The Antiretroviral Pregnancy Registry: Three decades of prospective monitoring for birth defects.

PURPOSE: Antiretrovirals (ARVs) are life-saving drugs used for the treatment and prevention of HIV infection and antiviral drugs (AVs) for the treatment of chronic HBV infection. ARVs have proven highly effective in reducing perinatal HIV transmission, however the risk of birth defects from prenatal exposure to ARVs/AVs is an ongoing concern. The Antiretroviral Pregnancy Registry (APR), an international, prospective exposure-registration cohort study, monitors ARV and AV use in pregnancy for early signals of teratogenicity. This communication reports results of 30-years' experience of ARV/AV exposure during pregnancy and lessons learned through continuous quality improvement. METHODS AND RESULTS: Birth defect prevalence is estimated and compared to internal and external groups. Statistical inference is based on exact methods for binomial proportions. Between 2006 and 2023, cumulative enrollment more than tripled from 6893 to 25 960 pregnancies and ARVs/AVs monitored increased from 29 to 222. Through January 2023, there were 21 636 live births and 631 outcomes with birth defects, for overall prevalence of 2.9/100 live births (95% CI 2.7, 3.2). The birth defect prevalence was 3.0% (95% CI 2.7%, 3.3%) among first trimester exposures and 2.8% (95% CI 2.5%, 3.2%) among second/third trimester exposures (prevalence ratio 1.04 [95% CI 0.89, 1.21]). CONCLUSIONS: Birth defect prevalence is not statistically significantly different between first trimester ARV/AV pregnancy exposures compared to second/third trimester exposures and is also not different from two population-based surveillance systems: 2.72/100 live births reported in the Metropolitan Atlanta Congenital Defects Program (MACDP); and 4.17/100 live births from the Texas Birth Defects Registry (TBDR).

Risk of Major Congenital Malformations and Exposure to Antiseizure Medication Monotherapy.

Importance: Women with epilepsy (WWE) require treatment with antiseizure medications (ASMs) during pregnancy, which may be associated with an increased risk of major congenital malformations (MCMs) in their offspring. Objective: To investigate the prevalence of MCMs after prenatal exposure to 8 commonly used ASM monotherapies and changes in MCM prevalence over time. Design, Setting, and Participants: This was a prospective, observational, longitudinal cohort study conducted from June 1999 to October 2022. Since 1999, physicians from more than 40 countries enrolled ASM-treated WWE before pregnancy outcome was known and followed up their offspring until 1 year after birth. Participants aged 14 to 55 years who were exposed to 8 of the most frequently used ASMs during pregnancy were included in this study. Data were analyzed from April to September 2023. Exposure: Maternal use of ASMs at conception. Main Outcomes and Measures: MCMs were assessed 1 year after birth by a committee blinded to type of exposure. Teratogenic outcomes across exposures were compared by random-effects logistic regression adjusting for potential confounders and prognostic factors. Results: A total of 10 121 prospective pregnancies exposed to ASM monotherapy met eligibility criteria. Of those, 9840 were exposed to the 8 most frequently used ASMs. The 9840 pregnancies occurred in 8483 women (mean [range] age, 30.1 [14.1-55.2] years). MCMs occurred in 153 of 1549 pregnancies for valproate (9.9%; 95% CI, 8.5%-11.5%), 9 of 142 for phenytoin (6.3%; 95% CI, 3.4%-11.6%), 21 of 338 for phenobarbital (6.2%; 95% CI, 4.1%-9.3%), 121 of 2255 for carbamazepine (5.4%; 95% CI, 4.5%-6.4%), 10 of 204 for topiramate (4.9%; 95% CI, 2.7%-8.8%), 110 of 3584 for lamotrigine (3.1%; 95% CI, 2.5%-3.7%), 13 of 443 for oxcarbazepine (2.9%; 95% CI, 1.7%-5.0%), and 33 of 1325 for levetiracetam (2.5%; 95% CI, 1.8%-3.5%). For valproate, phenobarbital, and carbamazepine, there was a significant increase in the prevalence of MCMs associated with increasing dose of the ASM. Overall prevalence of MCMs decreased from 6.1% (153 of 2505) during the period 1998 to 2004 to 3.7% (76 of 2054) during the period 2015 to 2022. This decrease over time was significant in univariable logistic analysis but not after adjustment for changes in ASM exposure pattern. Conclusions and Relevance: Of all ASMs with meaningful data, the lowest prevalence of MCMs was observed in offspring exposed to levetiracetam, oxcarbazepine, and lamotrigine. Prevalence of MCMs was higher with phenytoin, valproate, carbamazepine, and phenobarbital, and dose dependent for the latter 3 ASMs. The shift in exposure pattern over time with a declining exposure to valproate and carbamazepine and greater use of lamotrigine and levetiracetam was associated with a 39% decline in prevalence of MCMs, a finding that has major public health implications.

