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Background: Medication abortion, with a combination of mifepristone and misoprostol, is highly effective and safe. However, there is insufficient evidence on efficacy and safety at very early gestations before a pregnancy can be visualized with ultrasonography., Methods: We conducted a multicenter, noninferiority, randomized, controlled trial involving women requesting medication abortion at up to 42 days of gestation with an unconfirmed intrauterine pregnancy on ultrasound examination (visualized as an empty cavity or a sac-like structure without a yolk sac or embryonic pole). Participants were randomly assigned to either immediate start of abortion (early-start group) or standard-care treatment delayed until intrauterine pregnancy was confirmed (standard group). The primary outcome was complete abortion. The noninferiority margin was set at 3.0 percentage points for the absolute between-group difference., Results: In total, 1504 women were included at 26 sites in nine countries and were randomly assigned to the early-start group (754 participants) or the standard group (750 participants). In an intention-to-treat analysis, a complete abortion occurred in 676 of 710 participants (95.2%) in the early-start group and in 656 of 688 (95.3%) in the standard group; the absolute between-group difference was -0.1 percentage points (95% confidence interval, -2.4 to 2.1). Ectopic pregnancies occurred in 10 of 741 participants (1.3%) in the early-start group and in 6 of 724 (0.8%) in the standard group, with one rupture before diagnosis (early-start group). Serious adverse events occurred in 12 of 737 participants (1.6%) in the early-start group and in 5 of 718 (0.7%) in the standard group (P = 0.10); the majority were uncomplicated hospitalizations for treatment of ectopic pregnancy or incomplete abortion., Conclusions: Medication abortion before confirmed intrauterine pregnancy was noninferior to standard, delayed treatment with respect to complete abortion. (Funded by the Swedish Research Council and others; VEMA EudraCT number, 2018-003675-35; ClinicalTrials.gov number, NCT03989869.)., (Copyright © 2024 Massachusetts Medical Society.)

Mifepristone is an anti-progestational drug that is the first component of the standard medical abortion regimen. For women who take mifepristone and then do not take misoprostol, which is the second component of the medical abortion regimen, it is possible that their pregnancy may continue to live birth. Since mifepristone is commonly used for medical abortion up to 9-10 weeks gestation, any adverse or teratogenic effects on the developing embryo/fetus must be considered, given exposure during the critical time of its development and organogenesis. Toxicology and teratology reports have cited studies demonstrating teratogenic effect of mifepristone in some animals. Current clinical guidelines for women exposed to mifepristone in the first trimester of pregnancy state that it is not known to be teratogenic based on limited published evidence from humans. The aim of this narrative systematic review was to investigate embryonic/fetal exposure to mifepristone and any association with congenital or fetal anomalies. This study was conducted by systematic searches of health databases from inception to February 2024. The references of relevant citations were manually searched to retrieve any additional citations not captured in database searching. Congenital anomalies and adverse outcomes were encountered at various doses of mifepristone exposure. A number of the congenital anomalies encountered in this review were explained by circumstances other than exposure to mifepristone. The present systematic review did not find data to support mifepristone being implicated as a teratogen., (© 2024 The Author(s). Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Recent research suggests that fetal exposure to antidepressants (ADs) is significantly associated with fetal death, including stillbirth. However, there has been limited investigation into the timing of AD exposure during pregnancy, the specific effect of each drug, and the possibility of indication bias. To address these gaps in knowledge, we conducted a systematic review of literature and disproportionality analyses using the WHO Safety Database (VigiBase Ⓡ ). The systematic review provided evidence for increased risks of fetal death with exposure to any selective serotonin reuptake inhibitor (SSRI) at any time of pregnancy, stillbirth with exposure to any AD during the first trimester, and stillbirth with exposure to any SSRI during the first trimester. Disproportionality analyses revealed significant associations with citalopram, clomipramine, paroxetine, sertraline, and venlafaxine. Combining both sets of results, we conclude that exposure to ADs, especially during the first trimester of pregnancy, seems to be associated with fetal mortality, and that ADs with highest placental transfer may be particularly involved. Further research should investigate the links between ADs during early pregnancy and fetal mortality., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Introduction: Threatened miscarriages is a common complication of first-trimester pregnancy. Due to the beneficial effects, there are increasing clinical studies on Yunkang oral liquid(YKOL). However, the efficacy and safety of YKOL are still unknown. The aim of this systematic review was to assess the efficacy and safety of YKOL in the treatment of threatened miscarriage during the first-trimester pregnancy (TMFP)., Methods: This protocol will be prepared according to the preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) statement. The systematic review will include all randomized controlled trials (RCTs) studies published until April 2021. Electronic sources including CNKI, WF, VIP, CBM, MEDLINE(PubMed), Embase, Cochrane Library, and Web of Science will be searched for potentially eligible studies. The international clinical trial registration platform and the Chinese clinical trial registration platform of controlled trials will be searched from their inception until April 1st, 2021. According to the inclusion and exclusion criteria, screening literature, extraction data will be conducted by two researchers independently. Statistical analysis will use RevMan 5.3.5 software. The strength of evidence from the studies will be evaluated with the Grading of Recommendation, Assessment, Development and Evaluation (GRADE) methods., Results: This study will provide evidence for YKOL combined with conventional therapy for TMFP., Conclusion: The efficacy and safety of YKOL combined with conventional therapy for TMFP will be assessed., Systematic Review Registration: INPLASY202140105 (https://www.doi.org/10.37766/inplasy2021.4.0105)., Competing Interests: The authors have declaredthat no competing interests exist.

