Motherisk Int J 2020;1;25
Gideon Koren MD FRCPC FACMT(1,2), Asher Ornoy MD(1,3)
Adelson School of Medicine, Ariel University (1)
Motherisk International program (2),
Hebrew University Hadassah Medical School, Jerusalem
Over the last 40 years a large body of research has examined potential correlations between neural tube defects (NTD) after maternal drug exposure during pregnancy. Quite a small group of initial signals have survived the scrutiny of collection of convincing evidence of causality. This systematic review will focus on these medications. Exposure to the following drugs has convincing epidemiological evidence of risk for NTD: Valproic acid, carbamazepine, dulotegravil, and folic acid antagonists. For dydrogesterone and codeine there is convincing preliminary evidence that will need to be confirmed by additional studies. It is essential to inform women about such risks before conception. When such exposures have taken place due to unplanned pregnancy, it is critical to rule out NTD by ultrasound and maternal serum alpha fetoproteins.
Neural tube defects (NTD) are a class of congenital malformations characterized by failure of the neural tube to close during embryogenesis. The neural tube (NT), a precursor for the central and peripheral nervous systems as well as neural crest cells and derivatives (1,2) is typically fully developed by day 28 post-conception (1,2). The closure of the anterior neuropore at the cranial part of the NT occurs by day 25 and of the posterior neuropore in the caudal part on day 27 ( 1- Moore 2016). The main forms of NTD are spina bifida, characterized by incomplete closure at the caudal end, anencephaly, by incomplete closure at the cranial end, as well as less common forms of craniorachischisis, encephalocele and iniecephaly (Figure 1).
Children born with NTD may exhibit a wide range of disabilities, from early death (with anencephaly), open spinal sac (in spina bifida) and permanent neurological damage, with a range of severity of physical disability and paralysis, reduced IQ and impaired psychological development (3). They may also have a variety of additional CNS malformations and neurological complications (Gilbert et al, 1986). Mean direct lifetime cost per infant with spina bifida is estimated to be around $791,900 (4).
Presently, NTDs are the second most prevalent major congenital malformations after cardiovascular anomalies (5-6), affecting over 300,000 births each year worldwide. For example, spina bifida affects approximately 1,500 births annually in the United States, or about 3.5 in every 10,000 (0.035% of US births ). Following the discovery of folic acid prevention of NTD and the implementation of flour fortification and food supplementation, the prevalence of NTD has steadily decreased in countries that adhere to directives for fortification and supplementation. As an example, in Canada, following fortification of grain products with folic acid, the prevalence rates of NTD fell by half from 1.58 per 1000 births to 0.86 per 1000 (7).
It has been estimated that up to 70% of NTD are preventable by adequate pre-conceptional supplementation of folic acid; hence folic acid deficiency is by far the most identifiable cause of NTD. There is ample evidence that overweight and obesity, both of which are detected in increasing prevalence in developed countries, more than double the risk of NTD. Over a hundred candidate genes have been examined for risk association to human NTD, including those regulating folate metabolism. Yet, today, very few studies have identified candidate genes that confer even a minor effect on NTD risk (8).
Over the last 40 years a large body of research has examined potential associations between NTD and drug use during pregnancy. Quite a small group of initial signals have survived the scrutiny of collection of convincing evidence of causality. This review will focus on these medications. Because this review aims at prescription drugs, we did not include here evidence on maternal and environmental factors that have been associated with NTD, such as overweight and obesity, diabetes mellitus and hyperthermia.
We conducted a systematic review of all studies of drugs associated with NTD by searching Medline, EMBASE, Cochrane, Google and Google Scholar from inception to September 30, 2020 in any language. In these papers we evaluated the existence of significant associations between a medication and occurrence of NTD. We did not attempt to lump different papers examining a certain association into a meta-analysis.
During pregnancy maternal folate requirements increase by 5-10 fold, as folate is diverted towards the placenta and fetus, as well as supporting different maternal organs. Correspondingly, low maternal folate status has been associated with birth defects in fetal anatomical regions particularly sensitive to reduced folate intake including oral cleft, cardiovascular anomalies and NTD. Evidence accumulating since the 1960s has established that folate deficiency is associated with tangible risk for NTD, leading to directives for folic acid food fortification and supplementation in most countries worldwide (9).
