Prevalence Of Major Congenital Malformations Research Articles

Prevalence of fetal anomalies, stillbirth, neonatal morbidity, or mortality in pregnancies complicated by placenta accreta spectrum disorders.

Placenta accreta spectrum disorders (PAS) lead to major complications in pregnancy. While the maternal morbidity associated with PAS is well known, there is less information regarding neonatal morbidity in this setting. The aim of this study is to describe the neonatal outcomes (fetal malformations, neonatal morbidity, twin births, stillbirth, and neonatal death), using an international multicenter database of PAS cases. This was a prospective, multicenter cohort study based on prospectively collected cases, using the international multicenter database of the International Society for PAS, carried out between January 2020 and June 2022 by 23 centers with experience in PAS care. All PAS cases were included, regardless of whether singleton or multiple pregnancies and were managed in each center according to their own protocols. Data were collected via chart review. Local Ethical Committee approval and Data Use Agreements were obtained according to local policies. There were 315 pregnancies eligible for inclusion, with 12 twin pregnancies, comprising 329 fetuses/newborns; 2 cases were excluded due to inconsistency of data regarding fetal abnormalities. For the calculation of neonatal morbidity and mortality, all elective pregnancy terminations were excluded, hence 311 pregnancies with 323 newborns were analyzed. In our cohort, 3 neonates (0.93%) were stillborn; of the 320 newborns delivered, there were 10 cases (3.13%) of neonatal death. The prevalence of major congenital malformations was 4.64% (15/323 newborns), most commonly, cardiovascular, central nervous system, and gastrointestinal tract malformations. The overall prevalence of major neonatal morbidity in pregnancies complicated by PAS was 47/311 (15.1%). There were no stillbirths, neonatal deaths, or fetal malformations in reported twin gestations. Although some outcomes may be too rare to detect within our cohort and data should be interpreted with caution, our observational data supports reassuring neonatal outcomes for women with PAS.

Teratogenesis, Perinatal, and Neurodevelopmental Outcomes After In Utero Exposure to Antiseizure Medication: Practice Guideline From the AAN, AES, and SMFM.

This practice guideline provides updated evidence-based conclusions and recommendations regarding the effects of antiseizure medications (ASMs) and folic acid supplementation on the prevalence of major congenital malformations (MCMs), adverse perinatal outcomes, and neurodevelopmental outcomes in children born to people with epilepsy of childbearing potential (PWECP). A multidisciplinary panel conducted a systematic review and developed practice recommendations following the process outlined in the 2017 edition of the American Academy of Neurology Clinical Practice Guideline Process Manual. The systematic review includes studies through August 2022. Recommendations are supported by structured rationales that integrate evidence from the systematic review, related evidence, principles of care, and inferences from evidence. The following are some of the major recommendations. When treating PWECP, clinicians should recommend ASMs and doses that optimize both seizure control and fetal outcomes should pregnancy occur, at the earliest possible opportunity preconceptionally. Clinicians must minimize the occurrence of convulsive seizures in PWECP during pregnancy to minimize potential risks to the birth parent and to the fetus. Once a PWECP is already pregnant, clinicians should exercise caution in attempting to remove or replace an ASM that is effective in controlling generalized tonic-clonic or focal-to-bilateral tonic-clonic seizures. Clinicians must consider using lamotrigine, levetiracetam, or oxcarbazepine in PWECP when appropriate based on the patient's epilepsy syndrome, likelihood of achieving seizure control, and comorbidities, to minimize the risk of MCMs. Clinicians must avoid the use of valproic acid in PWECP to minimize the risk of MCMs or neural tube defects (NTDs), if clinically feasible. Clinicians should avoid the use of valproic acid or topiramate in PWECP to minimize the risk of offspring being born small for gestational age, if clinically feasible. To reduce the risk of poor neurodevelopmental outcomes, including autism spectrum disorder and lower IQ, in children born to PWECP, clinicians must avoid the use of valproic acid in PWECP, if clinically feasible. Clinicians should prescribe at least 0.4 mg of folic acid supplementation daily preconceptionally and during pregnancy to any PWECP treated with an ASM to decrease the risk of NTDs and possibly improve neurodevelopmental outcomes in the offspring.

