maternal FA supplementation was found to be associated with a decreased risk of CHD (OR = 0.82, 95% CI: 0.72–0.94). However, the heterogeneity of the association was high ( P < 0.001, I 2 = 92.7%). FA supplementation within 1 month before and after pregnancy correlated positively with CHD (OR 1.10, 95%CI 0.99–1.23), and high-dose FA intake is positively associated with atrial septal defect (OR 1.23, 95%CI 0.64–2.34). Pregnant women with irrational FA use may be at increased risk for CHD.

Conclusions

Data from the present study indicate that the heterogeneity of the association between maternal FA supplementation and CHD is high and suggest that the real relationship between maternal FA supplementation and CHD may need to be further investigated with well-designed clinical studies and biological experiments.

Peer Review reports

Introduction

Folic acid (FA) is a synthetic (that is, not generally occurring naturally) form of folate. Clinical and epidemiologic studies have demonstrated that folate deficiency during pregnancy can lead to birth defects, such as fetal neural tube defects (NTD) [ 1 , 2 , 3 ]. To prevent folate deficiency such as NTD, FA has been used as a substitute for natural folate because the folic acid, which due to its synthetic form has fully oxidized structure make it more stable than reduced folate [ 4 , 5 ]. The preventive effect of FA supplementation in pregnant women on the occurrence and recurrence of neural tube defects (NTD) has been fully confirmed, it is generally believed that FA supplementation in pregnant women is beneficial to reproductive outcomes, including the incidence of congenital heart disease (CHD). In recent decades, however, the prevalence of CHD continues to be increased worldwide [ 6 ]. In many countries and regions in the world, the updated birth rate of CHD has become the first human birth defects, which accounts for nearly one-third of all major congenital anomalies [ 6 , 7 ].

In China, the public health policy of FA supplementation for pregnant women originated from the US-China joint research project, which successfully reduced the incidence of NTD by 41–79% [ 8 ]. From 1987 to 2017, the incidence of NTD dropped from the first place among the 23 birth defects monitored during the perinatal period in China to the 12th place [ 9 , 10 ]. However, with the advancement of the FA supplement policy, the overall prevalence of birth defects has not been controlled as expected, rising from 109.79/10,000 in 2000 to 153.23/10,000 in 2011 [ 10 ]. The main factor for the above deviation is increased CHD because CHD has become the largest class of birth defects since 2005 [ 11 ]. Further analysis of the birth rate of specific CHD subtypes showed that the incidence of atrial septal defect (ASD) has increased significantly over time [ 12 ]. We are unable to explain the differences in temporal trends in incidence between NTD and CHD. Apparently, there is a large discrepancy between the current state of FA supplementation to prevent CHD knowledge and practice for clinical application. Therefore, the question of whether there exists an association between maternal FA supplementation and the risk of CHD is raised. To address this question, in the present study, we have conducted a systematic review and meta-analysis to evaluate the association of maternal FA supplementation on the risk of CHD, and to provide a scientific basis for further medical decision and research on maternal FA supplementation and prevention of CHD.

Search strategy

We searched the literature with a cut-off date of June 30, 2021, using PubMed, Web of Science and Google Scholar, for the peer-reviewed studies with English abstracts which reported CHD and FA. The main search terms used were (‘congenital heart disease’, or ‘congenital heart defect’, or ‘CHD’, or ‘septal defect’ or ‘atrial septal defect’) and (‘folic acid’, or ‘folate’, or ‘multivitamins’). In addition, we searched for the studies that using the key words of coronary artery disease and birth defects and examined the relevant references. We further followed published quality standards for conducting the meta-analyses [ 13 ].