In 1995, Daly et al (10) established the correlation between serum and RBC folate levels and the risk of NTD, and these have become the compass for dose recommendations. In general, serum folate levels >15.9 nmol/L and RBC levels above 906 nmol/L guarantee highest protection against NTD, whereas serum levels between 0-4.4 nmol/L are associated with 4 fold higher risk. Folic acid fortification of grain products has rapidly proven to be a successful public health initiative in increasing numbers of countries (7).
Specific medications associated with NTD:
The antiepileptic drug valproic acid (VPA) is an established human teratogen causing spina bifida aperta. In 1982 Robert and Guibaud were first to report an association between the use of valproic acid during pregnancy by women with seizure disorders and the occurrence of spina bifida in their offspring (11).
Spina bifida aperta has been linked specifically to valproic acid (VPA) with an estimated risk of 1 to 2%. In a prospective cohort study of pregnant women with epilepsy receiving AEDs the prevalence of anomalies after exposure to any AED was 6.9%. For fetuses exposed to VPA, the prevalence was 9.4%, including six cases of spina bifida, two of whom in monozygotic twins. Spina bifida was associated with a significantly higher average daily dose of VPA as compared with pregnancies with normal outcome (1,640 ± 136 mg/d vs 941 ± 48 mg/d, p = 0.0001). No relation was observed between the occurrence of spina bifida and type of maternal seizure or epilepsy, family history of epilepsy or neural-tube defects, or medical history. These results suggested that when the use of VPA during pregnancy cannot be avoided, the teratogenic risk might be dose-dependent (12).
The same group further found that regardless of exposure group, the frequency of major malformations increased with the dose of VPA, being highest at doses ≥1,500 mg/d (24) (24.0% for monotherapy, 31.0% for VPA + LTG, and 19.2% for VPA + other AEDs (13).
A cumulative and conventional meta‐analyses of cohort studies to determine the time profiles of signal emergence of VPA‐associated congenital malformations (CMs) also defined risk estimates of each of the CMs. Fifty‐nine studies were identified and analysed showing that significant risk signals began to emerge over the last 10–20 years even before large‐scale studies were performed: neural tube defects (the significant risk signal emerged in 1992); genitourinary and musculoskeletal anomalies (2004); cleft lip and/or palate (2005); and congenital heart defects (2006). At present, the risks of VPA‐associated CMs are 2–7‐fold higher than other common antiepileptic drugs leading to a large consensus that VPA should not be used as a first‐line therapy in women of childbearing age unless it is the only option for the patient.(14)
In 2005 Vajda and colleagues studied the possible dose dependence of fetal malformations rate after exposure to sodium valproate by analyzing the Australian Registry of Antiepileptic Drugs in Pregnancy exposed to valproate and to other antiepileptic drugs. The fetal malformation rate was significantly higher in the 110 fetuses exposed to valproate alone (17.1%), than among the 297 fetuses exposed to the other antiepileptic drugs without valproate (2.4%). The malformation rate in those exposed to valproate increased with increasing maternal drug dosage (P<0.05). Valproate doses exceeding 1400 mg per day were associated with higher rates of malformations (15).
Mawer a et al collected data from sixty nine pregnancies in women referred to their clinic, analysed for drug- and dose-dependent differences in outcome. A positive association with major malformations was found for sodium valproate but not for carbamazepine. Severe adverse outcomes were found only in children exposed to sodium valproate at maternal doses above 1000 mg per day (16).
These results were partially corroborated by a recent large systematic review and meta- analysis of 31 studies (17). Children exposed to carbamazepine (CBZ), phenobarbital, phenytoin, topiramate and valproic acid were all found to be at a higher risk of malformations when compared to children born to women without epilepsy. There was no increased risk of major malformation for lamotrigine. gabapentin, levetiracetam, oxcarbazepine, primidone. Children exposed to VPA had the greatest risk of malformation (10.9%, 95% CI 8.9 to 13.1). The analysis detected significantly higher rates of specific malformations associating VPA exposure with neural tube, cardiac, orofacial/craniofacial, skeletal and limb malformations in comparison to other AEDs. While dose of exposure mediated the risk of malformations following VPA exposure, a potential dose-response association for the other AEDs remained less clear.(17).