Risks of congenital malformations and neonatal intensive care unit admissions with gabapentin use in pregnancy: A cohort study and scoping review with meta-analysis.

The increasing and prevalent use of gabapentin among pregnant people highlights the necessity to assess its neonatal safety. This study aimed to investigate the foetal safety of gabapentin during pregnancy using a cohort study and scoping review with a meta-analysis of published evidence. We conducted a population-based cohort study using the Manitoba health databases between 1995 and 2019. We examined the association between gabapentin use during pregnancy and the prevalence of major congenital malformations, cardiac and orofacial malformations, and neonatal intensive care unit (NICU) admissions using multivariate regression models. We searched the literature in MEDLINE and EMBASE databases from inception to October 2022 to identify relevant observational studies and conducted a meta-analysis using random-effects models, including our cohort study results. Of the 289,227 included pregnancies, 870 pregnant people were exposed to gabapentin. Gabapentin exposure during the First trimester was not associated with an increased risk of any malformations (adjusted relative risk [aRR]) 1.16 (95%confidence interval [CI] 0.92, 1.46), cardiac malformations (aRR 1.29, 95% CI 0.72, 2.29), orofacial malformations (aRR 1.37, 95% CI 0.50, 3.75), and major congenital malformations (aRR 1.00, 95% CI 0.73, 1.36). whereas exposure during any trimester was associated with an increased NICU admission risk (aRR, 1.99, 95% CI 1.70, 2.32). The meta-analysis of unadjusted results revealed an increased risk of major congenital malformations (RR 1.44, 95% CI 1.28, 1.61, I2 = 0%), cardiac malformations (RR1.66, 95% CI 1.11, 2.47, I2 = 68%), and NICU admissions (RR 3.15, 95% CI 2.90, 3.41, I2 = 10%), and increased trend of orofacial malformations (RR 1.98, 95%CI 0.79, 5.00, I2 = 0%). Gabapentin use was associated with an increased risk of NICU admissions in the cohort study and pooled meta-analysis. Clinicians should prescribe gabapentin with caution during pregnancy and further studies are warranted.

Prescribing in pregnant women with inflammatory bowel disease and its relationship to congenital malformations in Japan.

Inflammatory bowel disease (IBD) frequently affects younger patients and poses various challenges concerning pregnancy and childbirth. Maintaining good disease control throughout pregnancy is crucial, but expectant and pregnant patients may worry about the fetal impact of medications, leading to treatment discontinuation due to uncertainty about this issue. This study investigated the real-world drug-prescribing practices for pregnant patients with IBD in Japan and their potential connection to major congenital malformations (MCMs). Overall, 277 female IBD patients who gave birth between 2010 and 2019 were selected from the JMDC claims database. The prescribing patterns of IBD medications and MCMs in the patients' offspring were analyzed. Among pregnant IBD patients, 74.4% received at least one medication from 90days before pregnancy to 90days after delivery. Trends in medication prescriptions during pregnancy in 2010-2019 revealed consistent use of oral 5-ASA, variable use of topical medications, a decrease in systemic steroids, and an increase in biologics. The prevalence of MCMs in children born to IBD-affected mothers did not differ significantly between those who did and did not receive IBD medications (8.6% vs 6.8%). Although circulatory system MCMs were slightly more common in the IBD medication group (4.9% vs 1.4%), this difference was not significant. Logistic regression analysis did not reveal an association between MCM risk and first-trimester use of IBD medications, including corticosteroids and biologics. This study provides insights into medication patterns in pregnant IBD patients and suggests no increased risk of MCMs associated with first-trimester IBD medication use.

Risk of Major Congenital Malformations and Exposure to Antiseizure Medication Monotherapy

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. To investigate the prevalence of MCMs after prenatal exposure to 8 commonly used ASM monotherapies and changes in MCM prevalence over time. 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. Maternal use of ASMs at conception. 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. 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. 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.

