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.

Dutch trends in the use of potentially harmful medication during pregnancy.

AIMS: Recent population-based data on drug utilization around pregnancy are lacking. This study aims to examine the prevalence of drug exposure in the Netherlands during the preconception, pregnancy and postpartum periods, with special emphasis on trends of potentially harmful medication over the years. METHODS: A population-based study was conducted using records from the PHARMO Perinatal Research Network. From 1999 to 2017, the proportion of pregnancies during which women used any medication or potentially harmful medication was assessed, overall and stratified by timing of exposure relative to pregnancy and by the year of delivery. RESULTS: Overall, 357 226 (73%) and 166 484 (34%) of 487 122 selected pregnancies were exposed to any and potentially harmful medication, respectively. Among these 487 122 pregnancies, preconception prevalence for use of potentially harmful medication was 43%, 24% during the first trimester, 19% during the second, 16% during the third, and 45% postpartum. A declining trend was observed for exposure to any medication, from 84% in 1999 to 68% in 2017. No clear changes were observed over time for the proportion of pregnancies exposed to potentially harmful medication. CONCLUSIONS: Our study shows that the use of potentially harmful medication was high over the last two decades. Although there was a declining trend over the years in overall medication use, during a steady one-third of pregnancies, women used potentially harmful medication. Our findings highlight the need for an increased sense of urgency among both healthcare providers and women of reproductive age regarding potential risks associated with pharmacological treatment during pregnancy.

Using Web-Based Questionnaires to Assess Medication Use During Pregnancy: A Validation Study in 2 Prospectively Enrolled Cohorts.

Medication use is often underreported in paper-based questionnaires or interviews. Web-based questionnaires may improve recall of medication use, but data on their validity are currently lacking. Participants in the Pregnancy and Infant Development (PRIDE) Study (2014-2016; n = 557) and the Pregnancy Drug Registry (pREGnant) (2015-2016; n = 169) completed a 6-week paper-based medication diary during gestational weeks 19-24 or 26-31. In week 34, they completed a Web-based questionnaire with questions on medication names, time period and frequency of use, and quantity taken. To assess the degree of underreporting, we calculated the questionnaire's sensitivity using the medication diary as the reference standard. Sensitivity was high for many medication groups, including antiepileptic medication (sensitivity (Sn) = 0.96, 95% confidence interval (CI): 0.89, 1.00), antacids (Sn = 0.89, 95% CI: 0.86, 0.93), and iron preparations (Sn = 0.81, 95% CI: 0.64, 0.98). However, medications for short-term use were underreported more frequently, with sensitivities of 0.54 (95% CI: 0.35, 0.72) for antihistamines, 0.63 (95% CI: 0.57, 0.69) for analgesic and antipyretic agents, and 0.57 (95% CI: 0.51, 0.64) for acetaminophen. Shortening the period of time between exposure and questionnaire administration increased sensitivity substantially. In conclusion, underreporting in Web-based questionnaires is limited for many medication groups. In prospective studies, underreporting of medications for short-term use may be reduced by decreasing the interval between consecutive questionnaires.

Pregnancy outcome following maternal exposure to mirtazapine: a multicenter, prospective study.

This multicenter, observational prospective cohort study addresses the risk associated with exposure to mirtazapine during pregnancy. Pregnancy outcomes after exposure to mirtazapine were compared with 2 matched control groups: (1) exposure to any selective serotonin reuptake inhibitor (SSRI, control subjects with a psychiatric condition) and (2) no exposure to medication known to be teratogenic or any antidepressant (general control subjects). Data were collected by members of the European Network of Teratology Information Services between 1995 and 2011. Observations from 357 exposed pregnancies were compared with 357 pregnancies from each control group. The rate of major birth defects between the mirtazapine and the SSRI group did not differ significantly (4.5% vs 4.2%; odds ratio [OR], 1.1; 95% confidence interval [95% CI], 0.5-2.3; P = 0.9). A trend toward a higher rate of birth defects in the mirtazapine group compared with general control subjects (4.5% vs 1.9%; OR, 2.4; 95% CI, 0.9-6.3; P = 0.08) reached statistical significance after exclusion of chromosomal or genetic anomalies (4.1% vs 1.3%; OR, 3.3; 95% CI, 1.04-10.3; P = 0.03), but this difference became again nonsignificant if cases of exposure not comprising the first trimester were excluded from the analysis (3.4% vs 1.9%; OR, 1.8; 95% CI, 0.6-5.0; P = 0.26). The crude miscarriage rate did not differ significantly between the mirtazapine, the SSRI, and the general control groups (12.1% vs 12.0% vs 9.3%; P = 0.44). However, a higher rate of elective pregnancy termination was observed in the mirtazapine group compared with SSRI and general control subjects (7.8% vs 3.4% vs 5.6%; P = 0.03). This study did not observe a statistically significant difference in the rate of major birth defects after first-trimester exposure between mirtazapine, SSRI-exposed, and nonexposed pregnancies. A marginally higher rate of birth defects was, however, observed in the mirtazapine and SSRI groups compared with the low rate of birth defects in our general control subjects. Overall pregnancy outcome after mirtazapine exposure was similar to that of the SSRI-exposed control group.

Male Sexual Health and Reproduction in Cutaneous Immune-Mediated Diseases: A Systematic Review.