It is interesting to note that VPA has similar teratogenic effects in rodents. However, in mice and rats, VPA does not cause spina bifida but would generally induce a high rate of exencephaly (Nau H et al, 1994).
Strengthening the existence of dose –response teratogenic relationship for valproic acid, a prospective study followed the outcome of 154 valproate-exposed pregnancies in the first trimester, as compared to 1315 pregnancies of control women (18). The rate of major anomalies after valproate exposure was higher compared with controls [6.7% vs 2.5%], yielding a relative risk RR of 2.7. A daily dose > or =1000 mg was associated with the highest teratogenic risk [(21.9% vs 2.5%), RR = 8.7].
In Southern India, the Kerala Registry of Epilepsy and Pregnancy prospectively evaluated women with epilepsy. There were 1,688 fetuses resulting in 1,622 live births. Valproate monotherapy had a dose-dependent relative risk for major malformations of 2.6 (95% CI 1.30-5.20) compared to the external control group (19).
The above studies are important in setting a clear teratogenic threshold for the drug, which has important clinical implications, both in counseling women who ultimately need the drug, as well as for those who were exposed before recognizing they had conceived, and who may consider, once malformations were detected, pregnancy termination.
In a similar manner, the adverse neurodevelopmental effects of VPA were also shown to be dose- dependent. The UK (Manchester) group published studies showing a threshold, with very few adverse neurobehavioral problems when daily doses were below 900 mg/day (20).
Shortly after Robert and Guibaud reported an association between the use of valproic acid during pregnancy by women with seizure disorders and the occurrence of spina bifida in their offspring, (11), carbamazepine was also implicated, on the basis of 12 cases of spina bifida among 60 infants with birth defects after exposure to carbamazepine in utero(21-22). Jones et al. reported the outcomes of pregnancy in a cohort of 56 women taking carbamazepine, (23) including a case of spina bifida. As of 1990, the Food and Drug Administration had reports of 64 cases of spina bifida associated with maternal exposure to carbamazepine, of which 36 were not confounded by concurrent exposure to valproic acid. These were among a total of 237 reports known to the FDA of infants with spina bifida whose mothers took antiepileptic agents during pregnancy. The reports included both domestic and foreign isolated case reports, cases compiled by birth-defect registries, and cohort studies of women taking antiepileptic agents during pregnancy.
In 1990 Frans Rosa first substantiated the relationship between carbamazepine and NTD (24). He tallied only studies that included women taking carbamazepine during pregnancy. When Rosa pooled the data from all the studies available to him ,there were 9 cases of spina bifida among a total of 984 exposures in utero to carbamazepine but not to valproic acid provide a relative risk of about 13.7 (95 percent confidence limits, 5.6 and 33.7) times the expected rate (approximately 1 in 1500 births).
A key question is whether the association of a birth defect is with the agent itself or confounded by the indication (i.e. epilepsy). In contrast to the risk associated with exposure to valproic acid or carbamazepine, there was only a borderline risk of spina bifida after exposure in utero to antiepileptic agents other than valproic acid or carbamazepine
The EURAP epilepsy pregnancy registry is an observational cohort representing a collaboration of physicians from 42 countries. The group prospectively monitored pregnancies exposed to monotherapy with four common antiepileptic drugs: carbamazepine (n=1402), lamotrigine (n=1280), valproic acid (n=1010) and phenobarbital (n=217). A dose - dependent increase in malformation rates was detected for all four drugs (5). The lowest rates of malformations were observed with less than 300 mg per day lamotrigine and less than 400 mg daily carbamazepine. The risk of malformations was significantly higher for valproic acid and phenobarbital at all investigated doses, and with carbamazepine at doses greater than 400 mg per day. However, similar to all other studies, the doses were not standardized for maternal body weight (25).