Risk of major birth defects after first-trimester exposure to carbocisteine and ambroxol: A multicenter prospective cohort study using counseling data for drug safety during pregnancy.

To assess the risk of major birth defects after first-trimester exposure to carbocisteine and ambroxol during pregnancy, we conducted a prospective cohort study using counseling data for drug use during pregnancy provided by the Japan Drug Information Institute in Pregnancy and Toranomon Hospital. Counseling information, including drug usage and participants' demographic information, was collected between April 1988 and December 2017. Pregnancy outcome data, including major birth defects, were obtained using a questionnaire administered 1 month after delivery. The risks of major birth defects after first-trimester exposure to carbocisteine (n = 588) and ambroxol (n = 341) were compared with those of nonteratogenic drug use during the first trimester (n = 1525). The adjusted odds ratio (aORs) for major birth defects was calculated using a multiple logistic regression analysis adjusted for confounders. The incidence of major birth defects was 1.2% (7/588) and 2.1% (7/341) in the carbocisteine and ambroxol groups, respectively, which was comparable to the control group (26/1525, 1.7%). Results of multiple logistic regression demonstrated similar nonsignificant risks for both carbocisteine (aOR: 0.66, 95% confidence interval [CI]: 0.40-1.1, p = 0.11) and ambroxol (aOR: 1.1, 95% CI: 0.18-7.2, p = 0.88). No specific major birth defects were reported in the carbocisteine or ambroxol groups. This study demonstrated that carbocisteine and ambroxol exposure during the first trimester was not associated with an increased risk of major birth defects. These results could help in counseling for the use of these drugs during pregnancy and further alleviate anxiety in patients.

Teratogenicity of zonisamide and other little-used antiseizure medications.

PURPOSE: To investigate the risk of teratogenesis occurring in relation to intrauterine exposure to infrequently used antiseizure medications in Australia. METHODS: Analysis of data contained in the Raoul Wallenberg Australian Pregnancy Register of Antiepileptic Drugs. RESULTS: There was statistically significant evidence that zonisamide, but not any other of nine infrequently used antiseizure medications in Australia, was associated with a risk of teratogenesis related to the maternal dose of the drug taken in at least the earlier half of pregnancy. CONCLUSIONS: The teratogenesis associated with zonisamide, like that associated with topiramate and possibly acetazolamide, may be an expression of a class effect shared among sulphonamide-derived carbonic anhydrase inhibitors that possess anti-seizure activity.

Lacosamide and pregnancy: Data from spontaneous and solicited reports.

