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.

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.

Safety of direct oral anticoagulant exposure during pregnancy: a retrospective cohort study.

BACKGROUND: Direct oral anticoagulants (DOACs) have largely replaced vitamin K antagonists in many indications for anticoagulation. Prescribed to millions of patients, including women of reproductive age, exposure to DOACs in early pregnancy is not uncommon, but data on the embryotoxic risks are scarce. We aimed to assess the risk of DOAC embryotoxicity in a large sample of reported cases. METHODS: In this retrospective cohort study, we collected individual case reports of DOAC exposure in pregnancy from gynaecologists, haematologists, and vascular specialists starting from May, 2015. We obtained exports in April and October, 2017, August, 2018, and December, 2019, from the pharmacovigilance databases of the DOAC manufacturers, the European Medicines Agency (EMA), the German drug authority, and searched the homepage of the US Food and Drug Administration (FDA) for pregnancy exposure reports. Data from the International Society of Thrombosis and Haemostasis (ISTH) registry were obtained in August, 2018, and on July 21, 2020; data from the Teratology Information Service in Ulm, Germany, were received July 22, 2020. We also ran a systematic literature search on July 22, 2020, for cases of DOAC exposure. These data were compiled with those from our 2016 risk assessment and duplicate reports were excluded. Fetal or neonatal abnormalities were classified as a major birth defect according to the European Concerted Action on Congenital Anomalies and Twins (EUROCAT) classification and adjudicated into four categories: relation to DOAC exposure likely, possible, unlikely, or unrelated. FINDINGS: We identified 1193 reports of DOAC exposure during pregnancy: 49 from physicians, 48 from the ISTH registry, 29 from the Teratology Information Service, 62 from the German drug authority, 536 from Bayer (extracted from the Bayer pharmacovigilance system, the WHO VigiBase, and from the FDA Adverse Event Reporting System), 87 from Boehringer Ingelheim, 16 from Daiichi Sankyo, 98 from the literature search, two from the FDA homepage search, ten from the Risk Evaluation and Mitigation Strategy Review, and 256 from the EMA reports. After excluding potential duplicates, we identified 614 unique cases of DOAC exposure in pregnancy occurring between Feb 1, 2007, and July 9, 2020, that consisted of rivaroxaban in 505 (82%) pregnancies, dabigatran in 36 (6%), apixaban in 50 (8%), and edoxaban in 23 (4%). The median duration of DOAC exposure was 5·3 weeks (IQR 4·0-7·0) into pregnancy. Information on pregnancy outcome was available in 336 (55%) of 614 pregnancies: 188 (56%) livebirths, 74 (22%) miscarriages, and 74 (22%) elective pregnancy terminations. 21 (6%; 95% CI 4-9) of 336 showed fetal abnormalities, of which 12 (4%; 2-6) were adjudicated as major birth defects potentially related to DOAC exposure. INTERPRETATION: Although reports of pregnancy outcomes after DOAC exposure are missing important details and predominantly describe rivaroxaban exposures, the available data do not suggest that DOAC exposure in pregnancy carries a high risk of embryopathy. The 2016 ISTH guidance against elective pregnancy termination for fear of DOAC embryotoxicity and the recommendation in favour of close pregnancy surveillance is still valid. Pregnancy outcome data are inconsistently captured in pharmacovigilance databases, indicating a strong need for a more robust system of reporting. FUNDING: None.

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).

Fetotoxic risk of AT1 blockers exceeds that of angiotensin-converting enzyme inhibitors: an observational study.

OBJECTIVE: The fetotoxic potential of prenatal exposure to angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin II receptor blockers (ARBs) has been known for many years. Symptoms range from transient oligohydramnios to neonatal anuria and permanent renal damage, joint contractures, hypocalvaria, lung hypoplasia and intrauterine or neonatal death. This study aims to investigate the critical gestational time for renin-angiotensin system inhibitor (RAS-I)-induced fetopathy, to quantify the fetopathy risk and to evaluate factors associated with the occurrence and severity of fetopathy. METHODS: Prospectively and retrospectively ascertained RAS-I exposed pregnancies from the databases of six teratology information services were analyzed. RESULTS: Eighty-nine pregnancies with ACE-I and 101 with ARB exposure beyond the first trimester were identified. Fifty-nine of these 190 pregnancies were classified as having evidence of RAS-I fetopathy. All pregnancies affected with fetopathy were exposed after 20 0/7 gestational weeks. Limited to prospectively enrolled cases with exposure at least 20 0/7 gestational weeks, the rate of fetopathy was 3.2% for ACE-I and 29.2% for ARB. The chance of recovery of amniotic fluid volume was higher with RAS-I discontinuation before 30 gestational weeks and with a longer exposure-free interval before delivery. CONCLUSION: Exposure to ARBs is associated with a higher fetopathy risk than exposure to ACE-Is. RAS-I should ideally be discontinued prior to pregnancy or immediately after recognition of pregnancy. Because symptoms may improve in cases of RAS-I-induced oligohydramnios, pregnancy should be maintained as long as there is fetal well being. Physicians and patients need to be alerted to the fetotoxic risks of RAS-I.