In a meta-analysis by Matalon et al (2002) that included 1255 prospective cases of carbamazepine therapy in the first trimester of pregnancy, a dose related increased rate of malformations was observed. The most common anomalies were NTD, cardiovascular and urinary tract anomalies, as well as cleft palate. The concomitant treatment with other antiepileptic drugs increased the rate of these malformations, especially if VPA was one of the additional drugs.
Folic acid in preventing AED- induced malformations
Although there are no interventional studies to show the potential preventative effects of folic acid on AED- induced malformations, including NTD, the beneficial effects of folic acid supplementation on neurodevelopmental outcomes among the children of women using AEDs were shown in several observational studies (26-29). For example, Husebye and colleagues have shown an apparent protective effect of folic acid on neurodevelopment when supplementation takes place during the first 4 months of pregnancy (27). However, the protective effect is probably small. It is important to acknowledge that there are also studies showing no such associations
In recent years preliminary safety signal for neural-tube defects were reported in association with the HIV drug dolutegravir taken from the time of conception. A comprehensive birth-outcomes surveillance at 18 hospitals throughout Botswana has allowed more accurate estimates (30). Trained midwives performed surface examinations of all live-born and stillborn infants, andresearch assistants photographed abnormalities.
From August 2014 through March 2019, surveillance captured 119,477 deliveries; 119,033 (99.6%) had an infant surface examination that could be evaluated, and 98 NTD were identified (0.08% of deliveries). The prevalence of neural-tube defects was higher in association with dolutegravir treatment at conception than with non-dolutegravir ART at conception (difference, 0.20 percentage points; 95% confidence interval [CI], 0.01 to 0.59) or with other types of ART exposure. Major external structural defects were found in 0.95% of deliveries among women exposed to dolutegravir at conception and 0.68% of those among women exposed to non-dolutegravir ART at conception (difference, 0.27 percentage points ; 95% CI, −0.13 to 0.87). In this study, the prevalence of NTD was higher (3/1000 vs 1/1000) in association with dolutegravir exposure at conception than with other types of ART exposure at conception (3 per 1000 deliveries vs. 1 per 1000 deliveries). Presently, despite higher risk for neural tube defects when dolutegravir is used at conception, this integrase inhibitor remains a first-line antiretroviral therapy (31). No other studies corroborated these findings.
Dydrogesterone (DYD) is a widely used progestin indicated for threatened and repeated miscarriages, as well as for numerous other obstetric and gynecological indications, including luteal insufficiency, dysmenorrhea, premenstrual syndrome, to mention a few (32). Since its introduction in 1961, the drug has been used worldwide, with repeated studies documenting efficacy equivalent to micronized vaginal progesterone (33-35). While the drug has been shown to have mostly mild adverse maternal effects, its' fetal safety has been only sparsely investigated.
The introduction of the oral contraceptive pills in the 1960' has led to concerns regarding sexual changes in the male fetus. However numerous studies and several meta- analyses have confirmed the safety of the "pill" (36-37). In contrast, no similar investigations had followed the introduction of DYD. DYD has been shown to be substantially more potent than other progestins, due to configuration at C9 and C10, and the enhanced rigidity due to the C6-C7 double bond (38). Hence one cannot extrapolate from the fetal safety of the oral contraceptive pill to DYD.
In August 2017, following removal of DYD from the American market, a citizen petition asked the FDA to determine whether this removal was based on safety concerns. In its official response, the FDA determined that the withdrawal from sale of oral 5mg and 10 mg tablets of DYD, was not due to safety or effectiveness concerns (39). In its analysis the FDA declared that its' review has failed to show safety concerns. However, the almost total lack of fetal safety studies of DYD has raised questions about the validity of such determination (39).
It has been estimated that during the period from 1977 to 2005 around 38 million women were treated with DYD and that fetuses were exposed to the drug in utero in more than 10 million pregnancies. It is therefore surprising that till 2019 only very few studies, with a total sample size of less than 600 were reported with regards to fetal safety (40). The main reason is probably the clear tendency of fertility clinicians and scientists to use the success in inducing pregnancy as their primary endpoint, and consequently, in most studies, fetal outcome and birth defects have not been reported. In order to prove a twofold increase in overall major malformation rates, a study needs thousands of cases to maintain a power of 80% and alpha of 5% (41). In the meantime, the argument that DYD is probably safe because so many millions of pregnancies did not detect a fetal safety signal, is acutely false, because safety follow up studies have not been conducted.
