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.

How to account for early overly small risk sets in the analysis of pregnancy outcome data?-Comparison of different methods for stabilizing the Aalen-Johansen estimator.

PURPOSE: In analyzing pregnancy data concerning drug exposure in the first trimester, the risk of spontaneous abortions is of primary interest. For estimating the cumulative incidence function, the Aalen-Johansen estimator is typically used, and competing risks such as induced abortion and livebirth are considered. However, the delayed study entry can lead to overly small risk sets for the first events. This results in large jumps in the estimated cumulative incidence function of spontaneous abortions or induced abortions using the Aalen-Johansen estimator, and consequently in an overestimation of the probability. METHODS: Several approaches account for early overly small risk sets. The first approach is conditioning on the event time being greater than the event time causing the large jump. Second, the events can be ignored by censoring them. Third, the events can be postponed until a large enough number is at risk. These three approaches are compared. RESULTS: All approaches are applied using data of 54 lacosamide-exposed pregnancies. The Aalen-Johansen estimate of the probability of spontaneous abortion is 22.64%, which is relatively large for only three spontaneous abortions in the dataset. The conditional approach and the ignore approach have an estimated probability of 7.17%. In contrast, the estimate of the postpone approach is 16.45%. In this small sample, bootstrapped confidence intervals seem more accurate. CONCLUSIONS: In the analyses of pregnancy data with rare events, the postpone approach is favorable as no events are excluded. However, the approach that ignores early events has the narrowest confidence interval.

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.

Fetal adverse effects following NSAID or metamizole exposure in the 2nd and 3rd trimester: an evaluation of the German Embryotox cohort.

BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAID) are frequently used to treat pain, fever and inflammatory conditions. Due to evidenced fetotoxicity, treatment with NSAID and metamizole should be avoided in the 3rd trimester of pregnancy. There is an ongoing debate on fetotoxic risk of 2nd trimester use which is why we have conducted this study. METHODS: In this observational cohort study outcome of pregnancies with NSAID and/or metamizole exposure in the 2nd and/or 3rd trimester (study cohort n = 1092) was compared with pregnancies exposed to NSAID and/or metamizole in the 1st trimester only (comparison cohort, n = 1154). The WHO-UMC system was used to assess causality between study medication and study endpoints. Prenatal study endpoints were constriction of ductus arteriosus Botalli, oligohydramnios, late spontaneous abortion (SAB) or stillbirth. Postnatal study endpoints were patent ductus arteriosus (PDA), anomalies of the right heart ventricle, primary pulmonary hypertension (PPHT), and neonatal impairment of kidney function. RESULTS: Ductus arteriosus constriction was diagnosed in 5/1092 (0.5%) in the study cohort versus 0/1154 pregnancies in the comparison cohort. In one fetus, ductus arteriosus constriction and oligohydramnios occurred already in the late 2nd trimester after long-term NSAID exposure. Oligohydramnios was diagnosed in 41/1092 (3.8%) in the study cohort versus 29/1154 (2.5%) cases in the comparison cohort [RR, 1.5 (95% CI 0.9-2.4)]. Limited to 2nd trimester, oligohydramnios occurred in 8/904 (0.9%) versus 2/1154 (0.2%) pregnancies [RR, 5.1 (95% CI 1.1-24.0)]. At least in four of the 2nd trimester exposed pregnancies NSAID exposure lasted several weeks. Late SAB or stillbirth occurred in 14/1092 (1.3%) versus 17/1154 (1.5%). Postnatal cardiovascular or renal pathology did not differ between the cohorts. CONCLUSIONS: NSAID use in the 2nd trimester limited to a few days does not appear to pose a relevant risk. Use for longer periods in the advanced 2nd trimester, however, may cause oligohydramnios and ductus arteriosus constriction similar to effects observed after 3rd trimester use.

Can non-responding mask or mimic drug effects on pregnancy outcome? Evaluation of case characteristics based on the national Embryotox cohort.

