Rate Of Major Congenital Malformations Research Articles

Epilepsy, Antiepileptic Drugs, and Adverse Pregnancy Outcomes, 2: Major Congenital Malformations With Antiepileptic Drug Monotherapy.

Women with epilepsy (WWE) are usually advised antiepileptic drug (AED) treatment even during pregnancy. It is therefore important to know what the major congenital malformation (MCM) risks might be with untreated epilepsy, and with first-trimester exposure to different AEDs in monotherapy. This article reviews recent findings from a large multinational registry, a large multinational population based study, and a large meta-analysis. In summary, data from the meta-analysis suggest that the MCM rate is 2%-3% in women without epilepsy and about 3% in WWE who were unexposed to AEDs during pregnancy. Data from the meta analysis also suggest that the MCM rate is approximately population level at 2.6%-3.5% with levetiracetam and lamotrigine and that it is about 4%-5% with carbamazepine, 2.8%-4.8% with oxcarbazepine, about 4% with topiramate, about 5%-7% with phenytoin, about 6%-9% with phenobarbital, and nearly 10% with valproate. The MCM risk with valproate is significantly higher than that with other AEDs (including topiramate and phenobarbital) that significantly increase the risk. Data from the registry suggest that risks are dose-dependent with valproate, phenobarbital, and carbamazepine and that the risk with valproate may be as high as 25% at doses >1,450 mg/d. Valproate is also associated with a wide range of MCMs. Data from the population-based study were generally confirmatory. Strengths and limitations of the studies are considered. The findings of these studies encourage the consideration of levetiracetam or lamotrigine monotherapy for WWE who are pregnant and strongly discourage the consideration of the older AEDs, especially phenytoin and phenobarbitone, and most especially valproate. These considerations also apply to all WWE of childbearing age because it may not be easy to change AEDs when pregnancy is planned and because pregnancy is often unplanned.

Pregnancy and fetal outcomes following maternal exposure to glatiramer acetate in all three trimesters of pregnancy.

Data on disease-modifying therapy (DMT) exposure throughout pregnancy in patients with multiple sclerosis are scarce. In this analysis, we assessed pregnancy and fetal outcomes following maternal glatiramer acetate (GA) exposure in all three trimesters among cases reported between 1997 and 2020. Pregnancy reports of maternal in utero exposure to 20 and 40 mg/mL GA in all three trimesters from 1997 to 2020 were eligible. Both prospective pregnancy data, reported prior to knowledge of pregnancy outcome, and retrospective data were included. The primary endpoint was major congenital malformations (MCMs) based on the European Surveillance of Congenital Anomalies and Twins (EUROCAT) classification. Additional endpoints included fetal death, preterm birth, and low birth weight. The MCM rate was compared to the EUROCAT background rate. A total of 618 GA-exposed pregnancies in all three trimesters resulted in 634 fetuses, including 14 twin pregnancies. One fetal death was reported. All 414 fetuses with data reported prior to knowledge of pregnancy outcome (prospective data) were live births and no fetal death was reported. Preterm birth was reported in 23/213 (10.8%) pregnancies with known gestational age. Low birth weight was reported in 13/203 (6.4%) infants with known birth weight. The prevalence of MCM in prospective live births ranged from 2.2% to 2.4%, which was similar to background rates (2.1%-3.0%). The frequency of these pregnancy and infant outcomes was comparable across GA doses. In utero exposure to 20 and 40 mg/mL GA in three trimesters of pregnancy does not appear to be related to adverse pregnancy or infant outcomes.

P-773 No impact of cleavage-stage or blastocyst-stage embryo biopsy on growth and health in children up to 2 years of age