A recent study investigated the fetal safety of DYD based on analysis of electronic health records of a large health maintenance organization (42). This cohort study included 8508 DYD- exposed cases and 738,583 controls calculated the OR for different congenital malformations. DYD exposure was associated with an increased risk of hypospadias, cryptorchidism, spina bifida, hydrocephalus, overall cardiovascular malformations and several specific cardiac malformations, including Tetralogy of Fallot, aortic insufficiency and pulmonary valve stenosis (Table).
The increased risk for spina bifida detected in this study is consistent with a large number of studies and meta- analyses showing that the use of oral contraceptives lead to reduction in blood folate concentrations, and hence may increase the risk for spina bifida (43). The study also detected increased risk of hydrocephalus without evidence of neural tube defects.
Several important methodological challenges must be considered when analyzing these results.
Because DYD is used to support women exhibiting subfertility, confounding by indication is a major challenge that needs to be addressed before one can relate increased fetal risks to DYD. In particular, the use of assisted reproductive technology (ART), including IVF, has been the focus of numerous recent studies and meta- analyses investigating fetal safety. Overall, there is a consensus that IVF/ICSI are associated with increased teratogenic risk (44-46). Even hypo-fertility without assisted reproduction has been shown to increase teratogenic risk (47). However, these are not the specific malformations detected in the 2020 Israeli study (42). In an attempt to further separate potential adverse fetal effects of DYD from those of IVF/ART, this study elected for their primary analysis to exclude pregnancies where the women were exposed concomitantly to DYD and/or ART, avoiding their potential additive effects (42). In a sensitivity analysis the study also calculated the fetal risk of the combined DYD plus ART cohort, showing a potential additive or synergistic adverse fetal effects, including cryptorchidism and congenital dislocation of the hip. Because these modalities are combined with DYD in 9% of women in our cohort, these additional teratogenic risks should also be considered in the overall risk-benefit assessment.
Importantly, the increased malformation rates described with sub-fertility are different from those found with DYD, which are biologically related to the effects of progestins. The 2020 study may suggest that DYD exhibits independent teratogenic effects that may have important implications for the child and family. Because the efficacy of DYD for threatened and repeated miscarriages appears to be equivalent to that of micronized vaginal progesterone (48), a careful risk - benefit assessment should be conducted to select the optimal choice. Till more studies are available, it may be wise to advise parents about these potential fetal effects. The risks of hypospadias and cryptorchidism have biological plausibility by the known effects on male genitalia, as is the risk for spina bifida, by the proven decrease in folic acid levels. Clinically, it may be reasonable for fertility experts to perform antenatal tests to rule out fetal cardiovascular effects and spina bifida, which can be visualized prenatally.
Opioids constitute a cornerstone of pain relief treatment. However, opioid safety during pregnancy has not been well established and some recent studies reported an association between in utero opioid exposure and spina bifida.
Fishman et al conducted a large historical cohort by linking four databases: medications dispensations, births, pregnancy terminations for medical reasons and infant hospitalizations during the years of 1999–2009 (49). Confounders that were controlled for included maternal age, ethnicity, maternal diabetes, smoking status, parity, obesity, year and folic acid intake. A secondary analysis for total major malformations and for spina bifida was performed using propensity score matching for first trimester exposure.
Of the 101,586 women included in the study, 3003 were dispensed opioids during the first trimester. Intrauterine exposure to opioids was not associated with an overall increase in major malformations (adjusted odds ratio (aOR) 0.97, 95% CI 0.83–1.13). However, the risk for spina bifida among newborns and abortuses who were exposed to codeine was four times higher than that of the unexposed (aOR = 4.42, 95% CI 1.60–12.23). This association remained significant in a secondary analysis using propensity score matching.
These findings suggest that opioids exposure (as a homogenous group) is not a significant risk factor for overall major malformations. Exposure to codeine during the first trimester was found to be associated with increased risk of spina bifida. However, this finding was based on a small number of cases and needs to be verified in future work.