Women and their health care provider (HCP) often seek advice for drug safety in pregnancy at Teratology Information Services (TIS). In turn, TIS ask for details of drug exposure and pregnancy outcome. These data constitute a valuable basis for research on prenatal drug risks in many countries. Non-response to follow-up questionnaires, however, may cause biased study results. To assess the potential of non-response bias, this study based on the German Embryotox cohort compares maternal and HCP characteristics of responders and non-responders. Change in loss of follow-up rates over time is investigated using logistic regression. From 2010 until the end of 2020, 48,410 pregnant women and/or their HCP consented to participation in follow-up. Of these, 25.0 % did not return follow-up questionnaires. Loss rates were similar for patients and HCP but increased over time. Participants from semi-dense populated areas had a smaller loss rate (20.4 %) than those from rural (28.4 %) or urban areas (25.6 %). Responding women were older than non-responders, had a lower BMI, a more positive attitude towards pregnancy, a higher educational level, a lower number of previous pregnancies, smoked less, and indicated alcohol consumption more but social drugs less often. Non-response bias cannot be ruled out in studies based on observational data on drug use in pregnancy as those collected by TIS. However, differences between the complete and lost-to follow-up cohort do not suggest a particularly high or low risk profile for one of the cohorts that might substantially confound study results or even mask or mimic potential drug toxicity.

First trimester naproxen exposure and outcome of pregnancy - A German case series.

In contrast to other non-steroidal anti-inflammatory drugs (NSAIDs), naproxen use during pregnancy is not well studied. The objective of this analysis was to assess negative effects on pregnancy outcomes following naproxen exposure in the first trimester of pregnancy. Out of 121 exposed pregnancies prospectively recorded by two German teratology information services (TIS) 15 ended as spontaneous abortion and ten were electively terminated; in one case for prenatal diagnosis of anencephaly. Four pregnancies were stillborn, in these cases naproxen was discontinued more than two months before the event. Of 95 live-born infants, including three pairs of twins, two were born with major birth defects: one with dysmelia of the left hand and foot and another with a complex congenital heart defect, esophageal atresia with tracheoesophageal fistula, and choanal stenosis. The results of this case series do not suggest that naproxen has a significant teratogenic effect. However, due to the limited cohort size and lack of comparable reference group results should be interpreted with caution and better studied NSAIDs such as ibuprofen should be preferred in the first and second trimester of pregnancy. This work was supported by the German Federal Institute for Drugs and Medical Devices (BfArM).

Ivabradine use in pregnant women-treatment indications and pregnancy outcome: an evaluation of the German Embryotox database.

PURPOSE: Ivabradine has been approved for the treatment of chronic heart failure and chronic stable angina pectoris in Europe. Based on adverse outcomes of reproductive animal studies and the lack of human data, ivabradine is considered contraindicated during pregnancy. The aim of this observational study is to analyse ivabradine use before and during pregnancy. METHODS: We evaluated all ivabradine-related requests to the German Embryotox Institute from 2007 to 2019. Exposed pregnancies were analysed as to their outcome. RESULTS: Off-label use for supraventricular tachycardia was frequent in women of childbearing age. Of 38 prospectively ascertained pregnancies with ivabradine exposure and completed follow-up, 32 resulted in live births, 3 in spontaneous abortions, and 3 were electively terminated. One neonate presented with major birth defects (atrial septal defect and cleft palate). In 33/38 patients, ivabradine was discontinued after confirmation of pregnancy without cardiac deterioration and 5/38 women continued ivabradine throughout pregnancy. In addition, there were 3 retrospectively reported pregnancies including one major birth defect (tracheal atresia). CONCLUSION: This case series represents the largest cohort of ivabradine-exposed pregnancies, published so far. According to our findings, ivabradine appears not to be a major teratogen. However, established drugs of choice with strong evidence of low risk for the unborn should be preferred in women planning pregnancy. After inadvertent exposure during pregnancy or lack of treatment alternatives, fetal ultrasound for structural anomalies and growth restriction is recommended. In addition, close monitoring is necessary in pregnant women with supraventricular arrhythmias or cardiac disease.

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.

Ulipristal acetate and pregnancy outcome-an observational study.