Proposal for reference values for the developmental effects of valproate based on human data using a benchmark dose approach

Following accidental release of valproate into ambient air during manufacture at a French production site in 2018, concerns were raised for inhabitants of the surrounding area. As no toxicological reference value (TRV) was available, the risks could not be properly assessed. The French Agency for Food, Environmental and Occupational Health and Safety (ANSES) was mandated to determine a TRV by inhalation to be used for risk assessment. Major congenital malformations (MCMs) in offsprings of mothers exposed to valproate during pregnancy have been reported in international scientific literature. As these adverse effects were the most sensitive effect identified, they were retained as the critical effect to be used for the TRV. The data from a robust registry on MCMs established by the International Registry of Antiepileptic Drugs and Pregnancy (EURAP) were modellized and support a strong DRR between the prevalence of MCMs in the fetus and in utero exposure. A benchmark dose (BMD) was then calculated as the dose that may trigger a 5% increase in this risk. A lower 95% confidence limit (BMD5%L95%) of 2.26 mg/kg/day, leading to an oral TRV of 0.08 mg/kg/day and a respiratory TRV of 0.26 mg.m-3 after applying an uncertainty factor of 30, was determined.

Atomoxetine in Early Pregnancy and the Prevalence of Major Congenital Malformations: A Multi ational 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.

Glycemic Control in Pregnancies Complicated by Pre-Existing Diabetes Mellitus and Congenital Malformations: A Danish Population-Based Study.

PurposeTo study the occurrence of major congenital abnormalities in children of women with type 1 and type 2 diabetes and investigate the association between glycated haemoglobin (HbA1c) and major congenital malformations according to type 1 diabetes and type 2 diabetes separately.Patients and methodsIn this register-based study, all singletons born alive from January 1, 2000 to December 31, 2015 in the North Denmark and Central Denmark regions of Denmark and their mothers were included. We used data from Danish health registers and the LABKA database. Logistic regression models were used to compute crude and adjusted prevalence odds ratios (cORs and aORs) with 95% confidence intervals (CIs) for major congenital malformations overall and for subtypes, by type of maternal pre-existing diabetes and HbA1c levels.ResultsAmong 314,245 infants included, 2020 (0.64%) had mothers with type 1 diabetes and 498 (0.16%) had mothers with type 2 diabetes. We found an aOR of 2.9 (95% CI: 2.5, 3.5) and 1.9 (95% CI: 1.3; 2.8) for major malformations for type 1 and type 2 diabetes, respectively. The highest occurrence was seen for major congenital heart diseases, but we also observed higher occurrence of several other non-cardiac malformations. For both type 1 and type 2 diabetes, the prevalence of major congenital malformations increased with higher levels of maternal HbA1c with no safe threshold level. Mothers with type 1 diabetes had higher risks than those without diabetes irrespective of HbA1c, and women with HbA1c levels ≥9.5% had 8 times the odds of major congenital malformations [aOR 8.7 (95% CI: 5.4; 14.5)].ConclusionsThe prevalence of major congenital malformations progressively increased with poorer glycemic control during pregnancy, with no obvious safe threshold level, for both type 1 and type 2 diabetes.

Second-generation antipsychotic use during pregnancy and risk of congenital malformations

PurposeTo study if second-generation antipsychotic (S-GA) use during the first trimester of pregnancy is associated with an increased risk of major congenital malformations (MCM).MethodsA population-based birth cohort study using national register data extracted from the Drugs and Pregnancy database in Finland, years 1996–2017. The sampling frame included 1,273,987 pregnant women. We included singleton pregnancies ending in live or stillbirth or termination of pregnancy due to severe malformation. Pregnancies with exposure to known teratogens were excluded. Women were categorized into three groups: exposed to S-GAs (n = 3478), exposed to first-generation antipsychotics (F-GAs) (n = 1030), and unexposed (no purchases of S-GAs or F-GAs during pregnancy, n = 22,540). We excluded genetic conditions and compared the prevalence of MCMs in S-GA users to the two comparison groups using multiple logistic regression models.ResultsUse of S-GAs during early pregnancy was not associated with an increased risk of overall MCMs compared to unexposed (adjusted odds ratio, OR 0.92; 95% CI 0.72–1.19) or to F-GA users (OR 0.82; 95% CI 0.56–1.20). Of individual S-GAs, olanzapine use was associated with an increased risk of overall MCMs (OR 2.12; 95% CI 1.19–3.76), and specifically, an increased risk of musculoskeletal malformations (OR 3.71; 95% CI 1.35–10.1) when compared to unexposed, while comparisons to F-GA users did not show significant results.ConclusionsOlanzapine use is associated with an increased risk of major congenital malformations and specifically, musculoskeletal malformations. Use during pregnancy should be restricted to situations where no safer alternatives exist.