Abstract Study question Does embryo biopsy for preimplantation genetic testing (PGT) followed by fresh or vitrified-warmed embryo transfer affect children’s health up to 2 years of age? Summary answer Cleavage- or blastocyst-stage embryo biopsy followed by fresh or vitrified-warmed-embryo transfer had neither impact on anthropometry at birth, infancy or childhood nor on health outcomes. What is known already Literature data regarding neonatal outcomes after embryo biopsy for PGT show mixed results due to small sample sizes and/or the heterogeneity in terms of embryo biopsy (cleavage- or blastocyst-stage) and type of embryo transfer (fresh or frozen-thawed). Even fewer data exist on the impact of embryo biopsy on children’s health beyond infancy, including growth. Study design, size, duration This single-center cohort-study compared outcomes in singletons conceived after cleavage- or blastocyst-stage embryo biopsy either in a fresh or vitrified-warmed transfer cycle with results after non-biopsied embryo transfer between 2014 and 2018. Pregnancies after IVM, oocyte vitrification or oocyte/embryo donation were excluded. Eligible singletons living in Belgium were invited for examination at 3-6 months and 2 years. Anthropometric measurements at birth, infancy and childhood and health outcomes including surgeries, medication use and hospitalisations are reported. Participants/materials, setting, methods Birth characteristics were available for 630 and 222 children after cleavage-stage and blastocyst-stage embryo biopsy and for 1532 children after transfer of a non-biopsied embryo. Follow-up data were available for 426, 131 and 662 children, respectively. The impact on children’s health following embryo biopsy in vitrification and fresh cycles was the primary outcome. Other outcomes were the impact of timing of biopsy and of vitrification. Subgroup analysis according to infertility background was additionally performed. Main results and the role of chance Regarding the impact of embryo biopsy, either at the cleavage or blastocyst stage, no differences in anthropometrics were found at birth, infancy or childhood in vitrified-warmed transfer cycles compared to outcomes in non-biopsied vitrified-warmed transfer cycles, even after adjustment for neonatal, treatment and maternal characteristics. Likewise, no impact of embryo biopsy (cleavage stage) was found in fresh transfer cycles. The timing (day 3 or day 5/6) of embryo biopsy did not affect anthropometrics at birth, infancy or childhood. However, children born after cleavage-stage embryo biopsy followed by a vitrified-warmed transfer cycle had larger birth sizes than children born after cleavage-stage biopsy followed by a fresh transfer. Weight and height gain from birth to infancy and from infancy to early childhood were comparable in all biopsied and non-biopsied groups. Reassuringly, comparable rates of major congenital malformations, (severe) developmental problems, hospital admissions, surgical interventions and of chronic medication use up to the age of 2 years were observed in biopsied and non-biopsied groups. Subgroup analysis in children born to parents with an infertility diagnosis showed that birth parameters were not different in children born after embryo biopsy. Limitations, reasons for caution As the majority of the PGT cycles in our center are performed for a genetic indication only, the number of children born after embryo biopsy in infertile parents is rather limited and the results should therefore be interpreted cautiously. Wider implications of the findings Our findings add reassurance that embryo biopsy does not adversely affect the health of offspring up to 2 years of age. This is of particular importance given the widespread shift to blastocyst-stage embryo biopsy in PGT. Trial registration number Not applicable

Pregnancy outcomes following maternal macrolide use: A systematic review and meta-analysis

To determine whether gestational use of all or specific macrolides (azithromycin, clarithromycin, roxithromycin or erythromycin) lead to an increase in rates of overall major congenital malformations, organ-specific malformations, and other adverse pregnancy outcomes in infants. PubMed/MEDLINE, Cochrane Central Register of Controlled Trials and Reprotox® databases were searched. Dichotomous outcomes or calculated log odds ratios and standard errors from observational studies are combined using the random-effects method in Review Manager 5.3. No significant increased risks for major congenital malformation (OR 1.06 [95% CI 0.99, 1.13]) and congenital heart defect (OR 1.05 [95% CI 0.92, 1.19]) following all macrolides use during the first trimester were detected. Prenatal azithromycin use was associated with a significantly increased risk of major congenital malformations in the analysis of cohort studies (OR 1.21 [95% CI 1.08–1.36]). This significance was also present in the sensitivity analysis. There were no statistically significant associations between the risk of organ specific malformations and all or specific macrolide exposures except for the decreased risk in hypospadias following erythromycin use in the meta-analysis of case-control studies (OR 0.38 [95% CI 0.18, 0.81]. Also, a significant 1.5-fold increased risk for spontaneous abortion following macrolide use was detected. A slight yet significantly increased rate of major congenital malformation with azithromycin exposure during pregnancy may be associated with maternal confounders. Nevertheless, level II ultrasound can be suggested following maternal azithromycin use during the first trimester. Future studies should take into account the inclusion of a disease-matched control group and accurate classification of the malformations.

Women of childbearing age: What antiseizure medications are they taking?

Women of childbearing age: What antiseizure medications are they taking?

Pregnancy outcomes following maternal exposure to statins: A systematic review and meta-analysis.