STUDY QUESTION: Is the failure of the selective progesterone receptor modulator ulipristal acetate (UPA) as emergency contraception (EC; 30 mg, single) or inadvertent exposure for myoma treatment (5 mg/d) in pregnancy associated with a higher risk of birth defects, spontaneous abortion (SAB) or elective termination of pregnancy (ETOP)? SUMMARY ANSWER: We did not find an increased risk for birth defects, SABs or ETOPs after UPA exposure during implantation and early embryogenesis. WHAT IS KNOWN ALREADY: Pregnancy outcome data after exposure to UPA are very limited. In cases of EC failure or unplanned pregnancy during myoma treatment, women need well-grounded risk assessment to minimize anxiety and prevent unjustified termination of pregnancy. STUDY DESIGN, SIZE, DURATION: Observational study of prospectively ascertained pregnancies from the German Embryotox institute with UPA exposure (EC, n = 95; myoma, n = 7). Four retrospectively reported pregnancy outcomes were evaluated separately. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 226 requests on ulipristal were directed to the German Embryotox institute during the study period 2010-2018. Outcomes of pregnancies exposed-(i) precycle, (ii) preconceptional or (iii) first trimester-were ascertained using standardized questionnaires. Descriptive statistics were applied. MAIN RESULTS AND THE ROLE OF CHANCE: Failed EC with UPA resulted in 95 prospectively ascertained pregnancies, of which 56 had completed follow-up: 37 live births, 7 SABs and 12 ETOPs. There was no major birth defect. Just 34% of women had taken UPA during the fertile window. Seven prospectively enrolled pregnancies were treated for myoma and had known pregnancy outcomes: five healthy live births and two SABs. Among the four retrospectively reported pregnancies after EC, there was one child diagnosed with Beckwith-Wiedemann syndrome (BWS). LIMITATIONS, REASONS FOR CAUTION: Our limited sample size does not allow concluding safety of UPA use in pregnancy. WIDER IMPLICATIONS OF THE FINDINGS: We provide a preliminary basis for reassuring women who wish to carry their pregnancy to term after EC or myoma treatment with UPA. However, because of the report of a BWS after UPA exposure, a possible epigenetic effect could not be excluded and requires further evaluation. STUDY FUNDING/COMPETING INTEREST(S): This work was performed with financial support from the German Federal Institute for Drugs and Medical Devices (BfArM). All authors declare that they have no conflicts of interest. TRIAL REGISTRATION NUMBER: Registered with the German Clinical Trial Register (DRKS00015155).

Risk estimation of fetal adverse effects after short-term second trimester exposure to non-steroidal anti-inflammatory drugs: a literature review.

PURPOSE: Non-steroidal anti-inflammatory drugs (NSAIDs) are not recommended in the 3rd trimester of pregnancy due to known fetal adverse effects in an advanced gestational age. This investigation was performed to assess whether there is a significant risk of NSAIDs being used as an analgesic or antipyretic medication in the 2nd trimester. METHODS: A systematic search for publications reporting 2nd trimester NSAID exposure was performed in MEDLINE. The search focused on case descriptions reporting defined adverse effects including prenatal ductus arteriosus constriction, oligohydramnios, neonatal renal failure, and primary pulmonary hypertension. Original articles published until February 2018 were considered for evaluation. RESULTS: Out of 681 identified publications, 26 included relevant information on the defined adverse effects. Among these publications, premature labor was the major reason for 2nd trimester indomethacin treatment while other clinical indications and other NSAIDs were underrepresented. Narrowing or closure of the ductus arteriosus in the 2nd trimester was described in 33 fetuses. Only eight publications reported adverse effects after less than 7-day exposure during the 2nd trimester. CONCLUSIONS: Based on these results, short-term use of NSAIDs as analgesics or antipyretics in the 2nd trimester does not appear to pose a substantial risk for fetal adverse effects. Long-term use in the late 2nd trimester, however, should always be monitored.

The Use of Medication in Pregnancy.

BACKGROUND: Drug safety has the highest priority in the treatment of pregnant women, as any effect on fetal development will not be immediately evident, and the harm that ensues may have lifelong adverse consequences. METHODS: This review is based on pertinent publications retrieved by a selective literature search and on expert assessment on the basis of the current evidence. RESULTS: The teratogenic and fetotoxic drugs that are most important in their magnitude of effect and/or frequency of exposure are discussed, along with their characteristic effects. For each of the main indications for drug treatment during pregnancy, the current drugs of choice are stated, regardless of their approval status for use by pregnant women. Drugs are designated as "tolerable" in pregnan- cy if there is currently no reliable evidence of a human teratogenic effect but the state of the evidence is still inadequate for a conclusive determination. Such drugs can be given, in consideration of the risks and benefits, in case the drugs of choice are out of the question. Unplanned pregnancies arising in women who are taking "tolerable" drugs do not necessitate the immediate switch or discontinuation of the drug. On the other hand, drugs with known teratogenic or fetotoxic effects are desig- nated as "contraindicated." For any pregnant woman exposed to such a drug, the risk must be assessed individually, and a risk management strategy must be determined. CONCLUSION: For most indications for drug treatment in pregnant women, drugs are available with adequate clinical experience supporting drug safety. In all fields of medicine, drug safety information for pregnant women needs to be stated more precisely and in a manner more suitable for clinical application; moreover, the explanation to the patient must enable her to assess the risk realistically, but should not arouse undue anxiety. Drug safety in pregnancy demands the continuous collec- tion of observational data, so that risks can be assessed as precisely as possible and false suspicions can be laid to rest, both for new drugs and for those that have already been in longstanding use. To this end, the Pharmacovigilance Institute (Pharmakovigilanz- und Beratungszentrum, PVZ) for Embryotoxicology critically assesses the current state of the evidence and carries out its own relevant observational studies.