Eligibility criteria

We selected the articles that (1) were original epidemiologic studies and clinical control studies (i.e., case–control, cohort or randomized controlled trial, RCT), (2) examined the association between periconceptional FA use and either CHD overall or ASD (or septal defects) subtypes in infants, (3) were published in the English language, (4) either the results reported as risk ratios or odds ratios (OR) and 95% confidence intervals (CI) or provided raw data from which these measures could be calculated, (5) defined CHD or ASD (or septal defects) subtypes as an outcome. We also excluded the results of research in the pregnant women with diseases (for instance, diabetes). In addition, non-peer reviewed articles and the studies with experimental animals, concerning ecological assessments, and mechanisms were excluded. Articles that reported results contained multiple populations were considered to consist of separate studies, with one study for each population investigated. Only first published article or the largest number of cases was included in our study, when multiple articles were found to examine the same study.

Date extraction

Data extraction and quality assessment were completed independently by two researchers to reduce the bias and errors of in the date extraction process. Disagreements between investigators were resolved through discussions until a consensus was reached. The following study characteristics were recorded: publication year, geographic region, the sample size, case classification information, exposure, and outcome assessments, adjusted estimates and their corresponding 95% Cl and confounding factors that were controlled for by adjustments in the data analysis. Because a proportion of women might take a multivitamin containing FA during pregnancy, in the current study, we thus analyzed the data separately and found similar results when taking FA alone or taking a multivitamin (Please see Supplemental Fig. 1 ). If the content of FA in the multivitamin could not be determined to be 0.4 mg, we did not include these data in the analysis. Additionally, the information on the dosage and the timing of FA intake were collected, grouped into three types of FA dose: high-dose, medium-dose, and low-dose. We assessed initiation of any folic intake for 3 times window: 4 weeks before conception, 4 weeks after conception, 5 to 12 weeks after conception. Some studies did not report the exact time of initiation of FA intake, we divided it into four types: short-term taking before pregnancy, long-term taking before pregnancy, short-term taking after pregnancy, long-term taking after pregnancy. To assess study quality, we used a 9-star system based on the Newcastle–Ottawa Scale [ 14 ]. We defined a high-quality study as one with a quality score greater than or equal to 7.

A flow chart of identification and selection of the studies in the current meta-analysis

Statistical analysis

As summary statistics, we used study-specific relative risks for the association between maternal FA supplementation and CHD risk. To simplify the procedure, an OR was used to represent results from case–control studies and an RR was used to represent all reported study-specific results from cohort studies. Heterogeneity among studies was evaluated using Cochran's Q and I 2 statistics.

We conducted subgroup analyses based on study design (i.e., RCT or cohort versus case–control studies), geographical region (i.e., USA, Europe, and China), study quality (i.e., low versus high quality) and relevant confounder (i.e., age). In addition, we have made statistics on the time and dose of FA intake. We evaluated heterogeneity between subgroups by meta-regression analysis. A P -value less than 0.05 for the meta-regression analysis was considered to indicate a significant difference between subgroups.

Publication bias was assessed by via visual inspection of a funnel plot for asymmetry using Egger's linear regression [ 15 ] and Begg's rank correlation methods [ 16 ]. For both tests, significant statistical publication bias was defined to be indicated by a P -value of < 0.05. All statistical analyses were performed using STATA software (version 14.0; StataCorp, College Station, Texas, USA).

Study characteristics

The initial search returned a total of 1,824 potentially eligible publications from databases. Finally, a total of 21 studies involving 106,920 CHD individuals were included for the analysis. The process of identification and selection in the studies for the current meta-analysis is summarized in Fig. 1 . All the studies were published in the period from 1993 to 2020, and they included 1 randomized controlled trial, 5 cohort studies and 15 case–control studies. The characteristics of all studies are summarized in Supplemental Table 1 . Of them, more than half of the studies (61.9%) were published after 2010, and 5 studies performed in the United States [ 17 , 18 , 19 , 20 , 21 ], 9 studies in Europe [ 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 ], 4 studies in China [ 31 , 32 , 33 , 34 ], 2 studies in Canada [ 35 , 36 ], and 1 study in Australia [ 37 ].

