Effects of valproate (VPA) dose and treatment discontinuation during the first trimester of pregnancy on the risks of spontaneous abortions (SAB) and major birth defects were analyzed. Pregnancies ...with first trimester VPA exposure (n = 484) prospectively recorded by the German Embryotox center in 1997-2016 were compared with a randomly selected, non-exposed cohort (n = 1446). The SAB risk was not significantly increased in the VPA cohort HR
1.31 (95% CI 0.85-2.02) but major birth defects were significantly more frequent 8.7% vs. 3.4%; OR
2.61 (95% CI 1.51-4.50). Risk was even higher in pregnancies with no VPA discontinuation in first trimester OR
3.66 (95% CI 2.04-6.54). Significant ORs were found for nervous system defects in general OR
5.69 (95% CI 1.73-18.78), severe microcephaly OR
6.65 (95% CI 1.17-37.68), hypospadias OR
19.49 (95% CI 1.80-211) and urinary system defects OR
6.51 (95% CI 1.48-28.67). VPA dose had a stronger effect than antiepileptic poly- versus monotherapy; for VPA dose ≥ 1500 mg/day the OR
was 5.41 (95% CI 2.32-12.66). A daily dose increase of 100 mg was calculated to raise the risk for major birth defects by 15% OR 1.15 (95% CI 1.08-1.23). Overall, maternal first trimester treatment regimen had a relevant impact on birth defect risk.
This prospective multicentre cohort study investigated pregnancy outcomes after fingolimod use for multiple sclerosis during pregnancy. Pregnancy outcomes of 63 fingolimod and 62 interferon-β-exposed ...pregnancies were compared. Rates of major congenital anomalies (MCA) were 4.8% (2/42) in the fingolimod group versus 2.3% (1/44) in the interferon-β group (odds ratio, 2.2; 95% confidence interval, 0.2–24.6). The adjusted hazard ratio for spontaneous abortion in fingolimod versus interferon-β-exposed pregnancies was 0.6 (95% confidence interval, 0.2–1.8). Further studies are needed to definitely rule out a moderately increased MCA risk after fingolimod exposure during pregnancy.
Estimating the beginning of pregnancy is crucial when studying drug safety in pregnancy, but important information in this regard, such as the last menstrual period (LMP), is generally not recorded ...in claims databases. The beginning of pregnancy is therefore usually estimated by subtracting a median length of pregnancy from the date of birth. Due to the variability in pregnancy lengths, this might result in non-negligible errors. German claims data may offer the possibility to estimate the beginning of pregnancy more precisely based on the expected delivery date (EDD) which can be coded once or more often during a pregnancy.
To estimate the beginning of pregnancy in German claims data focusing on the potential of the expected delivery date (EDD).
We included data of all pregnancies in women aged 12-50 years ending in a live birth between 2006 and 2015 identified in the German Pharmacoepidemiological Research Database (GePaRD). We assessed the number of coded EDDs per pregnancy and the concordance if ≥ 2 EDDs were coded. We estimated the beginning of pregnancy by subtracting 280 days from the EDD or the most frequent EDD (in case of discordant EDDs). To examine plausibility, we determined the distribution of pregnancy lengths and assessed whether the gestational age at which prenatal examinations were coded was plausible. For pregnancies without EDD, the beginning was estimated by subtracting the respective observed median lengths of pregnancy for preterm births, term births, and births after due date from the actual dates of birth.
In 82.4% of pregnancies, at least one EDD was available (thereof 6.1% with only one EDD and 80.9% with ≥ 2 EDDs that were all concordant). The maximal difference between discordant EDDs was in median 5 days (interquartile range: 3-7 days). Based on the EDD, the median length of pregnancy was 276 days for term births and in 84.7% of pregnancies the second antibody screening test was performed in the recommended interval ± 2 weeks. In pregnancies without EDD the respective proportion was 84.9%.
By using the EDD, the beginning of pregnancy can plausibly be estimated in German claims data.
Schizophrenic or schizoaffective disorders often occur in early adulthood and thus affect women of childbearing age. For paliperidone information about reproductive safety is wanting. Therefore, we ...evaluated data from the German Embryotox pharmacovigilance institute regarding paliperidone therapy during pregnancy. The German Embryotox pharmacovigilance institute offers risk assessment on drug use in pregnancy and documents the outcome of more than 3500 drug-exposed pregnancies per year. In our study, we analyze the outcome of all pregnancies with paliperidone exposure, which have been assessed by our institute between January 2007 and June 2016. Of the 17 prospectively assessed pregnancies, 14 resulted in 15 live-born children (including one pair of twins). None of the infants presented with major congenital malformations. There were two spontaneous abortions at gestational weeks 6 and 11, respectively, and one elective termination due to personal reasons. Sixty-five percent of the pregnant women smoked cigarettes throughout pregnancy, 17% consumed alcohol. Five children were born prematurely (< 37 gestational weeks) and four were small for gestational age, each group including the twins. The results of our study suggest that paliperidone may be administered during pregnancy. The increased rate of prematurity and small for gestational age children can at least partially be explained by other risk factors. Psychiatric and obstetric close monitoring as well as additional medical and social support are recommended to ensure a healthy pregnancy course in patients with a severe mental illness.