The objective of this meta-analysis was to determine whether maternal exposure to statins is associated with increased rates of major congenital malformations and other adverse pregnancy outcomes. PubMed/Medline, Web of Science and Reprotox® databases were searched. Cohort and case control studies with prenatal exposure to statins were included. Analysis of five cohort studies and one case-control study showed no significant increase in rate of major congenital malformations when the exposed group was compared with the control ([OR 1.27; 95% CI 0.80-2.04], [aOR 1.05; 95% CI 0.84-1.31]). A significant increase in heart defect risk was detected in the statin-exposed group when unadjusted ORs were combined (OR 2.47; 95% CI 1.36-4.49). Further analysis of the same outcome by using adjusted ORs showed no significant increase in heart defect risk in the statin-exposed group compared with the controls (aOR 1.24; 95% CI 0.93-1.66). A significantly lower live birth rate (OR 0.60, 95% CI 0.49-0.75) and a higher spontaneous abortion rate (OR 1.36; 95% Cl 1.06-1.75) were detected in the statin-exposed group. Gestational statin exposure was not associated with a significant increase in risk of major congenital malformations, heart defects and other adverse pregnancy outcomes, except spontaneous abortion and live birth rate, which may be associated with maternal comorbidity and other unadjusted risk factors. Further research focusing on particular statins is needed to draw more definitive conclusions.

Pregnancy Outcomes With Exposure to Second-Generation Antipsychotics During the First Trimester.

Objective: To investigate the risk of major congenital malformations associated with exposure to second-generation antipsychotics (SGAs) in the first trimester.Methods: Pregnant women who received consultation on drug exposure from the Japan Drug Information Institute in Pregnancy from October 2005 to December 2016 were asked to complete a questionnaire at 1 month after the expected delivery date. The questionnaire included items on pregnancy outcome, date of delivery, gestational age at delivery, malformations in the infant that were confirmed by the pediatrician's report, and the following parameters at birth: height, weight, head circumference, and chest circumference. Odds ratios (ORs) for major congenital malformations among live-born children of pregnant women with SGA exposure during the first trimester (SGA group) relative to children of women not exposed to SGAs and medications known to be teratogenic (comparison group) were estimated using an inverse probability of treatment weighting approach.Results: Of 404 women with SGA exposure during the first trimester, there were 351 live births, 3 stillbirths, 34 spontaneous abortions, and 16 elective abortions. The rate of major congenital malformations among live-born children was 0.9% (3/351) in the SGA group and 1.8% (70/3,899) in the comparison group. No statistically significant differences were observed in the adjusted OR for major congenital malformations (adjusted OR = 0.44; 95% CI, 0.12-1.48; P = .179).Conclusions: SGA exposure during the first trimester is not associated with an increased risk of major congenital malformations. These findings might be reassuring for pregnant women who require SGAs.

Risk of mayor and minor birth defects in children conceived by assisted reproductive technology (IVF/ICSI): A prospective controlled cohort study

IntroductionAbout 0.2–6.1% of newborns in the developed world have been conceived by assisted reproductive techniques (ART). Higher rate of major and minor malformations have been described in this population, but the multiple possible confounders associated make it difficult to establish a direct causal relationship and the specific factors involved. Material and methodsTo determine the risk of these malformations in our population, a collaborative prospective controlled cohort study was designed. We collected the specific ART-data related to the clinical gestation of women treated in a period of 2 years in the Reproduction Unit from a Spanish public tertiary-level hospital. 231 out of 267 newborns of these gestation (88%) participated in the study and were assessed by a pediatrician with expertise in Clinical Genetics and Dysmorphology at 12–20 and 26–40 months of age. At the same time a controlled group of children naturally conceived (NC) was selected according to the following criteria: the next NC newborn belonging to the same group of maternal and gestational age, and type of gestation (single or multiple). 230 controls were chosen and 208 participated in the study (90%). ResultsMajor malformations were presented in 7.8% of the ART-children and 7.2% of the controls, without founding statistically differences between groups. However, differences were found in the risk of some minor malformations such as capillary malformations and pigmentary lesions, higher in the ART-group. A recurrent pattern of craneofacial anomalies was also unexpectedly detected. ConclusionsIn spite of the high rate of major congenital malformations detected, there were no differences between groups. Thus, our results suggest that ART may affect the normal embryonic development but in a milder way than other confounding factors do. The facial phenotype identified has not previously been described, either the higher risk of capillary malformations and pigmentary lesions. More studies are needed to confirm this association.