Paternal Exposure to Immunosuppressive and/or Biologic Agents and Birth Outcomes in Patients With Immune-Mediated Inflammatory Diseases

We conducted a retrospective cohort study to inform the safety of exposure to immunosuppressive and/or biologic agents around conception in expectant fathers with immune-mediated inflammatory diseases (IMIDs) on birth outcomes. Using a deidentified administrative claims database (OptumLabs Data Warehouse), we identified 7453 expectant fathers with IMIDs (inflammatory bowel diseases, rheumatoid arthritis, psoriasis/psoriatic arthritis, and ankylosing spondylitis) linked to newborns with periconception medication exposure between 38 and 60 weeks before the newborn birth date (34-58 weeks prior for preterm newborns) and neonatal follow-up for 3 months after the birth date. Through logistic regression adjusting for paternal age and race (and, in a subset, for maternal age, race, presence of IMIDs, and nonsingleton births), we compared the risk of major congenital malformations (primary outcome) and preterm birth and low birth weight in fathers exposed to thiopurines (n= 461), methotrexate (n= 171), tumor necrosis factor (TNF) α antagonists (n= 1082), or non-TNF-targeting biologic agents (n= 132) vs fathers not exposed to any of these medications (n= 5607). As compared to unexposed fathers (3.4% prevalence of major congenital malformations), exposure to thiopurines (relative risk [RR], 1.12; 95% confidence interval [CI], 0.66-1.76), methotrexate (RR, 0.67; 95% CI, 0.21-1.55), TNF-α antagonists (RR, 1.14; 95% CI, 0.81-1.57), and non-TNF-targeting biologic agents (RR, 1.75; 95% CI, 0.80-3.24) was not associated with increased risk of major congenital malformations. No association was observed between paternal medication exposure and risk of preterm birth or low birth weight. Results were stable on subanalyses of linked father-mother-newborn triads. In a large cohort study of 7453 expectant fathers with IMIDs, exposure to immunosuppressive or biologic agents around conception was not associated with increased risk of adverse birth outcomes.

Declining malformation rates with changed antiepileptic drug prescribing: An observational study.

Changes in prescribing patterns of antiepileptic drugs (AEDs) in pregnant women with epilepsy would be expected to affect the risk of major congenital malformations (MCMs). To test this hypothesis, we analyzed data from an international pregnancy registry (EURAP). EURAP is an observational prospective cohort study designed to determine the risk of MCMs after prenatal exposure to AEDs. The Cochrane-Armitage linear trend analysis was used to assess changes in AED treatment, prevalence of MCMs, and occurrence of generalized tonic-clonic seizures (GTCs) over 3 time periods: 2000-2005 (n = 4,760), 2006-2009 (n = 3,599), and 2010-2013 (n = 2,949). There were pronounced changes in the use of specific AEDs over time, with a decrease in the use of valproic acid and carbamazepine and an increase in the use of lamotrigine and levetiracetam. The prevalence of MCMs with monotherapy exposure decreased from 6.0% in 2000-2005 to 4.4% in 2010-2013. The change over time in MCM frequency after monotherapy exposure showed a significant linear trend in the crude analysis (p = 0.0087), which was no longer present after adjustment for changes in AED treatment (p = 0.9923). There was no indication of an increase over time in occurrence of GTCs during pregnancy. There have been major changes in AED prescription patterns over the years covered by the study. In parallel, we observed a significant 27% decrease in the prevalence of MCMs. The results of adjusting the trend analysis for MCMs for changes in AED treatment suggest that changes in prescription patterns played a major role in the reduction of teratogenic events.

Teratogenicity of antiepileptic drugs.