[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.

No evidence of adverse pregnancy outcome after exposure to ibuprofen in the first trimester - Evaluation of the national Embryotox cohort.

Ibuprofen is an analgesic frequently used in the 1st and 2nd trimester of pregnancy. Most relevant studies deal with NSAID as a group and do not specifically focus on ibuprofen. In this study, 1117 women exposed to ibuprofen in the 1st trimester were compared to 2229 non-exposed women. Data were retrieved from the German Embryotox database. No significantly increased risk of major birth defects (4.8% vs. 4.1%; OR adjusted 1.11, 95% CI 0.75-1.64) or a distinct pattern of birth defects were found. The cumulative incidences of spontaneous abortions were similar across cohorts (15.5% vs. 16.6%; HR adjusted 0.85; 95% CI, 0.65-1.11). Subgroup analyses of pregnancies exposed for ≥7 (n = 223) and ≥30 days (n = 72) did not reveal a higher risk with increasing treatment duration. Ibuprofen does not seem to carry a substantial embryotoxic risk regarding the investigated endpoints.

Autosomal dominant Robinow syndrome associated with a novel DVL3 splice mutation.

Robinow syndrome is a clinically and genetically heterogeneous disorder characterized by mesomelic limb shortening, distinctive facial features, and variable oral, cardiac, vertebral, and urogenital malformations. We identified the novel de novo splice acceptor mutation c.1715-2A > C in DVL3 in a 15-year-old female patient with typical features of Robinow syndrome. By studying DVL3 transcripts in this patient, we confirmed expression of both wild-type and mutant alleles. Mutant DVL3 mRNAs were found to harbor a deletion of four nucleotides at the beginning of exon 15 and encode a protein product with a distinct -1 reading-frame C-terminus. The data demonstrate that mutant DVL3 proteins associated with Robinow syndrome show truncation of the C-terminus and share 83 novel amino acid residues before the stop codon confirming highly specific DVL3 alterations to be associated with this syndrome. The phenotype of the Robinow syndrome-affected female reported here is typical as she shows mesomelia and mild hand anomalies as well as characteristic facial anomalies. She also exhibited a supraumbilical midline abdominal raphe which has not been observed in other patients with Robinow syndrome. In contrast to the clinical data of four previously reported individuals with DVL3-related Robinow syndrome, short stature was not present in this individual at the age of 15 years. These findings expand the clinical spectrum of Robinow syndrome associated with DVL3 mutations. To date, comparison of clinical data of DVL3 mutation-positive individuals with those of patients with genetically different forms did not allow delineation of gene-specific phenotypes.

Safety of diclofenac use during early pregnancy: A prospective observational cohort study.

Diclofenac is a widely used analgesic so that exposure during pregnancy may frequently occur. Most publications have evaluated the safety of NSAIDs on pregnancy outcome as a group of substances. Specific data on diclofenac are rare. This observational cohort study used the German Embryotox pharmacovigilance database to assess the risk of major birth defects and spontaneous abortion after first trimester exposure to diclofenac. A group of 260 women who took diclofenac during first trimester was compared to 778 non-exposed pregnancies. In the diclofenac exposed cohort 4 major birth defects were observed among 220 live-born infants and 25 spontaneous abortions occurred. Neither the rate of major birth defects (1.8% vs. 3.1%; OR adjusted 0.59; 95% CI 0.17-2.08) nor the risk of spontaneous abortion (HR adjusted 0.90; 95% CI 0.56-1.46) was increased. The study results do not indicate that diclofenac exposure during first trimester is associated with a teratogenic risk.