Malformation risk of new anti-epileptic drugs in women with epilepsy; observational data from the Kerala registry of epilepsy and pregnancy (KREP)

Objectives: We aim to report the major congenital malformation (MCM) rates for new and old anti-epileptic drugs (AED) exposures during the first trimester of pregnancy in women with epilepsy (WWE). Methods: We extracted relevant data on drug exposure and malformation rate from the records of a prospective observational registry (Kerala Registry of Epilepsy and Pregnancy) for all completed pregnancies between 1998 and 2019. A comprehensive and uniform criterion with detailed guideline was used for assessment of malformations. We employed generalised linear model to generate adjusted incidence rate ratios (aIRR) of MCM in AED exposed group as compared to AED unexposed group, after adjustment for age and educational status of mothers’ and epilepsy classification. Results: The unadjusted MCM rate was 6.2% for all the infants included in the study (148/2328); 4.7% for the unexposed group (16/340), and 6.6% for the exposed group (132/1988). The aIRR of MCM as compared to unexposed group was similar for all monotherapies; lamotrigine (0.50; 95% CI 0.07–3.68), levetiracetam (1.16; 0.43–3.11), oxcarbazepine (1.61; 0.62–4.21) valproate (1.71, 0.93–3.19), phenytoin (1.21, 0.51–2.90), carbamazepine (0.99, 0.54–1.82), and phenobarbitone (1.20, 0.52–2.74). However, the point estimates suggest least risk with lamotrigine and highest risk with valproate. Polytherapy with high-dose valproate carried significantly higher risk of MCM as compared to the unexposed group (aIRR=4.12; 2.18–7.79, p<0.001). The aIRR of GTCS during pregnancy was 1.63 (95% CI 1.12–2.37, p = 0.011) for monotherapy with new AEDs (lamotrigine, levetiracetam or oxcarbazepine) as compared to old AEDs (phenobarbitone, phenytoin, carbamazepine, or valproate). Conclusion: The MCM risk was significantly higher for polytherapy with high dose valproate. It did not differ substantially between different AED monotherapies although point estimate was lowest with lamotrigine. Pregnant women on new AEDs report higher likelihood of GTCS than women on old AEDs during pregnancy.

Maternal and neonatal outcomes in mothers with diabetes mellitus in Qatari population

BackgroundDiabetes Mellitus (DM) is a major cause of maternal, fetal, and neonatal morbidities. Our objective was to estimate the effect of both pre-pregnancy and gestational DM on the growth parameters of newborns in the Qatari population.MethodsIn this population-based cohort study, we compared the data of neonates born to Qatari women with both pre-pregnancy and gestational diabetes mellitus in 2017 with neonates of healthy non-diabetic Qatari women.ResultsOut of a total of 17020 live births in 2017, 5195 newborns were born to Qatari women. Of these, 1260 were born to women with GDM, 152 were born to women with pre-pregnancy DM and 3783 neonates were born to healthy non-diabetic (control) women. The prevalence of GDM in the Qatari population in 2017 was 24.25%. HbA1C% before delivery was significantly higher in women with pre-pregnancy DM (mean 6.19 ± 1.15) compared to those with GDM (mean 5.28 ± 0.43) (P <0.0001). The mean birth weight in grams was 3066.01 ± 603.42 in the control group compared to 3156.73 ± 577.88 in infants born to women with GDM and 3048.78 ± 677.98 in infants born to women with pre-pregnancy DM (P <0.0001). There was no statistically significant difference regarding the mean length (P= 0.080), head circumference (P= 0.514), and rate of major congenital malformations (P= 0.211). Macrosomia (Birth weight > 4000 gm) was observed in 2.7% of the control group compared to 4.8% in infants born to women with GDM, and 4.6% in infants born to women with pre-pregnancy DM (P= 0.001). Multivariate logistic regression analysis demonstrated that higher maternal age (adjusted OR 2.21, 95% CI 1.93, 2.52, P<0.0001), obesity before pregnancy (adjusted OR 1.71, 95% CI 1.30, 2.23, P<0.0001), type of delivery C-section (adjusted OR 1.25, 95% CI 1.09, 1.44, P=0.002), and body weight to gestational age LGA (adjusted OR 2.30, 95% CI 1.64, 2.34, P<0.0001) were significantly associated with increased risk of GDM.ConclusionDespite the multi-disciplinary antenatal diabetic care management, there is still an increased birth weight and an increased prevalence of macrosomia among the infants of diabetic mothers. More efforts should be addressed to improve the known modifiable factors such as women's adherence to the diabetic control program. Furthermore, pre-pregnancy BMI was found to be significantly associated with gestational DM, and this is a factor that can be addressed during pre-conceptional counseling.

Congenital malformation and hemoglobin A1c in the first trimester among Japanese women with pregestational diabetes.