OBJECTIVE: In pregnancy, it is important to balance the risks of uncontrolled epileptic seizures to the mother and fetus against the potential teratogenic effects of antiseizure medications. Data are limited on pregnancy outcomes among patients taking lacosamide (LCM), particularly when taken as monotherapy. The objective of this analysis was to evaluate the pregnancy outcomes of LCM-exposed pregnancies. METHODS: This analysis included all reports in the UCB Pharma pharmacovigilance database of exposure to LCM during pregnancy from spontaneous sources (routine clinical settings) or solicited reports from interventional clinical studies and noninterventional postmarketing studies. Prospective and retrospective reports were analyzed separately. RESULTS: At the data cutoff (August 31, 2021), there were 202 prospective pregnancy cases with maternal exposure to LCM and known outcomes. Among these cases, 44 (21.8%) patients received LCM monotherapy and 158 (78.2%) received LCM polytherapy. Most patients received LCM during the first trimester (LCM monotherapy: 39 [88.6%]; LCM polytherapy: 143 [90.5%]). From the prospective pregnancy cases with maternal LCM exposure, there were 204 reported outcomes (two twin pregnancies occurred in the polytherapy group). The proportion of live births was 84.1% (37/44) in patients who received LCM as monotherapy, and 76.3% (122/160) for LCM polytherapy. The overall proportion of abortions (for any reason) was 15.9% (7/44) with LCM monotherapy, and 22.5% (36/160) with LCM polytherapy. Congenital malformations were reported in 2.3% (1/44) of known pregnancy outcomes with maternal exposure to LCM monotherapy, and 6.9% (11/160) with polytherapy. SIGNIFICANCE: Our preliminary data do not raise major concerns on the use of LCM during pregnancy. Most pregnancies with LCM exposure resulted in healthy live births, and no new safety issues were identified. These findings should be interpreted with caution, as additional data are needed to fully evaluate the safety profile of LCM in pregnancy.

The teratogenesis risk associated with antiseizure medication duotherapy in women with epilepsy.

PURPOSE: To investigate rates of occurrence of pregnancies associated with a foetal malformation (FM pregnancy rates) following simultaneous intrauterine exposure to two antiseizure medications in 524 pregnancies in women with epilepsy from the Australian Pregnancy Register who were treated simultaneously with various combinations and dosages of two antiseizure medications (duotherapy). RESULTS: FM pregnancy rates tended to be higher in those exposed simultaneously to two antiseizure medications, each of which was a statistically significant teratogen (valproate, topiramate, or carbamazepine), than when there was exposure to only one such teratogen. When there was exposure to only one such teratogen together with clonazepam or levetiracetam, for neither of which there was statistically significant evidence of heightened teratogenicity, the FM pregnancy rates also tended to be higher, but less so. When lamotrigine was the other component of the duotherapy with an established teratogen, FM pregnancy rates tended to be lower than that for the teratogen used as monotherapy. CONCLUSION: Leaving aside issues in relation to seizure control, our data suggest that it would be best to avoid using established teratogenic antiseizure medications (carbamazepine, valproate and topiramate) in combination with each other due to the increased FM risks. When combining an established teratogenic medication with a less teratogenic one, i.e. lamotrigine, levetiracetam or clonazepam, lamotrigine appears to be the safer option.

Genetically proxied low-density lipoprotein cholesterol lowering via PCSK9-inhibitor drug targets and risk of congenital malformations.

AIMS: Current guidelines advise against the use of lipid-lowering drugs during pregnancy. This is based only on previous observational evidence demonstrating an association between statin use and congenital malformations, which is increasingly controversial. In the absence of clinical trial data, we aimed to use drug-target Mendelian randomization to model the potential impact of fetal LDL-lowering, overall and through PCSK9 drug targets, on congenital malformations. METHODS AND RESULTS: Instrumental variants influencing LDL levels overall and through PCSK9-inhibitor drug targets were extracted from genome-wide association study (GWAS) summary data for LDL on 1 320 016 individuals. Instrumental variants influencing circulating PCSK9 levels (pQTLs) and liver PCSK9 gene expression levels (eQTLs) were extracted, respectively, from a GWAS on 10 186 individuals and from the genotype-tissue expression project. Gene-outcome association data was extracted from the 7th release of GWAS summary data on the FinnGen cohort (n = 342 499) for eight categories of congenital malformations affecting multiple systems. Genetically proxied LDL-lowering through PCSK9 was associated with higher odds of malformations affecting multiple systems [OR 2.70, 95% confidence interval (CI) 1.30-5.63, P = 0.018], the skin (OR 2.23, 95% CI 1.33-3.75, P = 0.007), and the vertebral, anorectal, cardiovascular, tracheo-esophageal, renal, and limb association (VACTERL) (OR 1.51, 95% CI 1.16-1.96, P = 0.007). An association was also found with obstructive defects of the renal pelvis and ureter, but this association was suggestive of horizontal pleiotropy. Lower PCSK9 pQTLs were associated with the same congenital malformations. CONCLUSION: These data provide genetic evidence supporting current manufacturer advice to avoid the use of PCSK9 inhibitors during pregnancy.

