Impact of maternal first trimester treatment regimen on the outcome of valproate exposed pregnancies: an observational Embryotox cohort study.

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 [HRadj 1.31 (95% CI 0.85-2.02)] but major birth defects were significantly more frequent [8.7% vs. 3.4%; ORadj 2.61 (95% CI 1.51-4.50)]. Risk was even higher in pregnancies with no VPA discontinuation in first trimester [ORadj 3.66 (95% CI 2.04-6.54)]. Significant ORs were found for nervous system defects in general [ORadj 5.69 (95% CI 1.73-18.78)], severe microcephaly [ORadj 6.65 (95% CI 1.17-37.68)], hypospadias [ORadj 19.49 (95% CI 1.80-211)] and urinary system defects [ORadj 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 ORadj 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.

Antiepileptic treatment with levetiracetam during the first trimester and pregnancy outcome: An observational study.

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.

Effects of maternal modafinil treatment on fetal development and neonatal growth parameters - a multicenter case series of the European Network of Teratology Information Services (ENTIS).

OBJECTIVE: In recent years, safety concerns about modafinil exposure during pregnancy have emerged. In particular, increased risks for major congenital anomalies (MCA) and impaired fetal growth were reported, although study results were conflicting. Our investigation aims to examine previously reported safety signals. METHOD: Multicenter case series based on data from 18 Teratology Information Services from 12 countries. Modafinil exposed pregnancies with an estimated date of birth before August 2019 were included in this study. For prospectively ascertained pregnancies, cumulative incidences of pregnancy outcomes, rate of nonchromosomal MCA in first trimester exposed pregnancies and percentiles of neonatal/infant weight and head circumference (HC) were calculated. Potential dose-dependent effects on fetal growth were explored by linear regression models. Retrospectively ascertained cases were screened for pattern of MCA and other adverse events. RESULTS: One hundred and seventy-five prospectively ascertained cases were included, of which 173 were exposed at least during the first trimester. Cumulative incidences for live birth, spontaneous abortion and elective termination of pregnancy were 76.9% (95% CI, 68.0%-84.8%), 9.3% (95% CI, 5.0%-16.9%), and 13.9% (95% CI, 8.1%-23.1%), respectively. Nonchromosomal MCA was present in 3/150 live births, corresponding to an MCA rate of 2.0% (95%CI, 0.6%-6.1%), none were reported in pregnancy losses. Compared to reference standards, birth weight (BW) tended to be lower and neonatal HC to be smaller in exposed newborns (data available for 144 and 73 of 153 live births, respectively). In nonadjusted linear regression models, each 100 mg increase of average dosage per pregnancy day was associated with a decrease in standard deviation score (SDS) of -0.28 SDS (95% CI, -0.45 to -0.10) for BW and of -0.28 SDS (95% CI, -0.56 to 0.01) for HC. Screening of 22 retrospectively reported cases did not reveal any specific pattern of MCA or other adverse outcomes. CONCLUSION: The results do not indicate an increased risk of MCA after in utero exposure to modafinil, but a tendency toward lower BW and reduced neonatal HC. However, these findings should be regarded as preliminary. Until further studies allow for a definite conclusion, modafinil should not be used during pregnancy.

Increasing use of newer antiseizure medication during pregnancy: An observational study with special focus on lacosamide.

INTRODUCTION: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Investigating drug safety in pregnancy based on the German Pharmacoepidemiological Research Database (GePaRD): A proof-of-concept analysis on the association between valproate and spina bifida.

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.

Pregnancy outcome following first-trimester exposure to fingolimod: A collaborative ENTIS study.

This prospective multicentre cohort study investigated pregnancy outcomes after fingolimod use for multiple sclerosis during pregnancy. Pregnancy outcomes of 63 fingolimod and 62 interferon-ß-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-ß group (odds ratio, 2.2; 95% confidence interval, 0.2-24.6). The adjusted hazard ratio for spontaneous abortion in fingolimod versus interferon-ß-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.

Corrigendum: Estimating the Beginning of Pregnancy in German Claims Data: Development of an Algorithm With a Focus on the Expected Delivery Date.

[This corrects the article DOI: 10.3389/fpubh.2020.00350.].

Estimating the Beginning of Pregnancy in German Claims Data: Development of an Algorithm With a Focus on the Expected Delivery Date.

Background: 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. Purpose: To estimate the beginning of pregnancy in German claims data focusing on the potential of the expected delivery date (EDD). Methods: 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. Results: 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%. Conclusions: By using the EDD, the beginning of pregnancy can plausibly be estimated in German claims data.

[Prescribing valproate to girls and women of childbearing age in Germany : Analysis of trends based on claims data]. / Valproatverordnungen bei Mädchen und Frauen im gebärfähigen Alter in Deutschland : Untersuchung zeitlicher Trends basierend auf Versichertendaten.

BACKGROUND: Measures to raise awareness of the teratogenic potential of valproate and restrict its use in girls/women of childbearing age have been intensified. For Germany, the impact of these measures on valproate prescription rates remains unknown. OBJECTIVES: Trends in prescribing valproate, the underlying treatment indication, and the specialty of the prescribing physician are analyzed. MATERIALS AND METHODS: With claims data from several statutory health insurance providers from 2004 to 2016 (approximately 3.5 million insured persons per year) considering treatment indication and medical specialties of prescribing physicians, we assessed the rate of girls/women (12 to 50 years) with at least one valproate dispensation per year. RESULTS: The age-standardized rate of girls/women with at least one valproate dispensation declined by 28% between 2004 and 2016 (2.91/1000 vs. 2.09/1000). For 2015, the indications were epilepsy (66.9%), bipolar disorder (13.6%), migraine/headache (5.6%), schizoaffective disorder (4.3%), and other mental disorders (8.9%). Among epilepsy patients, the proportion treated with valproate declined from 26.2 to 16.8%, but changed little in patients with bipolar disorder (9.3% vs. 8.0%). A total of 46.3% of valproate dispensations were issued by neurologists or psychiatrists and 29.6% by general practitioners, internal medicine specialists, or family doctors. CONCLUSIONS: Based on German claims data, a decline of valproate dispensations was shown for epilepsy patients of childbearing age, while the proportion in other indications has hardly changed since 2004.

Paliperidone and pregnancy-an evaluation of the German Embryotox database.

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.

The acute antipanic activity of aerobic exercise.

OBJECTIVE: Regular physical activity is anxiolytic for both healthy subjects and patients with panic disorder. However, the acute antipanic activity of exercise has not yet been studied systematically. METHOD: The effects of quiet rest or aerobic treadmill exercise (30 minutes at 70% of maximum oxygen consumption) on cholecystokinin tetrapeptide (CCK-4)-induced panic attacks were studied in a crossover design in 15 healthy subjects. The effects were measured with the Acute Panic Inventory. RESULTS: Panic attacks occurred in 12 subjects after rest but in only six subjects after exercise. In both conditions, CCK-4 administration was followed by a significant increase in Acute Panic Inventory scores; however, prior exercise resulted in significantly lower scores than quiet rest. CONCLUSIONS: Aerobic exercise has an acute antipanic activity in healthy subjects. If the authors' results are confirmed in patients, the optimum intensity and duration of acute exercise for achieving antipanic effects will have to be characterized.