We review data on the comparative teratogenicity of antiepileptic drugs (AEDs), focusing on major congenital malformations (MCMs), intrauterine growth restriction, impaired cognitive development, and behavioral adverse effects following prenatal exposure. Prospective registries and meta-analyses have better defined the risk of MCMs in offspring exposed to individual AEDs at different dose levels. Valproate is the drug with the highest risk, whereas prevalence of MCMs is lowest with lamotrigine, levetiracetam, and oxcarbazepine. For valproate, phenobarbital, phenytoin, carbamazepine, and lamotrigine, the risk of MCMs is dose-dependent. Prenatal exposure to valproate has also been confirmed to cause an increased risk of cognitive impairments and autistic traits. In a population-based study, the risk of AED-induced autistic traits was attenuated by periconceptional folate supplementation. The risk of adverse fetal effects differs in relation to the type of AED and for some AEDs also the daily dose. Although for MCMs the risk is primarily associated with the first trimester of gestation, influences on cognitive and behavioral development could extend throughout pregnancy. Available information now permits a more rational AED selection in women of childbearing potential, and evidence-based counseling on optimization of AED treatment before conception.

Comparative Risk of Major Congenital Malformations With 8 Different Antiepileptic Drugs: A Prospective Cohort Study of the EURAP Registry.

Teratogenesis of 8 Antiepileptic Drugs in Multinational Experience Tomson T, Battino D, Bonizzoni E, Craig J, Lindhout D, Perucca E, Sabers A, Thomas SV, Vajda F for the EURAP Study Group. Lancet Neurol. 2018;17(6):530-538. doi:10.1177/1535759719835353Background:Evidence for the comparative teratogenic risk of antiepileptic drugs is insufficient, particularly in relation to the dosage used. Therefore, we aimed to compare the occurrence of major congenital malformations following prenatal exposure to the 8 most commonly used antiepileptic drugs in monotherapy.Methods:We did a longitudinal, prospective cohort study based on the EURAP international registry. We included data from pregnancies in women who were exposed to antiepileptic drug monotherapy at conception, prospectively identified from 42 countries contributing to EURAP. Follow-up data were obtained after each trimester, at birth, and 1 year after birth. The primary objective was to compare the risk of major congenital malformations assessed at 1 year after birth in offspring exposed prenatally to 1 of 8 commonly used antiepileptic drugs (carbamazepine, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital, phenytoin, topiramate, and valproate) and, whenever a dose dependency was identified, to compare the risks at different dose ranges. Logistic regression was used to make direct comparisons between treatments after adjustment for potential confounders and prognostic factors.Findings:Between June 20, 1999, and May 20, 2016, 7555 prospective pregnancies met the eligibility criteria. Of those eligible, 7355 pregnancies were exposed to 1 of the 8 antiepileptic drugs for which the prevalence of major congenital malformations was 142 (10·3%) of 1381 pregnancies for valproate, 19 (6·5%) of 294 for phenobarbital, 8 (6·4%) of 125 for phenytoin, 107 (5·5%) of 1957 for carbamazepine, 6 (3·9%) of 152 for topiramate, 10 (3·0%) of 333 for oxcarbazepine, 74 (2·9%) of 2514 for lamotrigine, and 17 (2·8%) of 599 for levetiracetam. The prevalence of major congenital malformations increased with the dose at time of conception for carbamazepine (P = .0140), lamotrigine (P = .0145), phenobarbital (P = .0390), and valproate (P < .0001). After adjustment, multivariable analysis showed that the prevalence of major congenital malformations was significantly higher for all doses of carbamazepine and valproate as well as for phenobarbital at doses of more than 80 mg/d than for lamotrigine at doses of 325 mg/d or less. Valproate at doses of 650 mg/d or less was also associated with increased risk of major congenital malformations compared with levetiracetam at doses of 250 to 4000 mg/d (odds ratio [OR]: 2.43, 95% confidence interval [CI]: 1·30-4·55; P = .0069). Carbamazepine at doses of more than 700 mg/d was associated with increased risk of major congenital malformations compared to levetiracetam at doses of 250 to 4000 mg/d (OR: 2.41, 95% CI: 1.33-4.38; P = .0055) and oxcarbazepine at doses of 75 to 4500 mg/d (OR: 2.37, 95% CI: 1.17-4.80; P = .0169).Interpretation:Different antiepileptic drugs and dosages have different teratogenic risks. Risks of major congenital malformation associated with lamotrigine, levetiracetam, and oxcarbazepine were within the range reported in the literature for offspring unexposed to antiepileptic drugs. These findings facilitate rational selection of these drugs, taking into account comparative risks associated with treatment alternatives. Data for topiramate and phenytoin should be interpreted cautiously because of the small number of exposures in this study.