Using genetic techniques to mimic the effects of PCSK9-inhibitors, a group of lipid-lowering medications, this study provides evidence to support recommendations to avoid the use of these medications in pregnancy due to potential risk of multiple malformations in the newborn.This study provides genetic evidence to support potential associations of PCSK9-inhibitor medications with newborn malformations affecting multiple organ systems, the skin, and a cluster of structural defects simultaneously affecting the spine, anus/rectum, heart, throat, kidneys, arms and legs.There was also weaker evidence of an association of PCSK9-inhibitor medications with newborn malformations resulting in blockages of the kidneys and urine system, though the evidence was less certain for these than for the other malformations.

Use of isotretinoin among girls and women of childbearing age and occurrence of isotretinoin-exposed pregnancies in Germany: A population-based study.

BACKGROUND: Exposure to isotretinoin during pregnancy must be avoided due to its teratogenicity, but real-world data on its use are scarce. We aimed to describe (i) isotretinoin use in women of childbearing age in Germany; (ii) the occurrence of isotretinoin-exposed pregnancies; and (iii) malformations among children exposed in utero. METHODS AND FINDINGS: Using observational data from the German Pharmacoepidemiological Research Database (GePaRD, claims data from approximately 20% of the German population), we conducted annual cross-sectional analyses to determine age-standardized prevalence of isotretinoin use between 2004 and 2019 among girls and women aged 13 to 49 years. In cohort analyses, we estimated the number of exposed pregnancies by assessing whether there was prescription supply overlapping the beginning of pregnancy (estimated supply was varied in sensitivity analyses) or a dispensation within the first 8 weeks of pregnancy. Data of live-born children classified as exposed in a critical period according to these criteria were reviewed to assess the presence of congenital malformations. The age-standardized prevalence of isotretinoin use per 1,000 girls and women increased from 1.20 (95% confidence interval [CI]: 1.16, 1.24) in 2004 to 1.96 (95% CI: 1.92, 2.01) in 2019. In the base case analysis, we identified 178 pregnancies exposed to isotretinoin, with the number per year doubling during the study period, and at least 45% of exposed pregnancies ended in an induced abortion. In sensitivity analyses, the number of exposed pregnancies ranged between 172 and 375. Among live-born children, 6 had major congenital malformations. The main limitation of this study was the lack of information on the prescribed dose, i.e., the supply had to be estimated based on the dispensed amount of isotretinoin. CONCLUSIONS: Isotretinoin use among girls and women of childbearing age increased in Germany between 2004 and 2019, and there was a considerable number of pregnancies likely exposed to isotretinoin in a critical period. This highlights the importance of monitoring compliance with the existing risk minimization measures for isotretinoin in Germany.

Face-to-face: isotretinoin use and pregnancy outcome.

Isotretinoin has been used to treat severe acne for more than 40 years. There are no accurate data on the absolute risk of potential teratogenicity to all fetuses exposed to isotretinoin. According to current guidelines, isotretinoin should be discontinued at least 1 month before pregnancy. This study enrolled pregnant women who contacted the Clinical Pharmacology and Toxicology Unit for individual drug risk assessment between 2016 and 2020. Data on maternal characteristics and isotretinoin exposures were obtained at first consultation. After delivery, follow-up calls were conducted using a structured questionnaire. Of 2,323 pregnant women consulted, 1.3% (31/2,323) had systemic isotretinoin exposure during and before pregnancy. Of 31 prospectively followed pregnancies, eight terminated electively. Most elective terminations (7/8) were performed because of the fear of fetal malformation. The majority of continued pregnancies (16/23) resulted in healthy live birth. There were no major birth defects. In six pregnancies, intrauterine deaths (three first trimester, three second trimester) were reported. Cesarean section was performed in 70.5% (12/17) of all deliveries. The median gestational age at birth was 39, and no preterm births were reported. Local isotretinoin treatments in six cases were evaluated and presented additionally, and all babies were born healthy. Based on the results of this study, there was no evidence of major birth defect, mental disorder, or retinoid embryopathy associated with the use of isotretinoin in pregnancy. Not local use, but systemic exposure to isotretinoin is of great concern that results in pregnancy termination.