Maternal FA supplementation and CHD

Figure 2 represents the results of the association between maternal FA supplementation and the risk of CHD in this study. The overall results of this meta-analysis showed the decreased risk of CHD with maternal FA supplementation (OR = 0.82, 95% CI: 0.72–0.94; Fig. 2 A). Figure 2 B shows the comparison results with each dose level of the maternal FA supplementation and the association of CHD. Of the 21 studies included in the current study, data from 4 studies were adopted to evaluate CHD for the intake of FA during pregnancy. Each of the studies included in FA intake is not consistent, we thus summarized and roughly divided into high-dose group, low-dose group, and middle-dose group, while the middle-dose group was taken into OR calculation as a reference. FA dosage information included in these studies is summarized and represented in Table 1 . The results of this meta-analysis provided evidence that FA intake affected the association of CHD. The summary OR for any type of heart defect of low dose intake compared with middle dose intake was 1.23 (95% CI, 0.99–1.52), with no significant heterogeneity between studies ( I 2 = 0%, P = 0.429); the high-dose group was 1.06 (95% CI, 0.82–1.38), with no significant heterogeneity between studies ( I 2 = 0%, P = 0.542).

Possible association between maternal FA supplementation and CHD. FA: folic acid; CHD: congenital heart disease; A. Odd ratio (OR) estimates for the overall association of maternal FA supplementation with the risk of CHD; B. OR estimates for the association between maternal FA supplement intake and CHD; C. OR estimates for the association between the initiation of FA supplementation on CHDs; D. Estimated OR of the association between FA supplementation time and CHD

As presented in Fig. 2 C, the meta-analysis showed that the initiation of FA supplementation within 1 month before conception and 1 month after conception was associated with an increased risk of CHD, the ORs of any heart defect in offspring was 1.10 (95% CI, 0.99–1.23), 1.08 (95% CI, 0.95–1.24), compared with the reference group with no FA intake. Only 4 studies assessed the effects of time of pregnant women FA exposure on CHD [ 19 , 22 , 31 , 34 ]. With above studies, 2 studies evaluated initiation of any FA intake within one month before or after pregnancy [ 19 , 22 ], one month after pregnancy, the remained 2 studies evaluated the effect of maternal FA supplementation on CHD by the length of time [ 31 , 34 ]. The association between the duration of maternal FA supplementation and CHD occurrence is summarized in Table 2 . Data from the meta-analysis demonstrated that the association between short-term FA supplementation after pregnancy was weakest. The OR of any heart defect in offspring was 0.79 (95% CI, 0.42–1.47) compared with the reference group with no FA intake (Fig. 2 D).

Maternal FA supplementation and ASD

As seen in Fig. 3 , there was the association between maternal FA supplementation and the risk of ASD in this study. The overall results of this meta-analysis showed a decreased in the risk of ASD (or septal defect) with maternal FA supplementation (OR 0.83, 95% CI: 0.72–0.96; Fig. 3 A). The summary OR for ASD (or septal defect) of low dose intake compared with middle dose intake was 1.46 (95% CI, 0.86–2.48); the high-dose group was 1.23 (95% CI, 0.64–2.34), with no heterogeneity (Fig. 3 B). FA dosage information included in these studies is summarized and represented in Table 1 .

Possible association between maternal FA supplementation and ASD. FA: folic acid; ASD: atrial septal defects; A. Odd ratio (OR) estimates for the overall association of maternal FA supplementation with the risk of ASD; B. OR estimates for the association between Maternal folic acid supplement intake and ASD; C. OR estimates for the association between the initiation of folic acid supplementation on ASD; D. Estimated OR of the association between folic acid supplementation time and ASD

The initiation of FA supplementation was represented by three variables: within 1 month before pregnancy, within 1 month after pregnancy, after 1 month of pregnancy, the ORs of ASD in offspring was 1.09 (95% CI, 0.94–1.27), 1.11 (95% CI, 1.02–1.22), 1.02 (95% CI, 0.86–1.21) compared with the reference group with no FA intake (Fig. 3 C). The initiation of FA supplementation within 1 month after conception was associated with an increased OR for ASD. Data from the meta-analysis demonstrated that the association between short-term FA supplementation after pregnancy was weakest. The OR of ASD in offspring was 0.66 (95% CI, 0.41–1.07) compared with the reference group with no FA intake (Fig. 3 D). The association between the duration of maternal FA supplementation and CHD occurrence is summarized in Table 2 .