Comparative risk of major congenital malformations with eight different antiepileptic drugs: a prospective cohort study of the EURAP registry

Evidence for the comparative teratogenic risk of antiepileptic drugs is insufficient, particularly in relation to the dosage used. Therefore, we aimed to compare the occurrence of major congenital malformations following prenatal exposure to the eight most commonly used antiepileptic drugs in monotherapy. We did a longitudinal, prospective cohort study based on the EURAP international registry. We included data from pregnancies in women who were exposed to antiepileptic drug monotherapy at conception, prospectively identified from 42 countries contributing to EURAP. Follow-up data were obtained after each trimester, at birth, and 1 year after birth. The primary objective was to compare the risk of major congenital malformations assessed at 1 year after birth in offspring exposed prenatally to one of eight commonly used antiepileptic drugs (carbamazepine, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital, phenytoin, topiramate, and valproate) and, whenever a dose dependency was identified, to compare the risks at different dose ranges. Logistic regression was used to make direct comparisons between treatments after adjustment for potential confounders and prognostic factors. Between June 20, 1999, and May 20, 2016, 7555 prospective pregnancies met the eligibility criteria. Of those eligible, 7355 pregnancies were exposed to one of the eight antiepileptic drugs for which the prevalence of major congenital malformations was 142 (10·3%) of 1381 pregnancies for valproate, 19 (6·5%) of 294 for phenobarbital, eight (6·4%) of 125 for phenytoin, 107 (5·5%) of 1957 for carbamazepine, six (3·9%) of 152 for topiramate, ten (3·0%) of 333 for oxcarbazepine, 74 (2·9%) of 2514 for lamotrigine, and 17 (2·8%) of 599 for levetiracetam. The prevalence of major congenital malformations increased with the dose at time of conception for carbamazepine (p=0·0140), lamotrigine (p=0·0145), phenobarbital (p=0·0390), and valproate (p<0·0001). After adjustment, multivariable analysis showed that the prevalence of major congenital malformations was significantly higher for all doses of carbamazepine and valproate as well as for phenobarbital at doses of more than 80 mg/day than for lamotrigine at doses of 325 mg/day or less. Valproate at doses of 650 mg/day or less was also associated with increased risk of major congenital malformations compared with levetiracetam at doses of 250-4000 mg/day (odds ratio [OR] 2·43, 95% CI 1·30-4·55; p=0·0069). Carbamazepine at doses of more than 700 mg/day was associated with increased risk of major congenital malformations compared with levetiracetam at doses of 250-4000 mg/day (OR 2·41, 95% CI 1·33-4·38; p=0·0055) and oxcarbazepine at doses of 75-4500 mg/day (2·37, 1·17-4·80; p=0·0169). Different antiepileptic drugs and dosages have different teratogenic risks. Risks of major congenital malformation associated with lamotrigine, levetiracetam, and oxcarbazepine were within the range reported in the literature for offspring unexposed to antiepileptic drugs. These findings facilitate rational selection of these drugs, taking into account comparative risks associated with treatment alternatives. Data for topiramate and phenytoin should be interpreted cautiously because of the small number of exposures in this study. Bial, Eisai, GlaxoSmithKline, Janssen-Cilag, Novartis, Pfizer, Sanofi-Aventis, UCB, the Netherlands Epilepsy Foundation, and Stockholm County Council.

Antiretroviral combination use during pregnancy and the risk of major congenital malformations.