INTRODUCTION: Information about the possible effects of cutaneous immune-mediated diseases (cIMDs) on male sexual function and reproduction is scarce. Factors known to impair sexual health and reproduction, such as inflammation, medication use, and hypogonadism, can be present in a significant proportion of male patients with cIMD. OBJECTIVES: To systematically review the literature for the influence of paternal cIMD on many aspects of male sexual and reproductive health, such as sexual function, reproductive hormones, fertility, and pregnancy and offspring outcomes. METHODS: A systematic literature search was performed. The searches combined keywords regarding male sexual function and fertility, pregnancy outcomes, and offspring's health with a list of cIMDs. RESULTS: The majority of the identified studies included patients with psoriasis (22 of 27), and sexual function was the most common outcome of interest (20 of 27). For patients diagnosed with psoriasis, the prevalence of male sexual dysfunction reported in these studies ranged from 34 to 81%. Hypogonadism in patients with psoriasis was reported in 2 of 3 studies. Sperm analysis abnormalities in patients with psoriasis were reported in 3 of 4 studies. No information about the effect of paternal disease on pregnancy and offspring outcomes was identified. CONCLUSIONS: Disease activity in psoriasis might play an important role in the development of sexual dysfunction, hypogonadism, and abnormal sperm quality. For the other cIMD included in this review, there is insufficient information regarding male sexual and reproductive health to draw firm conclusions. More research is needed to understand the association between cIMD and impaired male sexual and reproductive health. Perez-Garcia LF, Dolhain R, te Winkel B, et al. Male Sexual Health and Reproduction in Cutaneous Immune-Mediated Diseases: A Systematic Review. Sex Med Rev 2021;9:423-433.

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.

Aim and Design of pREGnant, the Dutch Pregnancy Drug Register.

Information on the safety of medication use during pregnancy and breastfeeding is scarce, yet use of medication among pregnant and breastfeeding women is widespread. The pREGnant, the Dutch Pregnancy Drug Register, was set up to obtain insight into medication use among pregnant and breastfeeding women and potential effects on maternal and fetal/infant health. The systematically documented, good quality data on medication use during pregnancy and lactation in pREGnant will be used in signal detection, epidemiologic studies and counseling of healthcare providers and patients. The register has a prospective cohort design. The population is derived from pregnant women throughout the Netherlands. Data collection started in April 2014 and enrollment of women is continuous and is characterized by a relative high proportion of women born in the Netherlands with a high education compared with the general Dutch pregnant population. Data on current pregnancy, obstetric history, maternal lifestyle, health and medication use, delivery, and infant health are collected through web-based questionnaires completed by the participating women (three times during pregnancy and three times during the infant's first year of life). If permission is given, the self-reported data can be complemented with information retrieved from Perined, the perinatal registry of the Netherlands, and from obstetric and medical records, and/or pharmacy records. Here, we provide detailed information on the design of the pREGnant, the Dutch Pregnancy Drug Register, as well as descriptive information on characteristics of the participants so far. Currently, steps are being taken to implement the register on a large scale in the Netherlands.

Assessment of medication use during pregnancy by Web-based questionnaires, pharmacy records and serum screening.

OBJECTIVE: To compare assessment of early pregnancy medication exposure using three methods of data collection. METHODS: Serum samples were obtained from 752 women participating in the PRegnancy and Infant DEvelopment (PRIDE) Study before gestational week 17. For 52 women using medication at the date of blood sampling according to Web-based questionnaires or pharmacy records, we analysed serum samples using untargeted liquid chromatography time-of-flight spectrometry. RESULTS: Medication was detected in 18 serum samples (35%). Medications taken orally for chronic conditions reported in the questionnaire were detected in serum and vice versa. Pharmacy records did not identify additional exposed women, but missed exposure in 5 women mainly due to unavailability. We observed substantial discordance between the three methods for inhaled medication, dermatological preparations, and medications for short-term use, which went often undetected in serum. CONCLUSIONS: It remains challenging to assess medication use in large-scale studies as no 'gold standard' is currently available.

Web-based questionnaires to assess perinatal outcome proved to be valid.

OBJECTIVES: The objective of this study was to validate a Web-based questionnaire completed by the mother to assess perinatal outcome used in a prospective cohort study. STUDY DESIGN AND SETTING: For 882 women with an estimated date of delivery between February 2012 and February 2015 who participated in the PRegnancy and Infant DEvelopment (PRIDE) Study, we compared data on pregnancy outcome, including mode of delivery, plurality, gestational age, birth weight and length, head circumference, birth defects, and infant sex, from Web-based questionnaires administered to the mothers 2 months after delivery with data from obstetric records. For continuous variables, we calculated intraclass correlation coefficients (ICCs) with 95% confidence intervals (CIs), whereas sensitivity and specificity were determined for categorical variables. RESULTS: We observed only very small differences between the two methods of data collection for gestational age (ICC, 0.91; 95% CI, 0.90-0.92), birth weight (ICC, 0.96; 95% CI, 0.95-0.96), birth length (ICC, 0.90; 95% CI, 0.87-0.92), and head circumference (ICC, 0.88; 95% CI, 0.80-0.93). Agreement between the Web-based questionnaire and obstetric records was high as well, with sensitivity ranging between 0.86 (termination of pregnancy) and 1.00 (four outcomes) and specificity between 0.96 (term birth) and 1.00 (nine outcomes). CONCLUSION: Our study provides evidence that Web-based questionnaires could be considered as a valid complementary or alternative method of data collection.