To investigate the incidence of major congenital malformations in Japanese women with pregestational diabetes, and to determine the cutoff value of hemoglobin A1c (HbA1c) in the first trimester associated with congenital malformations. This retrospective cohort study included singleton pregnancies in Japanese women with pregestational diabetes, including type 1 and type 2 diabetes, and specific types of diabetes due to other causes. The primary outcome was the incidence of major congenital malformations. The secondary outcome was the incidence of all congenital malformations. The cutoff value of HbA1c for congenital malformations was calculated using receiver operating characteristic curve analysis. The adjusted odds ratios (aOR) of major congenital malformations were calculated using multiple logistic regression analyses. This study enrolled 292 patients, including 132 (45.2%) with type 1 diabetes, 156 (53.4%) with type 2 diabetes, and 4 (1.4%) with other specific types. The incidence rates of major congenital malformations and all congenital malformations were 7.2% (21/292) and 12.7% (37/292), respectively. The cutoff value of HbA1c in the first trimester for major malformations and for all congenital malformations was 6.5%. HbA1c ≥ 6.5% was significantly associated with major malformations (aOR 3.5; 95% confidence interval: 1.2-12.6; p=0.018). The incidence of major congenital malformations significantly increased in pregnant Japanese women with HbA1c values of 6.5% or higher. The recommended HbA1c value during the first trimester used in other countries can be applied to pregnant Japanese women.

Riesgo de malformaciones mayores y menores en niños concebidos por técnicas de reproducción asistida (FIV/ICSI): estudio prospectivo de cohorte controlado

IntroductionAbout 0.2–6.1% of newborns in the developed world have been conceived by assisted reproductive techniques (ART). Higher rate of major and minor malformations have been described in this population, but the multiple possible confounders associated, make it difficult to establish a direct causal relationship, and the specific factors involved. Material and methodsTo determine the risk of these malformations in our population, a collaborative prospective controlled cohort study was designed. We collected the specific ART-data related to the clinical gestation of women treated in a period of 2 years in the Reproduction Unit from a Spanish public tertiary-level hospital. 231 out of 267 newborns of these gestation (88%) were exhausted assessed by a Clinical Geneticist expertise in Dysmorphology at 12–20 and 26–40 months of age. At the same time a controlled group of children naturally conceived (NC) was selected according to the following criteria: the next NC newborn belonging to the same group of maternal and gestational age, and type of gestation (single or multiple). 230 controls were chosen and 208 participated in the study (90%). ResultsMajor malformations were presented in 7.8% of the ART-children and 7.2% of the controls, without founding statistically differences between groups. However, differences were found in the risk of some minor malformations such as capillary malformations and pigmentary lesions, higher in the ART-group. A recurrent pattern of craneofacial anomalies was also unexpectedly detected. ConclusionsIn spite of the high rate of major congenital malformations detected, there were no differences between groups. Thus, our results suggest that ART may affect the normal embryonic development but in a milder way than other confounding factors do. The facial phenotype identified has not previously, either the higher risk of capillary malformations and pigmentary lesions. More studies are needed to confirm this association.

Zonisamide safety in pregnancy: Data from the UK and Ireland epilepsy and pregnancy register

BackgroundAnimal data suggest teratogenic effects with zonisamide use and risk of pregnancy losses. Human data following zonisamide exposure are presently limited, but suggest low risk of malformation with elevated risk of low birth weight. ObjectiveTo calculate the major congenital malformation (MCM) rate of zonisamide in human pregnancy and assess for a signal of any specific malformation pattern and associations with birth weight. Methods and materialsData were obtained from the UK and Ireland Epilepsy and Pregnancy register (UKIEPR) which is an observational, registration, and follow up study from December 1996 to July 2020. Eligibility criteria were use of zonisamide and to have been referred to the UKIEPR before the outcome of the pregnancy was known. Primary outcome was evidence of MCM. ResultsFrom December 1996 through July 2020 there were 112 cases of first trimester exposure to zonisamide, including 26 monotherapy cases. There were 3 MCM for monotherapy cases (MCM rate 13.0% (95% confidence interval 4.5–32.1)), and 5 MCM for polytherapy cases (MCM rate 6.9% (95% confidence interval 3.0–15.2)). While the median birth weight was on 71st and 44th centile for monotherapy and polytherapy cases respectively, there was a high rate of infants born small for gestational age (21% for both). ConclusionThese data raise concerns about a signal for potential teratogenicity with zonisamide in human pregnancy. Given the low numbers reported, further data will be required to adequately counsel women who use zonisamide in pregnancy.