Heterogeneity analysis

Although our meta-analysis showed that maternal FA supplementation reduced the risk of CHD and ASD (or septal defect), we found that the heterogeneity of studies for possible association between FA supplementation and CHD was significant ( P < 0.001, I 2 = 92.7%), with no publication bias (Begg’s test: P = 0.211; Fig. 4 A). Furthermore, a significant heterogeneity of studies for possible association between FA supplementation and ASD was also detected ( P < 0.001, I 2 = 86.5%), with no publication bias (Begg’s test: P = 0.621; Fig. 4 B).

Begg’s test for possible association between FA supplementation and CHD/ASD. FA: folic acid; CHD: congenital heart disease; ASD: atrial septal defects; A. Begg's test of studies examining the association between maternal folate supplementation and the risk of CHD; B. Begg's test of studies examining the association between maternal folate supplementation and the risk of ASD

To clarify the sources of heterogeneity, we conducted a sensitivity analysis. However, I 2 did not decrease substantially when any individual study was removed. Subsequently, a subgroup analysis was carried out on the studies of CHD and maternal FA supplementation. In the subgroup analyses, the corresponding pooled OR was not materially altered in any stratification (Please see Supplemental Figs. 2 and 3 , Table 3 ). However, the results of the meta-analysis have changed in different regions, different designs. Studies in Europe/Australia showed that there was no statistical difference between FA supplementation and the incidence of CHD (OR 0.96, 95%CI 0.84–1.09), and the cohort study/RCT study showed that there was no statistical difference between FA supplementation and the incidence of CHD (OR 0.94, 95%CI 0.84–1.05) but there is still significant heterogeneity between studies. We also found that the differences in age, maternal smoking, family history may contribute to the heterogeneity.

Table 4 represents the subgroup analyses of studies examining the association between maternal FA supplementation and the risk of ASD (or septal defect) in offspring. We found that differences in the geographical region, design, age, Maternal smoking, family history may contribute to the heterogeneity we observed. In subgroup analyses, the corresponding pooled ORs for studies of “Cohort or RCT”, “America”, “Before 2010” were 1.010, 1.008, 1.200, and were materially altered (Table 4 and see Supplemental Figs. 4 and 5 ). Design of the studies may change the results of association between maternal FA supplementation and ASD. However, RCT is believed to yield the highest level of evidence for causality because of no recall bias and other advantages. Moreover, the prevalence of ASD was shown an upward trend since 2009 [ 6 ]. Therefore, the effect of maternal FA supplementation to prevent ASD may be still under question.

We have conducted a meta-analysis of the recent 21 studies concerning maternal FA supplementation and CHD. Although the data from our analysis implicate that maternal FA supplementation is associated with the reduced risk of CHD, the heterogeneity of this association is high. First, the association is presented to be geographically different. The reports from China suggest that FA supplementation is associated with the decreased incidence of CHD [ 31 , 32 , 33 , 34 ], while the studies in Europe and Australia demonstrate that the association was not statistically significant [ 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 37 ]. Second, the designs of these studies are related with the different results. The case–control studies implicate that FA supplementation reduced the incidence of CHD, but the cohort/RCT studies indicate no significant association [ 22 , 29 , 30 , 34 , 35 , 36 ]. There could be several explanations for the high heterogeneity. First, the baseline FA levels among fertile women in the developing regions or countries are lower. Second, the case–control studies are observational and may not provide the evidence as cohort study/RCT at the same levels [ 38 ] because the case–control study may be confounded by the factors, including age, maternal smoking, maternal alcohol, maternal BMI fetal sex, and family history. Indeed, confounding is always an issue when assessing the association of a single environmental factor with a complex outcome like CHD, particularly, the incidence of CHD is low [ 6 ]. Third, the dosage of FA could be one more issue for these conflicting results.