To quantify the risk of major congenital malformations (MCMs) associated with gestational combination antiretroviral use. Population-based prospective cohort study. Using the Quebec Pregnancy Cohort from 1998 to 2015, we included women who were covered by the Quebec Drug Plan and had a singleton livebirth. All antiretroviral use alone or in combination were considered. MCMs overall and organ-specific malformations in the first year of life were identified. In total, 214 240 pregnancies met inclusion criteria; 0.09% (n = 198) occurred while on antiretroviral combinations during the first trimester; 169 HIV-positive women without antiretroviral treatment were included. Compared with the general population in this cohort, the prevalence of MCMs was significantly higher in unexposed HIV-positive women (14.8 vs. 8.6%, P = 0.004) but not in antiretroviral-exposed HIV-positive women (10.3%, P = 0.41). Adjusting for potential confounders, including maternal HIV status, antiretroviral use during the first trimester was not associated with the risk of MCMs (adjusted odds ratio 0.59, 95% confidence interval 0.33-1.06). However, antiretroviral combination use during the first trimester was associated with an increased risk of defects of the small intestine (adjusted odds ratio 10.32, 95% confidence interval 2.85-37.38, P = 0.0004). Antiretroviral therapy during the first trimester was not associated with the risk of overall MCMs but may be associated with an increased risk of defects of the small intestine. However, HIV-positive pregnant women who are not treated with antiretrovirals during pregnancy seem to have a higher risk of malformations; this is not seen among those who are treated, which could indicate that the underlying condition puts women at risk and not the treatment.

Anterior Abdominal Wall Defects, Diaphragmatic Hernia, and Other Major Congenital Malformations of the Musculoskeletal System in Barbados, 1993–2012

This study describes the prevalence and patterns of major congenital malformations of the musculoskeletal system and the resulting morbidity and mortality. It is a retrospective population-based study over the period 1993 to 2012. The overall prevalence of major congenital malformations of the musculoskeletal system was 9.02/10,000 live births. The prevalences of omphalocele, gastroschisis, and diaphragmatic hernia were 2.53, 2.22, and 1.42 per 10,000 live births, respectively. The case fatality ratio for the omphalocele, gastroschisis, and diaphragmatic hernia was 12.5, 28.5, and 67%, respectively. In conclusion, the prevalence rate of the major congenital malformations of the musculoskeletal system was higher than those reported in retrospective studies from other countries and remained static during the study period. These defects were associated with a high mortality rate and contributed significantly to the overall neonatal mortality in this country.

Antiepileptic drugs prescribed in pregnancy and prevalence of major congenital malformations: comparative prevalence studies.

ObjectiveThe aim of this study was to examine the prevalence of major congenital malformations associated with antiepileptic drug (AED) treatment in pregnancy.Patients and methodsUsing data from The Health Improvement Network, we identified women who have given live birth and their offspring. Four subgroups were selected based on the AED treatment in early pregnancy, valproate, carbamazepine, lamotrigine and women not receiving AED treatment. We compared the prevalence of major congenital malformations within children of these four groups and estimated prevalence ratios (PRs) using Poisson regression adjusted for maternal age, sex of child, quintiles of Townsend deprivation score and indication for treatment.ResultsIn total, 240,071 women were included in the study. A total of 229 women were prescribed valproate in pregnancy, 357 were prescribed lamotrigine and 334 were prescribed carbamazepine and 239,151 women were not prescribed AEDs. Fifteen out of 229 (6.6%) women prescribed valproate gave birth to a child with a major congenital malformation. The figures for lamotrigine, carbamazepine and women not prescribed AEDs were 2.7%, 3.3% and 2.2%, respectively. The prevalence of major congenital malformation was similar for women prescribed lamotrigine or carbamazepine compared to women with no AED treatment in pregnancy. For women prescribed valproate in polytherapy, the prevalence was fourfold higher. After adjustments, the effect of estimates attenuated, but the prevalence remained two- to threefold higher in women prescribed valproate.ConclusionThe results of our study suggest that lamotrigine and carbamazepine are safer treatment options than valproate in pregnancy and should be considered as alternative treatment options for women of childbearing potential and in pregnancy.

The Impact of Different Case Ascertainment Definitions on the Prevalence of Major Congenital Malformations and their Association with Asthma During Pregnancy.