Association of Chemotherapy Timing in Pregnancy With Congenital Malformation

Chemotherapy during the first trimester of pregnancy should be avoided owing to the risk of congenital malformations. However, the precise gestational age at which chemotherapy can be initiated safely remains unclear. To assess congenital malformation rates associated with gestational age at initiation of chemotherapy among pregnant women with cancer. This multicenter cohort study evaluated all pregnant women who received chemotherapy between 1977 and 2019 registered in the International Network on Cancer, Infertility and Pregnancy (INCIP) database. Data were analyzed from February 15 to June 2, 2020. Cancer treatment with chemotherapy during pregnancy. Analysis was focused on major and minor structural malformations in offspring, defined by EUROCAT, detected during pregnancy or at birth. A total of 755 women in the INCIP database who underwent cancer treatment with chemotherapy during pregnancy were included in analysis. The median (range) age at cancer diagnosis was 33 (14-48) years. Among offspring, the major congenital malformation rate was 3.6% (95% CI, 2.4%-5.2%), and the minor congenital malformation rate was 1.9% (95% CI, 1.0%-3.1%). Chemotherapy exposure prior to 12 weeks gestational age was associated with a high rate of major congenital malformations, at 21.7% (95% CI, 7.5%-43.7%; odds ratio, 9.24 [95% CI, 3.13-27.30]). When chemotherapy was initiated after gestational age 12 weeks, the frequency of major congenital malformations was 3.0% (95% CI, 1.9%-4.6%), which was similar to the expected rates in the general population. Minor malformations were comparable when exposure occurred before or after gestational age 12 weeks (4.3% [95% CI, 0.1%-21.9%] vs 1.8% [95% CI, 1.0-3.0]; odds ratio, 3.13 [95% CI, 0.39-25.28]). Of 29 women who received chemotherapy prior to 12 weeks gestation, 17 (58.6%) were not aware of pregnancy, and 6 (20.7%) experienced a miscarriage (3 women [10.3%]) or decided to terminate their pregnancy (3 women [10.3%]). This cohort study found that chemotherapy was associated with an increased risk of major congenital malformations only in the first 12 weeks of pregnancy. The risk of congenital malformations when chemotherapy was administered during the first trimester and the high number of incidental pregnancies during cancer treatment in the INCIP registry underscore the importance of contraceptive advice and pregnancy testing at the start of chemotherapeutic treatment in young women with cancer.

Contemporary trends in antiepileptic drug treatment among women of childbearing age with epilepsy in the United States: 2004–2015

ObjectiveCertain antiepileptic drugs are associated with an increased risk for major congenital malformations (MCM). However, little is known regarding recent patterns of antiepileptic drug (ASM) prescriptions to women of childbearing age with epilepsy (WCE) in the United States. MethodsData from the Medical Expenditure Panel Survey was analyzed between the years 2004–2015 to determine trends in national antiepileptic drug prescriptions for WCE. Analysis of associations between demographic covariates and prescription of ASMs with MCM rate > 5% (topiramate, valproate, or phenobarbital) was performed with logistic regression. ResultsThere was a weighted total of 395,292 WCE. 29.1% (23.2%–35.8%) of WCE were prescribed an AED with MCM rate > 5%. The odds of a LEV prescription significantly increased in the 2010–2012 (OR 2.91, 95% CI 1.09–7.79) and 2013–2015 (OR 5.06, 95% CI 2.02–12.67) intervals compared to 2004–2006. Conversely, the odds of PB prescriptions significantly decreased in 2010–2012 (OR 0.13, 95% CI 0.02–0.83) and 2013–2015 (OR 0.13, 95% CI 0.02–0.93) compared to 2004–2006. WCE between the ages of 25–34 (OR = 2.67, 95% CI = 1.32–5.41) and 35–44 years (OR = 2.59, 95% CI = 1.23–5.45), had lower odds of being prescribed ASMs with MCM rate > 5% compared to those between the ages of 15–24 years. SignificanceBetween 2004 and 2015, the prescriptions of ASMs given to WCE has changed. Regardless, nearly one third were prescribed potentially teratogenic medications despite available and affordable safer alternatives. Identifying factors associated with the prescription of teratogenic drugs to WCE is critical so that it may be further limited in the future.

Valproate usage in pregnancy: An audit from the Kerala Registry of Epilepsy and Pregnancy.