Neonatal effects of intrauterine metoprolol/bisoprolol exposure during the second and third trimester: a cohort study with two comparison groups.

OBJECTIVES: Our aim was to evaluate the effects of beta-blockers during the second and third trimester on fetal growth, length of gestation and postnatal symptoms in exposed infants. METHODS: The current prospective observational cohort study compares 294 neonates of hypertensive mothers on metoprolol or bisoprolol during the second and/or third trimester with 225 methyldopa-exposed infants and 588 infants of nonhypertensive mothers. The risks for reduced birth weight, prematurity, neonatal bradycardia, hypoglycaemia and respiratory disorders were analysed. RESULTS: The rate of small-for-gestational-age children was significantly higher in long-term beta-blocker exposed infants (24.1%) compared with the methyldopa cohort [10.2%, odds ratio (OR)adj 2.5, 95% confidence interval (CI) 1.2-5.2] and the nonhypertensive cohort (9.9%, ORadj 4.3, 95% CI 2.6-7.1). The risk for preterm birth was significantly increased compared with nonhypertensive pregnancies (ORadj 2.2, 95% CI 1.3-3.8) but not compared with the methyldopa cohort. Neonatal adverse outcomes occurred more frequently in the study cohort (11.5%) compared with the nonhypertensive comparison group (6.5%) and the methyldopa cohort (8.4%), but without statistical significance (ORadj 1.5, 95% CI 0.7-3.0 and ORadj 1.5, 95% CI 0.7-3.3, respectively). CONCLUSION: Long-term intrauterine exposure to metoprolol or bisoprolol may increase the risk of being born small-for-gestational-age. It is still a matter of debate to which extent maternal hypertension contributes to the lower birth weight. Serious neonatal symptoms are rare. Altogether, metoprolol and bisoprolol are well tolerated treatment options, but a case-by-case decision on close neonatal monitoring is recommended.

Pregnancy outcome after first-trimester exposure to fosfomycin for the treatment of urinary tract infection: an observational cohort study.

PURPOSE: The primary aim of our study was to assess pregnancy outcome after first-trimester exposure to fosfomycin. METHODS: We performed an observational cohort study analysing prospectively ascertained pregnancies including 152 women exposed to fosfomycin in the first trimester of pregnancy in comparison with a randomly selected cohort comprising 456 pregnancies not exposed to fosfomycin. All pregnancies were identified through risk consultations using structured questionnaires between January 2000 and December 2016 by the German Embryotox pharmacovigilance institute in Berlin. Primary objectives were the risks of major birth defects and spontaneous abortion. RESULTS: Only 1 out of 146 exposed infants was affected by a major birth defect (0.7%, 95% CI 0.04-4.33%) in comparison to 15/399 in the non-exposed cohort (3.8%, 95% CI 2.2-6.26%). Spontaneous abortions were observed in 5/152 cases in the fosfomycin cohort vs. 53/456 cases in the comparison cohort (cumulative incidence 6.2% vs. 23.1%; HR adjusted 0.35, 95% CI 0.14-0.90). CONCLUSION: This is the first study specifically examining the teratogenic risk of fosfomycin. The study results do not indicate an increased risk of adverse pregnancy outcome after fosfomycin exposure during early pregnancy. However, larger studies are needed to confirm the safety of fosfomycin during the first trimester.

Estimating cumulative incidence functions in competing risks data with dependent left-truncation.