According to clinical phenotypes, ASD is classified as one of subtypes of CHD [ 39 ]. In the current study, we found that the summary OR of ASD at the high-dose group of FA intake was increased by nearly 20% compared with what at the middle dose group. It is interesting that we found a positive association between FA supplementation within 1 month before and after pregnancy and CHD, and high-dose FA intake is positively associated with ASD. FA supplementation may have a negative effect on heart development in high doses or specific time windows, the precise biological mechanisms of FA on heart development remain to be elucidated [ 40 ]. At present, little is known about the effects of dosage of FA supplementation on infant birth outcome. However, several studies have reported the association between the dosage of FA supplements and adverse pregnancy outcomes. A cohort reported that FA supplement use ≥ 800 µg/day during pregnancy was related to elevated gestational diabetes mellitus risk [ 41 ]. In addition, the use of high-dose (≥ 800 µg/d) FA supplements is associated with an increased risk of gestational hypertension [ 42 ], FA also affect fetal cardiovascular system [ 43 ].

In epidemiological studies, there are many factors that may affect the analysis of the results and the results of the analysis. Differences in methods used for studies are probably the most common factor contributing to heterogeneity. Some scholars have proposed that the addition of multivitamins containing folic acid may improve the effect of primary prevention of CHD compared with the use of FA alone [ 44 ]. To exclude interfering factors, in the current study, we not only analyzed taking FA alone and taking multivitamins containing FA, but also excluded the content of FA in multivitamins below 0.4 mg from the analysis. By using zebrafish, an experimental study has demonstrated that maternal micronutrient and homocysteine status are associated with the risk of CHD in offspring [ 45 ]. Furthermore, FA and other micronutrient deficiencies can lead to accumulation of homocysteine and mitotic dysfunction [ 45 , 46 ]. In China, after the implementation of public health policies to increase FA intake in women, population statistics should theoretically support the preventive effect of FA intake during pregnancy on CHD, but the results are not consistent with expectations [ 11 ]. This problem cannot be fully explained, as more than 90% of women take supplements [ 47 ]. Therefore, through the analysis progress of this study, we believe that due to the different methods of taking FA to avoid the generation of heterogeneity, it may be more important to strengthen the within-group comparison than the between-group comparison in the analysis method and process.

Several studies have demonstrated that the continued FA supplementation after pregnancy may increase the risk of large-for-gestational-age birth [ 48 ], childhood asthma [ 49 ], childhood allergic [ 50 ], negative neurodevelopmental outcomes [ 51 , 52 ]. Thereby, we have an assumption that FA supplementation may not negatively but positively be associated with the risk of CHDs was consistent with the trend of CHD epidemic. Further research should be done on the reasonable time and dosage of FA intake and the mechanism of adverse pregnancy caused by excessive supplementation.

Data from the current meta-analysis suggest that although the maternal FA supplementation seems associated with a decreased risk of CHD, the heterogeneity of this association is significantly high. The heterogeneity may be caused by the confounders such as timing and dose of FA administration, and the heterogeneity may subsequently influence the outcome on actual effect of FA supplementation on CHD. On this basis, we believe it is necessary to correctly assess the association of FA supplementation with CHD. Further experiments designed to study the association between FA and CHD and its molecular mechanisms have been taken into consideration.

Availability of data and materials

All the data in this study were available in the figures in the main text and supplemental documents of this manuscript.

Abbreviations

Atrial septal defect

Body mass index

Congenital heart disease

Neural tube defect

Tetrahydrofolate

Ventricular septal defect

Rasmussen LB, Andersen NL, Andersson G, Lange AP, Rasmussen K, et al. Folate and neural tube defects Recommendations from a Danish working group. Dan Med Bull. 1998;45(2):213–7.

CAS PubMed Google Scholar

Green NS. Folic acid supplementation and prevention of birth defects. J Nutr. 2002;132(Suppl 8):2356S-2360S.