This is an audit of the use of valproate (VPA) during pregnancy in women with epilepsy (WWE). We identified all pregnancies exposed to VPA in the Kerala Registry of Epilepsy and Pregnancy between January 2010 and December 2019. Subjects' past usage of antiepileptic drugs (AEDs), seizure count before and during pregnancy, fetal outcome, and major congenital malformations (MCMs) were abstracted from the registry records. The presumed reason for usage of VPA was deducted from the clinical records. There were 221 pregnancies (17.75%) exposed to VPA (monotherapy, n = 149) during the audit period. The MCM rate for the completed pregnancies exposed to VPA was higher (n=20, 10.36%) than that of VPA-unexposed pregnancies (n=39, 4.96%). The relative risk for MCM with VPA exposure was 2.1 (95% confidence interval = 1.24-3.48, number needed to treat with VPA to result in MCM = 19). Reasons for using VPA during pregnancy (some women had more than one reason) were (1) VPA was the first AED prescribed and was effective (68, 29.06%), (2) other AEDs were ineffective (128, 54.70%), and (3) other AEDs were discontinued due to adverse effects (17, 7.28%). Other reasons (21, 8.97%) were (1) VPA was selected after the epilepsy classification was revised (3, 1.28%), (2) other AEDs were expensive (2, .85%), and (3) patient switched to VPA from other AEDs for unspecified reason (16, 6.83%). VPA was discontinued during pregnancy for 6 (2.71%) persons. Less than 10% of women were tried on lamotrigine or levetiracetam before switching to VPA. Nine MCMs per thousand pregnancies can be avoided if VPA is not used in WWE. Safe and effective AEDs as alternatives to VPA are the need of the hour. Professional bodies and regulatory authorities need to implement updated guidelines on AED usage in girls and women.

Effect of gabapentin on hyperemesis gravidarum: a double-blind, randomized controlled trial

Hyperemesis gravidarum is a disabling disease of nausea, vomiting, and undernutrition in early pregnancy for which there are no effective outpatient therapies. Poor weight gain in hyperemesis gravidarum is associated with several adverse fetal outcomes including preterm delivery, low birthweight, small for gestational age, low 5-minute Apgar scores, and neurodevelopmental delay. Gabapentin is most commonly used clinically for treating neuropathic pain but also substantially reduces chemotherapy-induced and postoperative nausea and vomiting. Pregnancy registry data have shown maternal first-trimester gabapentin monotherapy to be associated with a 1.2% rate of major congenital malformations among 659 infants, which compares favorably with the 1.6% to 2.2% major congenital malformation rate in the general population. Open-label gabapentin treatment in hyperemesis gravidarum was associated with reduced nausea and vomiting and improved oral nutrition. This study aimed to determine whether gabapentin is more effective than standard-of-care therapy for treating hyperemesis gravidarum. A double-blind, randomized, multicenter trial was conducted among patients with medically refractory hyperemesis gravidarum requiring intravenous hydration. Patients were randomized (1:1) to either oral gabapentin (1800-2400 mg/d) or an active comparator of either oral ondansetron (24-32 mg/d) or oral metoclopramide (45-60 mg/d) for 7 days. Differences in Motherisk-pregnancy-unique quantification of nausea and emesis total scores between treatment groups averaged over days 5 to 7, using intention-to-treat principle employing a linear mixed-effects model adjusted for baseline Motherisk-pregnancy-unique quantification of nausea and emesis scores, which served as the primary endpoint. Secondary outcomes included Motherisk-pregnancy-unique quantification of nausea and emesis nausea and vomit and retch subscores, oral nutrition, global satisfaction of treatment, relief, desire to continue therapy, Nausea and Vomiting of Pregnancy Quality of Life, and Hyperemesis Gravidarum Pregnancy Termination Consideration. Adjustments for multiple comparisons were made employing the false discovery rate. A total of 31 patients with hyperemesis gravidarum were enrolled from October 2014 to May 2019. Among the 21 patients providing primary outcome data (12 assigned to gabapentin and 9 to the active comparator arm), 18 were enrolled as outpatients and all 21 were outpatients from days 5 to 7. The study groups' baseline characteristics were well matched. Gabapentin treatment provided a 52% greater reduction in days 5 to 7 baseline adjusted Motherisk-pregnancy-unique quantification of nausea and emesis total scores than treatment with active comparator (95% confidence interval, 16-88; P=.01). Most secondary outcomes also favored gabapentin over active comparator treatment including 46% and 49% decreases in baseline adjusted Motherisk-pregnancy-unique quantification of nausea and emesis nausea (95% confidence interval, 19-72; P=.005) and vomit and retch subscores (95% confidence interval, 21-77; P=.005), respectively; a 96% increase in baseline adjusted oral nutrition scores (95% confidence interval, 27-165; P=.01); and a 254% difference in global satisfaction of treatment (95% confidence interval, 48-459; P=.03). Relief (P=.06) and desire to continue therapy (P=.06) both showed trends favoring gabapentin treatment but Nausea and Vomiting of Pregnancy Quality of Life (P=.68) and Hyperemesis Gravidarum Pregnancy Termination Consideration (P=.58) did not. Adverse events were roughly equivalent between the groups. There were no serious adverse events. In this small trial, gabapentin was more effective than standard-of-care therapy for reducing nausea and vomiting and increasing oral nutrition and global satisfaction in outpatients with hyperemesis gravidarum. These data build on previous findings in other patient populations supporting gabapentin as a novel antinausea and antiemetic therapy and support further research on gabapentin for this challenging complication of pregnancy.