•Pregnant women are increasingly exposed to newer antiseizure medication like lacosamide although their safety has not been evidenced yet.•Preliminary data indicate no increased risk for spontaneous ...abortion or major birth defects related to lacosamide during pregnancy.•Effects of newer antiseizure medication on pregnancy outcome are difficult to specify, because of limited numbers of well documented pregnancies, frequent antiseizure co-medication and a high rate of terminated pregnancies.
Epilepsy is a common neurological disease requiring long-term therapy also during pregnancy. Most studies on pregnancy outcomes in women with epilepsy are based on antiseizure medication (ASM) in monotherapy. However, about 20–30% of epilepsy patients require polytherapy and newer ASMs are an option, when seizure control is not achieved with first line ASMs.
Observational study evaluating the use of newer ASMs with marketing authorization since 2005 reported to the Embryotox Center of Clinical Teratology and Drug Safety in Pregnancy between 2004 and 2019. In addition, course and outcome of lacosamide exposed pregnancies were analysed.
Our study confirms the increasing use of newer ASMs also in pregnant women. This is especially true for lacosamide, eslicarbazepine and brivaracetam with rising numbers of exposed pregnancies soon after marketing authorization. Analysis of 55 prospectively and 10 retrospectively ascertained lacosamide exposed pregnancies does not indicate increased risks of major birth defects or spontaneous abortion. However, bradycardia observed in 3 neonates might be related to prenatal lacosamide exposure.
Available data do not support the assumption of lacosamide being a major teratogen. The increasing use of newer ASMs during pregnancy underscores the need for more studies to guide preconception counselling, especially for lacosamide, eslicarbazepine and brivaracetam.
Purpose
Large health‐care databases are increasingly used for research on drug utilization and safety in pregnancy. For the German Pharmacoepidemiological Research Database (GePaRD), covering ~20% of ...the German population, algorithms have been developed to identify pregnancies, to estimate their date of onset and to link mothers to their babies. Using this methodology, we aimed to conduct a proof‐of‐concept analysis on the known association between valproate (VPA) exposure in early pregnancy and spina bifida in the exposed child.
Methods
We identified all pregnancies in GePaRD between 2006 and 2016 in women aged 12 to 50 years. To each VPA dispensation of these women, an exposure period was assigned, based on the dispensation date and the number of defined daily doses in the dispensed package. A pregnancy was classified as exposed to VPA in the critical time window if this exposure period overlapped with the first 55 days of pregnancy. Risk ratios were calculated for spina bifida in live births and induced abortions comparing VPA‐exposed ones to all pregnancies.
Results
Overall, we identified 1 271 384 pregnancies fulfilling the inclusion criteria. Of these, 668 pregnancies (0.053%) were classified as exposed to VPA in the critical time window regarding spina bifida. An induced abortion accompanied by a diagnosis of spina bifida was observed in one of the VPA‐exposed pregnancies (0.15%) and in 154 of all pregnancies (0.012%), yielding a risk ratio of 12.4 (95% confidence interval CI: 1.7–88.2). Out of 775 875 pregnancies ending in a live birth, 366 (0.047%) were classified as VPA exposed. A diagnosis of spina bifida was coded in 3 of 366 VPA‐exposed live births (0.82%) and in 260 of all live births (0.03%), yielding a relative risk of 24.5 (95% CI: 7.9–76.0).
Conclusions
Our proof‐of‐concept analysis based on GePaRD showed a strong association between intrauterine exposure to VPA and occurrence of spina bifida. The results are plausible and consistent with the literature, supporting the suitability of GePaRD and the developed algorithms to conduct studies on drug safety in pregnancy.
Objective
Levetiracetam is increasingly used in pregnant women with epilepsy. Although teratogenic effects have not been observed so far, data on the risks of spontaneous abortion and major birth ...defects are still limited, especially for the frequently used dual therapy of levetiracetam and lamotrigine. Our primary aim was to analyze rates of major birth defects and spontaneous abortion after maternal levetiracetam treatment.
Methods
This was a cohort study based on pregnancies recorded by the Embryotox Center from 2000 to 2017. Outcomes of prospectively ascertained pregnancies with first trimester levetiracetam monotherapy (n = 221) were compared to pregnancies with lamotrigine monotherapy for epilepsy (n = 469). In addition, all pregnancies with levetiracetam (n = 364) exposure during the first trimester were analyzed in comparison to a nonexposed cohort (n = 729). Pregnancies with the most frequently used combination therapy comprising levetiracetam and lamotrigine (n = 80) were evaluated separately.
Results
There was no significantly increased risk of major birth defects or of spontaneous abortions after first trimester exposure to levetiracetam. Birth weight of male neonates was significantly lower after levetiracetam monotherapy compared to lamotrigine monotherapy. Dual therapy with levetiracetam and lamotrigine resulted in a significantly increased risk of spontaneous abortion (adjusted hazard ratio = 3.01, 95% confidence interval CI = 1.43–6.33) and a nonsignificant effect estimate for major birth defects (7.7%, n = 5/65, adjusted odds ratio = 1.47, 95% CI = .48–4.47) compared to a nonexposed cohort.
Significance
Our study confirms the use of levetiracetam as a suitable antiepileptic drug in pregnancy. The lower birth weight of male neonates after maternal levetiracetam monotherapy and the unexpectedly high risk of spontaneous abortion and birth defects after dual therapy with levetiracetam and lamotrigine require further investigation.
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