Use of Acitretin Among Girls and Women of Childbearing Age and Occurrence of Acitretin-Exposed Pregnancies in Germany.

BACKGROUND AND OBJECTIVE: Acitretin has long-lasting teratogenic properties. Therefore, pregnancies must be avoided during and within 3 years after acitretin treatment. We aimed to describe (i) acitretin use in women of childbearing age in Germany, (ii) the occurrence of acitretin-exposed pregnancies, and (iii) malformations among children exposed in utero. METHODS: Using 2004-2019 data from the German Pharmacoepidemiological Research Database (GePaRD-claims data from ~ 20% of the German population), we determined annual age-standardized prevalence of acitretin use among girls and women aged 13-49 years. In longitudinal analyses, we estimated the number of exposed pregnancies by assessing whether the exposure window assigned to the last dispensation before pregnancy (days covered by dispensation plus 3 years) overlapped the onset of pregnancy or whether there was a dispensation in the first eight weeks of pregnancy. Data of live-born children with in utero exposure to acitretin were reviewed to assess the presence of congenital malformations. RESULTS: The age-standardized prevalence of acitretin use per 1000 girls and women was 0.04 in 2019. We identified 35 acitretin-exposed pregnancies; 94.3% of these pregnancies were classified as exposed because they occurred within 3 years after stopping acitretin treatment. Among 18 live-born children linked to their mother, four children (22.2%) had congenital malformations (three children with a major malformation). CONCLUSIONS: We observed 35 acitretin-exposed pregnancies mainly because treatment ended too late before pregnancy. Approximately one in five children born from these pregnancies had malformations, highlighting the importance of drawing more attention to the long-lasting teratogenicity of this drug.

A new perspective on isotretinoin in pregnancy: Pregnancy outcomes, evaluation of complex phenotypes, and importance of teratological counselling.

OBJECTIVES: Teratogens are responsible for 5% of all known causes of congenital anomalies. Isotretinoin, a retinoic acid-derived agent, leads to congenital anomalies in 21-52% of cases when exposure occurs during pregnancy according to studies conducted before 2006. However, rates of congenital anomalies were much lower in later studies. The purpose of this study was to investigate the rates of congenital anomalies in isotretinoin exposure during pregnancy, isotretinoin exposure before pregnancy, and a control group unexposed to any teratogenic agents. STUDY DESIGN: In this cohort study, we divided pregnant women admitted to our center between 2009 and 2020 into two groups: isotretinoin exposure before and during the pregnancy (n = 77) and isotretinoin exposure before the pregnancy (n = 75). We selected the control group from among the non-teratogen exposed pregnant women with a simple random sampling method. Obstetricians calculated the ages of all pregnancies via ultrasound (USG) (crown-rump diameter for the first trimester; biparietal diameter and femur length for the second trimester). After birth, a pediatric genetics specialist examined all babies. Whole-exome sequencing (WES) was conducted on the babies who displayed complex phenotypes. RESULTS: Among the isotretinoin exposure before and during the pregnancy, isotretinoin exposure before the pregnancy, and the control groups, there were statistically significant differences in live births (respectively, 64.3 %, 88 %, 93.3 %), congenital anomalies (respectively, 28.6 %, 6.1 %, 1.4 %), miscarriages (respectively, 13 %, 2.7 %, 4 %), terminations (respectively, 32.5 %, 9.3 %, 2.7 %), and premature births (11.9 %, 16.7 %, 2.9 %) (respectively, p < 0.001, p < 0.001, p = 0.014, p < 0.001). We detected novel phenotypical features in five patients. CONCLUSIONS: Our study demonstrated that study design, long-term follow-up, teratological counseling, and implementation of advanced molecular analysis in complex phenotypes with novel phenotypical features are beneficial for understanding the association of congenital anomalies with isotretinoin exposure. While evaluating congenital anomalies, we detected statistically significant differences between isotretinoin exposure before and during the pregnancy vs control, but we did not detect any statistically significant differences between isotretinoin exposure before the pregnancy and controls. Another finding of the study is that WES might be an efficient way to evaluate complex phenotypes in isotretinoin-exposed babies; however, further research is required.