Article CAS PubMed Google Scholar

Czeizel AE. Primary prevention of neural-tube defects and some other major congenital abnormalities: recommendations for the appropriate use of folic acid during pregnancy. Paediatr Drugs. 2000;2(6):437–49.

Nguyen MT, Hendrickx IM. Model studies on the stability of folic acid and 5-methyltetrahydrofolic acid degradation during thermal treatment in combination with high hydrostatic pressure. J Agric Food Chem. 2003;51(11):3352–7.

Ohrvik VE, Witthoft CM. Human folate bioavailability. Nutrients. 2011;3(4):475–90.

Article CAS PubMed PubMed Central Google Scholar

Liu Y, Chen S, Zühlke L, Black GC, Choy MK, Li N, et al. Global birth prevalence of congenital heart defects 1970–2017: updated systematic review and meta-analysis of 260 studies. Int J Epidemiol. 2019;48(2):455–63.

Article PubMed PubMed Central Google Scholar

van der Linde D, Konings EE, Slager MA, Witsenburg M, Helbing WA, et al. Birth prevalence of congenital heart disease worldwide: a systematic review and meta-analysis. J Am Coll Cardiol. 2011;58(21):2241–7.

Article PubMed Google Scholar

Berry RJ, Li Z, Erickson JD, Li S, Moore CA, et al. Prevention of neural-tube defects with folic acid in China. China-U.S. collaborative project for neural tube defect prevention. N Engl J Med. 1999;341(20):1485–90.

National Health Commission of the People's Republic of China. China Maternal and Child Health Development Report (2019) (I). Chinese Journal of Women and Children Health. 2019;10(5):1–8.

Ministry of Health of the People's Republic of China. China Birth Defect Prevention Report. 2012. http://www.gov.cn/gzdt/att/att/site1/20120912/1c6f6506c7f811bacf9301.pdf . accessed 13 August 2021.

Xu WL, Deng CF, Li WY, Wang K, Tao J, Gao YY, et al. National perinatal prevalence of selected major birth defects — China, 2010–2018. China CDC Wkly. 2020;2(37):711–7.

Article Google Scholar

Zhao L, Chen L, Yang T, Wang T, Zhang S, et al. Birth prevalence of congenital heart disease in China, 1980–2019: a systematic review and meta-analysis of 617 studies. Eur J Epidemiol. 2020;35(7):631–42.

Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA. 2000;283(15):2008–12.

Wells GA, Shea B, O'Connell D, Peterson J, Welch V, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomized studies in meta-analyses comparison. http://www.ohri.ca/programs/clinical_epidemiology /oxford.asp. accessed 13 August 2021.

Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315(7109):629–34.

Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics. 1994;50(4):1088–101.

Correa A, Gilboa SM, Botto LD, Moore CA, Hobbs CA, et al. Lack of periconceptional vitamins or supplements that contain folic acid and diabetes mellitus-associated birth defects. Am J Obstet Gynecol. 2012;206(3):218.e1-13.

Article CAS Google Scholar

Scanlon KS, Ferencz C, Loffredo CA, Wilson PD, Correa-Villaseñor A, et al. Preconceptional folate intake and malformations of the cardiac outflow tract. Baltim-Wash Infant Study Group Epidemiol. 1998;9(1):95–8.

CAS Google Scholar

Werler MM, Hayes C, Louik C, Shapiro S, Mitchell AA. Multivitamin supplementation and risk of birth defects. Am J Epidemiol. 1999;150(7):675–82.

Shaw GM, Carmichael SL, Yang W, Lammer EJ. Periconceptional nutrient intakes and risks of conotruncal heart defects. Birth Defects Res A Clin Mol Teratol. 2010;88(3):144–51.

CAS PubMed PubMed Central Google Scholar

Shaw GM, O’Malley CD, Wasserman CR, Tolarova MM, Lammer EJ. Maternal periconceptional use of multivitamins and reduced risk for conotruncal heart defects and limb deficiencies among offspring. Am J Med Genet. 1995;59(4):536–45.