Objectives To compare the prevalence of major malformations using different case ascertainment definitions and to evaluate their impact on maternal asthma-major malformations association. Methods A cohort of pregnancies with and without asthma between 1990 and 2010 was formed. We used two classification methods: the Two step Congenital Malformation Classification (TCMC) and the Canadian Congenital Anomalies Surveillance System (CCASS). Within each method, three case definitions were compared: (1) ≥1 diagnosis in the hospital database; (2) ≥1 diagnosis in the hospital database or ≥2 in the medical claims; and (3) ≥1 diagnosis in the hospital database or ≥1 in the medical claims. We calculated the prevalence of major malformations and adjusted odds ratios (aORs) for maternal asthma association. Results Of 467,946 pregnancies, 12.3% were with active asthma. The prevalence estimates were: TCMC 5.10-7.08% and CCASS 7.03-10.57%. Asthma-major malformations association was weaker with the CCASS (aOR 1.14-1.20) versus TCMC (aOR 1.22-1.26). Discussion The case ascertainment definitions with ≥1 hospitalization are likely to be the most reliable in similar administrative databases. The case ascertainment definition had a considerable impact on the prevalence of major malformations, but hardly influenced the aORs. Future studies should formally assess the validity of the case ascertainment definitions and allow generalizability to other maternal exposures.

Topiramate use during pregnancy and major congenital malformations in multiple populations.

We measured birth prevalence of major congenital malformations (MCMs) after topiramate use during pregnancy to screen for a possible signal of increased risk. Using four healthcare databases, we identified three cohorts of pregnant women: cohort 1, used topiramate during the first trimester; cohort 2, used topiramate or another antiepileptic drug previously but not during pregnancy; and cohort 3, were pregnant and did not use topiramate but had indications for use individually matched to those of users. Cohort 1 was compared with cohorts 2 and 3. MCMs were a code for any major congenital malformation dated within 30 days of the delivery date on the mother's claims or within 365 days after infant birth date, excluding a genetic or syndromic basis, and with procedure or healthcare usage consistent with the MCM diagnosis code in the 365 days after infant birth. Of the 10 specific common MCMs evaluated, 1 (conotruncal heart defects) had a prevalence ratio greater than 1.5 for both primary comparisons, and 4 (ventricular septal defect, atrial septal defect, hypospadias, coarctation of the aorta) had a prevalence ratio greater than 1.5 for one of the two comparisons. Following screening of organ systems with elevated MCMs, the prevalence ratio was greater than 1.5 for patent ductus arteriosus in both comparisons and for obstructive genitourinary defects in one comparison. To evaluate a large number of MCMs across many pregnancies, we used crude methods for detecting potential signals. Therefore, these results should be seen as potential signals, not causal.

PRM72 - The impact of two different case definitions of major congenital malformations identified from Quebec (Canada) administrative databases on their association with asthma controller medications taken during pregnancy

Accurate identification of major malformation cases from administrative databases is crucial for perinatal epidemiology. In Quebec, most of major malformations are detected in hospital, however administrative databases capture diagnoses data from both hospitals and other medical facilities. We aimed to compare the prevalence of major congenital malformations identified from administrative databases diagnostic codes (ICD-9 and ICD-10) with 2 definitions: diagnoses made in hospital only vs. diagnoses made in hospital and other medical facilities. We further evaluated the impact of using each definition to quantify the association between maternal use of asthma controller medications and the prevalence of major malformations at birth and during the first year of life. A cohort of pregnancies from asthmatic women between 1990 and 2010 was formed through the linkage of administrative databases from Quebec. We calculated the prevalence of major malformations identified in the 1st year of life of the newborn using the 2 case definitions. We also calculated the crude odds ratio (OR) of major malformations associated with maternal use of inhaled corticosteroids (ICS) and long-acting beta2-agonists (LABA) in the 1st trimester of pregnancy. From 30655 pregnancies, 2090 (6.8%) major malformations were identified with hospital diagnostic codes only vs. 2748 (9.0%) with hospital and other medical facilities diagnostic codes. The OR of major malformations associated with ICS was 1.1 (95%CI: 1.0-1.2) with the first and 1.1 (95%CI: 1.0-1.2) with the second case definition. Corresponding results were 1.3 (95%CI: 1.0-1.6) and 1.1 (95%CI: 0.9-1.4) for LABA exposure. The case definition of congenital malformations had a considerable impact on the prevalence of major congenital malformations, but less impact on the associations we examined. The percentage of false positive cases when using all medical facilities diagnostic codes in the case definition is unknown and should be the objective for future research.