Metformin Versus Insulin and Risk of Major Congenital Malformations in Pregnancies With Type 2 Diabetes: A Nordic Register-Based Cohort Study.

OBJECTIVE: To assess the risk of major congenital malformations with metformin versus insulin in pregnancies with type 2 diabetes. RESEARCH DESIGN AND METHODS: This cohort study used four Nordic countries' nationwide registers of live and stillborn infants exposed to metformin or insulin during first trimester organogenesis. Main exclusion criteria were type 1 diabetes, polycystic ovary syndrome, fertility treatment, and exposure to other diabetes drugs. Adjusted risk ratios (RRs) and 95% CIs were estimated for any and cardiac malformations. RESULTS: Of 3,734,125 infants in the source population, 25,956 were exposed to metformin or insulin in the first trimester, and 4,023 singleton infants were included. A malformation was diagnosed in 147 (4.7%) of 3,145 infants with exposure to any metformin (alone or in addition to insulin) and 50 (5.7%) of 878 infants with exposure to insulin alone (RR 0.84, 95% CI 0.46-1.54). Among 2,852 infants exposed to metformin alone and 293 infants exposed to metformin in addition to insulin 127 (4.4%) and 20 (6.8%), respectively, had a malformation. The adjusted risk was not increased for either metformin alone (0.83, 0.44-1.58) or both metformin and insulin (0.98, 0.56-1.69) versus insulin alone. Corresponding RRs for cardiac malformations were 1.01 (0.55-1.84) for any metformin, 0.92 (0.47-1.81) for metformin alone, and 1.72 (0.76-3.91) for both metformin and insulin. CONCLUSIONS: No evidence of an increased malformation risk with metformin versus insulin in the first trimester was found. Results should be interpreted with caution since information on glycemic control was missing.

Maternal traditional Chinese medicine exposure and risk of congenital malformations: a multicenter prospective cohort study.

INTRODUCTION: The potential teratogenic risk of traditional Chinese medicine (TCM) is of widespread concern; however, related evidence is largely absent in humans. This study aimed to compare the prevalence of congenital malformations between pregnant women with and without TCM exposure. MATERIAL AND METHODS: This was a multicenter prospective cohort study of 17 713 women who participated in a survey on periconceptional TCM exposure. Primary outcome was congenital malformations diagnosed from a survey conducted on the day 42 after delivery. RESULTS: A total of 16 751 pregnant women with 273 congenital malformations were included in the analysis. Fetuses exposed to TCM had an increased risk of congenital malformations compared to those without exposure (odds ratio [OR] 2.10; 95% confidence interval [CI] 1.09-4.02) after controlling for potential confounders. There were significant associations with congenital malformations in women with early pregnant exposure (OR 2.04, 95% CI 1.00-4.20) and for those who received ≥2 TCM formulas (OR 5.84, 95% CI 1.44-23.65). Pre-pregnancy TCM exposure was significantly associated with an increased risk of congenital heart defects (OR 12.69; 95% CI 3.01-53.51). CONCLUSIONS: Periconceptional TCM exposure is associated with an increased risk of congenital malformation. This effect was cumulative and sensitive to periconceptional age. Therefore, TCM deserves more attention and should be used cautiously for pregnant women and those trying to become pregnant.

Atomoxetine in Early Pregnancy and the Prevalence of Major Congenital Malformations: A Multinational Study.