Øyen N, Olsen SF, Basit S, Leirgul E, Strøm M, et al. Association between maternal folic acid supplementation and congenital heart defects in offspring in birth cohorts from Denmark and Norway. J Am Heart Assoc. 2019;8(6):e011615.

Csáky-Szunyogh M, Vereczkey A, Kósa Z, Urbán R, Czeizel AE. Association of maternal diseases during pregnancy with the risk of single ventricular septal defects in the offspring–a population-based case-control study. J Matern Fetal Neonatal Med. 2013;26(8):738–47.

Czeizel AE, Vereczkey A, Szabó I. Folic acid in pregnant women associated with reduced prevalence of severe congenital heart defects in their children: a national population-based case-control study. Eur J Obstet Gynecol Reprod Biol. 2015;193:34–9.

Leirgul E, Gildestad T, Nilsen RM, Fomina T, Brodwall K, et al. Periconceptional folic acid supplementation and infant risk of congenital heart defects in Norway 1999–2009. Paediatr Perinat Epidemiol. 2015;29(5):391–400.

Csáky-Szunyogh M, Vereczkey A, Urbán R, Czeizel AE. Risk and protective factors in the origin of atrial septal defect secundum–national population-based case-control study. Cent Eur J Public Health. 2014;22(1):42–7.

Csáky-Szunyogh M, Vereczkey A, Kósa Z, Gerencsér B, Czeizel AE. Risk and protective factors in the origin of conotruncal defects of heart–a population-based case-control study. Am J Med Genet A. 2013;161A(10):2444–52.

PubMed Google Scholar

van Beynum IM, Kapusta L, Bakker MK, den Heijer M, Blom HJ, de Walle HE. Protective effect of periconceptional folic acid supplements on the risk of congenital heart defects: a registry-based case-control study in the northern Netherlands. Eur Heart J. 2010;31(4):464–71.

Czeizel AE. Prevention of congenital abnormalities by periconceptional multivitamin supplementation. BMJ. 1993;306(6893):1645–8.

Czeizel AE, Dobó M, Vargha P. Hungarian cohort-controlled trial of periconceptional multivitamin supplementation shows a reduction in certain congenital abnormalities. Birth Defects Res A Clin Mol Teratol. 2004;70(11):853–61.

Li X, Li S, Mu D, Liu Z, Li Y, Lin Y, et al. The association between periconceptional folic acid supplementation and congenital heart defects: a case-control study in China. Prev Med. 2013;56(6):385–9.

Qu Y, Lin S, Zhuang J, Bloom MS, Smith M, et al. First-trimester maternal folic acid supplementation reduced risks of severe and most congenital heart diseases in offspring: a large case-control study. J Am Heart Assoc. 2020;9(13):e015652.

Feng Y, Cai J, Tong X, Chen R, Zhu Y, Xu B, Mo X. Non-inheritable risk factors during pregnancy for congenital heart defects in offspring: A matched case-control study. Int J Cardiol. 2018;264:45–52.

Mao B, Qiu J, Zhao N, Shao Y, Dai W, et al. Maternal folic acid supplementation and dietary folate intake and congenital heart defects. PLoS One. 2017;12(11):e0187996.

Liu S, Joseph KS, Luo W, León JA, Lisonkova S, et al. Effect of folic acid food fortification in Canada on congenital heart disease subtypes. Circulation. 2016;134(9):647–55.

Bedard T, Lowry RB, Sibbald B, Harder JR, Trevenen C, et al. Folic acid fortification and the birth prevalence of congenital heart defect cases in Alberta, Canada. Birth Defects Res A Clin Mol Teratol. 2013;97(8):564–70.

Bower C, Miller M, Payne J, Serna P. Folate intake and the primary prevention of non-neural birth defects. Aust N Z J Public Health. 2006;30(3):258–61.

Song JW, Chung KC. Observational studies: cohort and case-control studies. Plast Reconstr Surg. 2010;126(6):2234–42.

Bradley EA, Zaidi AN. Atrial septal defect. Cardiol Clin. 2020;38(3):317–24.