Both delayed study entry (left-truncation) and competing risks are common phenomena in observational time-to-event studies. For example, in studies conducted by Teratology Information Services (TIS) on adverse drug reactions during pregnancy, the natural time scale is gestational age, but women enter the study after time origin and upon contact with the service. Competing risks are present, because an elective termination may be precluded by a spontaneous abortion. If left-truncation is entirely random, the Aalen-Johansen estimator is the canonical estimator of the cumulative incidence functions of the competing events. If the assumption of random left-truncation is in doubt, we propose a new semiparametric estimator of the cumulative incidence function. The dependence between entry time and time-to-event is modeled using a cause-specific Cox proportional hazards model and the marginal (unconditional) estimates are derived via inverse probability weighting arguments. We apply the new estimator to data about coumarin usage during pregnancy. Here, the concern is that the cause-specific hazard of experiencing an induced abortion may depend on the time when seeking advice by a TIS, which also is the time of left-truncation or study entry. While the aims of counseling by a TIS are to reduce the rate of elective terminations based on irrational overestimation of drug risks and to lead to better and safer medical treatment of maternal disease, it is conceivable that women considering an induced abortion are more likely to seek counseling. The new estimator is also evaluated in extensive simulation studies and found preferable compared to the Aalen-Johansen estimator in non-misspecified scenarios and to at least provide for a sensitivity analysis otherwise.

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.

Multistate methodology improves risk assessment under time-varying drug intake-a new view on pregnancy outcomes following coumarin exposure.

PURPOSE: Observational cohort studies are essential to evaluate the risk of adverse pregnancy outcomes associated with drug intake. Besides left truncation and competing events, it is crucial to account for the time-dynamic pattern of drug exposure. In fact, potentially harmful medications are often discontinued, which might affect the outcome. Ignoring these challenges may lead to biased estimation of drug-related risks highlighting the need for adequate statistical techniques. METHODS: We reanalyze updated data of a recently published study provided by the German Embryotox pharmacovigilance institute. The aim of the study was to quantify the effect of discontinuation of vitamin K antagonist phenprocoumon on the risk of spontaneous abortion. RESULTS: We outline multistate methodology as a powerful method removing bias in probability estimation inherent to commonly used crude proportions. We incorporate time-dependent discontinuation and competing pregnancy outcomes as separate states in a multistate model, which enables the formulation of hazard-based Cox proportional hazard models and the application of so-called landmark techniques. Results show that early discontinuation of phenprocoumon substantially reduces the risk of spontaneous abortion, which is of great importance for both pregnant women and treating physicians. CONCLUSIONS: An adequate handling of discontinuation times is essential when analyzing the risk of spontaneous abortion. The proposed concepts are not restricted to pregnancy outcome studies but have broad usage in other fields of epidemiology. Our nontechnical report may provide guidance for the design and analysis of future studies. Example code is provided.

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.

Increased rate of birth defects after first trimester use of angiotensin converting enzyme inhibitors - Treatment or hypertension related? An observational cohort study.

OBJECTIVES: To analyze the risk of spontaneous abortions and major birth defects in pregnancies of women treated with angiotensin converting enzyme inhibitors (ACEIs) during the first trimester. STUDY DESIGN: Observational cohort study of prospectively ascertained pregnancies from the German Embryotox pharmacovigilance institute. Pregnancy outcomes after maternal exposure to ACEIs during the first trimester were compared with pregnancies without antihypertensive treatment. In a sensitivity analysis, ACEI exposed hypertensive women were compared with hypertensive women on methyldopa. RESULTS: The risk of spontaneous abortion among 329 ACEI exposed women was not increased compared to 654 women without antihypertensive treatment (adjusted hazard ratio 1.20, 95% confidence interval (CI) 0.74-1.92), whereas the risk for major birth defects (14/255; 5.5% vs. 19/567; 3.4%) was significantly increased (adjusted odds ratio 2.41, 95% CI 1.07-5.43). In contrast, birth defect rates were not significantly different between hypertensive women on ACEIs and hypertensive women on methyldopa. In addition, we did not observe a distinct pattern of birth defects among retrospectively ascertained pregnancies after ACEI exposure during the first trimester. CONCLUSIONS: Women with hypertension treated with ACEIs in early pregnancy are at higher risk for major birth defects, which may be explained by other factors associated with maternal hypertension. Women (inadvertently) exposed during early pregnancy may be reassured and treatment switched to antihypertensive drugs recommended for pregnancy.