Objective: Most research on safety of attention-deficit/hyperactivity disorder (ADHD) medications during pregnancy concerns central nervous system stimulants, while little is known about the safety of atomoxetine, a primary treatment alternative. We assessed the prevalence of major congenital malformations overall, and cardiac malformations and limb malformations specifically, after first-trimester exposure.Methods: In this cohort study, we included all approximately 2.4 million pregnancies ending in live births recorded in the population-based nationwide health registers of Denmark, Iceland, Norway, and Sweden (2003-2017) and approximately 1.8 million publicly insured pregnancies ending in live births recorded in the US Medicaid Analytic eXtract (MAX, 2001-2013) health care claims database. We compared the prevalence of major congenital malformations in the newborn among pregnancies exposed and unexposed to atomoxetine. For each country, we calculated prevalence ratios (PRs), crude and stratified by propensity scores (PSs). We pooled the country-specific PS strata to obtain a PR adjusted for potential confounding factors.Results: We identified 368 pregnancies exposed to atomoxetine during the first trimester in the 4 Nordic countries and 622 in the US. The pooled crude PR for any major congenital malformation was 1.18 (95% CI, 0.88-1.60), and the adjusted PR was 0.99 (95% CI, 0.74-1.34). For cardiac malformations, the adjusted PR was 1.34 (95% CI, 0.86-2.09). For limb malformations, the adjusted PR was 0.90 (95% CI, 0.38-2.16).Conclusions: After atomoxetine exposure in early pregnancy, we observed no increase in major congenital malformations overall and, although with some uncertainty due to sample size, no statistically increased risk estimates for cardiac malformations and limb malformations.

Association Between Proton Pump Inhibitor Use During Early Pregnancy and Risk of Congenital Malformations.

Importance: Proton pump inhibitors (PPIs) are increasingly used during pregnancy; however, several observational studies have raised concerns about an increased risk of specific types of congenital malformations. Objective: To examine the association between PPI exposure during early pregnancy and the risk of congenital malformations. Design, Setting, and Participants: This population-based cohort study used data from the National Health Insurance Service-National Health Information Database of South Korea (2010-2020); sibling-controlled analyses were conducted to account for familial factors. A total of 2 696 216 pregnancies in women aged 19 to 44 years between June 1, 2011, and December 31, 2019, and their live-born infants were identified. Pregnant women who were exposed to known teratogens or who delivered infants with chromosomal abnormalities or genetic syndromes were excluded. Data on participant race and ethnicity were not collected because the National Health Information Database does not report this information. Exposures: Proton pump inhibitor use during the first trimester. Main Outcomes and Measures: Primary outcomes were major congenital malformations, congenital heart defects, cleft palate, hydrocephalus, and hypospadias. The subtypes of major congenital malformations and congenital heart defects were evaluated as exploratory outcomes. Propensity score fine stratification was used to control for potential confounders, and a weighted generalized linear model was used to estimate relative risks with 95% CIs. Results: Of 2 696 216 pregnancies (mean [SD] maternal age, 32.1 [4.2] years), 40 540 (1.5%; mean [SD] age, 32.4 [4.6] years) were exposed to PPIs during the first trimester. The absolute risk of major congenital malformations was 396.7 per 10 000 infants in PPI-exposed pregnancies and 323.4 per 10 000 infants in unexposed pregnancies. The propensity score-adjusted relative risks were 1.07 (95% CI, 1.02-1.13) for major congenital malformations, 1.09 (95% CI, 1.01-1.17) for congenital heart defects, 1.02 (95% CI, 0.72-1.43) for cleft palate, 0.94 (95% CI, 0.54-1.63) for hydrocephalus, and 0.77 (95% CI, 0.51-1.17) for hypospadias. In the sibling-controlled analyses, no associations were observed between PPI use and primary outcomes, including major congenital malformations (odds ratio, 1.05; 95% CI, 0.91-1.22) and congenital heart defects (odds ratio, 1.07; 95% CI, 0.88-1.30). A range of sensitivity analyses revealed results that were similar to the main findings. Conclusions and Relevance: In this cohort study, the use of PPIs during early pregnancy was not associated with a substantial increase in the risk of congenital malformations, although small increased risks were observed for major congenital malformations and congenital heart defects; findings from sibling-controlled analyses revealed that PPIs were unlikely to be major teratogens. These findings may help guide clinicians and patients in decision-making about PPI use in the first trimester.