A large number of medicinal drugs are folate antagonists which are dihydrofolate reductase inhibitors. These include trimethoprim, sulfasalazine and methotrexate, which block the conversion of folate to its more active metabolites, and other folic acid antagonists, which produce low serum and tissue concentrations of folate due to various pharmacokinetic mechanisms, and include mainly antiepileptics (carbamazepine, phenytoin, lamotrigine, primidone, valproic acid and phenobarbital), and cholestyramine . Folic acid supplementation or fortification in early pregnancy reduces the risk for neural tube defects and possibly other congenital malformations (10). This has led several groups to investigate whether folic acid antagonists increase teratogenic risk in humans. Over the last decade, several case–control studies have shown that intrauterine exposure to folic acid antagonists is associated with specific birth defects, including neural tube, cardiovascular and urinary tract malformations.
A study by Matok et al investigated the safety of folic acid antagonists during the first trimester of pregnancy in a large cohort(50).Computerized databases for medications dispensed from 1998 to 2007 to women registered in a large health fund, was linked with maternal and infant hospitalization records, and to therapeutic abortions data. The risk for adverse pregnancy outcomes of folic acid antagonist's exposure was assessed by adjusting for known confounders.
Eighty‐four thousand, eight hundred and twenty‐three infants were born and 998 therapeutic abortions took place; 571 fetuses and infants were exposed to one or more folic acid antagonists in the first trimester of pregnancy. Exposure was associated with an overall increased risk of congenital malformations [odds ratio (OR) 2.43, 95% confidence interval (CI) 1.92, 3.08], due mainly to increased risk for neural tube (adjusted OR 6.5, 95% CI 4.34, 9.15) and cardiovascular defects (OR 1.76, CI 1.05, 2.95). This study established that first‐trimester exposure to folic acid antagonists is associated with increased risk of neural tube defects.
It is essential to inform women about such risks for NTD before conception to consider alternative medications. If such exposures have taken place, it is critical to rule out NTD by detailed ultrasound and serum alpha fetoproteins. It is important to discuss the size of the risks with the family. Most families becoming aware of an unborn baby with NTD will consider termination of pregnancy. There is some evidence that favorable folic acid balance is associated with potential protective effects (e.g. with antiepileptic drugs). Women should be encouraged to increase folate intake, to optimize the effort to prevent NTD (51).
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Odds ratios (95% confidence interval) of selected congenital malformations in children exposed in utero to DYD, vs. an unexposed control group, after excluding those exposed also to IVF/ART, or when combined with those exposed to IVF/ART, and after adjusting for potential confounders
Dydrogesterone DYD+ IVF/ART
Hypospadias 1.28(1.06-1.55) 1.56(1.31-1.85)
Undescended testis/ 1.0 (0.85 -1.19) 1.37 (1.19-1.58)
Cong. Hip Dislocation 0.9 (0.78-1.04) 1.58(1.42-1.78)
Fallot Tetralogy 1.1 (0.72-1.33) 1.35 (0.5- 3.62)
VSD 1.02 (0.91- 1.32) 1.07 (0.86-1.34)
Renal Dysplasia 1.04(0.85-1.33) 2.16(1.22-3.82)
Cong. Pylorus 1.04(0.84-1.18) 1.25(0.86-1.82)
PDA 1.27(0.96-1.67) 1.51(1.17-1.95)
Cong. Aortic 1.65(1.008-2.71) 1.96 (1.25-3.1)
Pulm. Stenosis 0.95(0.81-1.48) 1.21(0.81-1.81)
Cong. Catarct 1.52(0.84-2.76 1.52(0.84-2.76)
Spina Bifida 2.29(1.32-3.97) 2.29(1.32-3.97)
Cong. Hydocephalus 1.75 (1.03-1.96) 2.04(1.28-3.25)
TGA* 2.03(0.75-5.4) 2.03(0.75-5.4)
Overall cardiovascular 1.18 (1.06-1.33) 1.31(1.12-1.42)
*Transposition of great arteries
Features of the neural tube and different neural tube defects. Adopted with permission from Botto et al, N Engl J Med 341:1509-19, 1999