Han X, Wang B, Jin D, et al. Precise dose of folic acid supplementation is essential for embryonic heart development in Zebrafish. Biology (Basel). 2021;11(1):28.

Li Q, Zhang Y, Huang L, Zhong C, Chen R, et al. High-dose folic acid supplement use from prepregnancy through midpregnancy is associated with increased risk of gestational diabetes mellitus: a prospective cohort study. Diabetes Care. 2019;42(7):e113–5.

Li Q, Xu S, Chen X, Zhang X, Li X, et al. Folic acid supplement use and increased risk of gestational hypertension. Hypertension. 2020;76(1):150–6.

Sinclair KD, Allegrucci C, Singh R, Gardner DS, Sebastian S, et al. DNA methylation, insulin resistance, and blood pressure in offspring determined by maternal periconceptional B vitamin and methionine status. Proc Natl Acad Sci U S A. 2007;104(49):19351–6.

Czeizel AE, Bánhidy F. Vitamin supply in pregnancy for prevention of congenital birth defects. Curr Opin Clin Nutr Metab Care. 2011;14(3):291–6.

Elizabeth KE, Praveen SL, Preethi NR, Jissa VT, Pillai MR. Folate, vitamin B12, homocysteine and polymorphisms in folate metabolizing genes in children with congenital heart disease and their mothers. Eur J Clin Nutr. 2017;71(12):1437–41.

Tang LS, Wlodarczyk BJ, Santillano DR, Miranda RC, Finnell RH. Developmental consequences of abnormal folate transport during murine heart morphogenesis. Birth Defects Res A Clin Mol Teratol. 2004;70(7):449–58.

Zhang X, Liu J, Jin Y, et al. Folate of pregnant women after a nationwide folic acid supplementation in China. Matern Child Nutr. 2019;15(4):e12828.

Wang S, Ge X, Zhu B, Xuan Y, Huang K, et al. Maternal continuing folic acid supplementation after the first trimester of pregnancy increased the risk of large-for-gestational-age birth: a population-based birth cohort study. Nutrients. 2016;8(8):493.

Article PubMed Central Google Scholar

Brown SB, Reeves KW, Bertone-Johnson ER. Maternal folate exposure in pregnancy and childhood asthma and allergy: a systematic review. Nutr Rev. 2014;72(1):55–64.

Chen Z, Xing Y, Yu X, Dou Y, Ma D. Effect of folic acid intake on infant and child allergic diseases: systematic review and meta-analysis. Front Pediatr. 2021;8:615406.

DeSoto MC, Hitlan RT. Synthetic folic acid supplementation during pregnancy may increase the risk of developing autism. J Pediatr Biochem. 2012;2:251–61.

Raghavan R, Riley AW, Volk H, Caruso D, Hironaka L, et al. Maternal multivitamin intake, plasma folate and vitamin B12 levels and autism spectrum disorder risk in offspring. Paediatr Perinat Epidemiol. 2018;32(1):100–11.

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Acknowledgements

We wish to thank Ms. Lili Qiu for scientific discussion.

The research grants from China Pharmaceutical University (CPU-180815 HFG).

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Rui Gu and Zhengpei Cheng: Literature study, data analysis and manuscript preparation; Zenglin Lian: Data interpretation and scientific discussion; Harvest F. Gu: Study concept and manuscript revision. All authors agreed and approved the final version of manuscript.

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Zhengpei Cheng is a graduate student in China Pharmaceutical University and University of Strathclyde. Rui Gu hold the degree of Master of Sciences, Zenglin Lian is a professor in Beijing Yichuang Institute of Biotechnology Industry. Harvest F. Gu used to be a senior researcher in Department of Molecular Medicine, Karolinska Institutet, Sweden, and is presently a Professor in China Pharmaceutical University.

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Cheng, Z., Gu, R., Lian, Z. et al. Evaluation of the association between maternal folic acid supplementation and the risk of congenital heart disease: a systematic review and meta-analysis. Nutr J 21 , 20 (2022). https://doi.org/10.1186/s12937-022-00772-2

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