Paternal exposure to antiepileptic drugs and offspring outcomes: a nationwide population-based cohort study in Sweden

ObjectivesTo investigate the association between paternal use of antiepileptic drugs (AEDs) and adverse neurodevelopmental outcomes and major congenital malformations (MCM) in the offspring.MethodsUsing nationwide Swedish registries, we included 1 144...

Safety of MenACWY-CRM vaccine exposure during pregnancy

BackgroundAlthough the meningococcal conjugate MenACWY-CRM vaccine is not approved for use in pregnant women, unintentional exposure during pregnancy can occur, especially during early pregnancy among women of child-bearing age. This study provides safety information about inadvertent MenACWY-CRM vaccination during pregnancy. MethodsThe evaluated population consisted of pregnant female members of Kaiser Permanente Southern California who inadvertently received MenACWY-CRM at 11–21 years of age during 09/30/2011-06/30/2013 within 28 days prior to conception or during pregnancy. Chart abstraction was conducted to identify pregnancy and birth outcomes, including spontaneous and induced abortions, preterm births, low weight births, and major congenital malformations (MCMs). ResultsThere were 92 women who received MenACWY-CRM during the pregnancy exposure period, mainly during the first trimester (76.1%). Hispanics represented the largest race/ethnicity category (68.5%). Among the known pregnancy outcomes (n = 66; excluding induced abortions and unknown pregnancy outcomes), the prevalence of spontaneous abortions was 18.2% (n = 12). Among live born infants (n = 55; from 54 pregnancies), 14.5% (n = 8) were born preterm (<37 weeks gestation) and 9.1% (n = 5) had a low birthweight (<2500 g). The prevalence rate of MCMs among live born infants (n = 55) was 1.8% (n = 1). ConclusionsThis study provides baseline prevalence estimates of spontaneous abortions, preterm births, low weight births, and MCMs among women inadvertently exposed to MenACWY-CRM during the pregnancy period. These estimates appear to be comparable with U.S. background prevalence estimates.

Safety of MenACWY-CRM vaccine exposure during pregnancy

BACKGROUND Although the meningococcal conjugate MenACWY-CRM vaccine is not approved for use in pregnant women, unintentional exposure during pregnancy can occur, especially during early pregnancy among women of child-bearing age. This study provides safety information about inadvertent MenACWY-CRM vaccination during pregnancy. METHODS The evaluated population consisted of pregnant female members of Kaiser Permanente Southern California who inadvertently received MenACWY-CRM at 11-21 years of age during 09/30/2011-06/30/2013 within 28 days prior to conception or during pregnancy. Chart abstraction was conducted to identify pregnancy and birth outcomes, including spontaneous and induced abortions, preterm births, low weight births, and major congenital malformations (MCMs). RESULTS There were 92 women who received MenACWY-CRM during the pregnancy exposure period, mainly during the first trimester (76.1%). Hispanics represented the largest race/ethnicity category (68.5%). Among the known pregnancy outcomes (n = 66; excluding induced abortions and unknown pregnancy outcomes), the prevalence of spontaneous abortions was 18.2% (n = 12). Among live born infants (n = 55; from 54 pregnancies), 14.5% (n = 8) were born preterm (<37 weeks gestation) and 9.1% (n = 5) had a low birthweight (<2500 g). The prevalence rate of MCMs among live born infants (n = 55) was 1.8% (n = 1). CONCLUSIONS This study provides baseline prevalence estimates of spontaneous abortions, preterm births, low weight births, and MCMs among women inadvertently exposed to MenACWY-CRM during the pregnancy period. These estimates appear to be comparable with U.S. background prevalence estimates.