Background: Per- and polyfluoroalkyl substances (PFAS) are persistent organic pollutants that have become globally ubiquitous in humans and the environment. In utero PFAS exposure is associated with neurodevelopmental effects; however, the mechanism is poorly understood. Brain-derived neurotrophic factor (BDNF) signaling is critical to fetal neurodevelopment during pregnancy and maintains important regulatory roles later in life. This study aims to characterize placental BDNF signaling and investigate whether PFAS exposure disrupts the signaling pathway in placental trophoblast cells., Methods: The expression and localization of BDNF receptors-p75 NTR and TrkB-in first trimester and term human placentas and trophoblast cells were investigated by immunofluorescence staining. To assess the effects of PFAS exposure on the BDNF pathway, BeWo cells were treated with PFAS mixtures that mimicked blood levels in a highly exposed population and major PFAS compounds in the mixture at 0.01, 0.1, 1, and 10 µM concentrations. Changes in pro-BDNF levels and phosphorylation of TrkB receptors were examined by Western blot., Results: In first trimester human placentas, TrkB and p75 NTR receptors were primarily localized to syncytiotrophoblast and cytotrophoblast cells. At term, TrkB and p75 NTR receptors were primarily observed in the placental villous stroma. TrkB receptor staining in trophoblasts was reduced at term, while p75 NTR receptor staining was negative. TrkB receptors were confined to the nuclear and perinuclear spaces, and phosphorylation occurred at the Tyr816 residue in BeWo cells. Exposure to PFOS, PFOA, PFBS, and the six-PFAS mixture did not significantly affect BDNF levels or activation (phosphorylation) of TrkB. Treating cells with 1 μM and 10 μM of PFNA resulted in increased TrkB phosphorylation compared to unexposed controls, but BDNF levels were unchanged., Conclusions: BDNF receptors are present in different regions of human placental villi, indicating diverse functions of BDNF signaling in placental development. Our findings suggest that the BDNF pathway in placental trophoblast cells is not disrupted by exposures to PFOS, PFOA, PFBS, and a PFAS mixture, but may be affected by PFNA exposures. Further investigation is needed on how PFAS affects other critical signaling pathways during fetal neurodevelopment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Marchese, Li, Liu, Zhang and Feng.)

Acetaminophen, aspirin, and ibuprofen are mild analgesics commonly used by pregnant women, the sole current recommendation being to avoid ibuprofen from the fifth month of gestation. The nephrotoxicity of these three analgesics is well documented in adults, as is their interference with prostaglandins biosynthesis. Here we investigated the effect of these analgesics on human first trimester kidneys ex vivo. We first evaluated prostaglandins biosynthesis functionality by performing a wide screening of prostaglandin expression patterns in first trimester human kidneys. We demonstrated that prostaglandins biosynthesis machinery is functional during early nephrogenesis. Human fetal kidney explants aged 7-12 developmental weeks were exposed ex vivo to ibuprofen, aspirin or acetaminophen for 7 days, and analyzed by histology, immunohistochemistry, and flow cytometry. This study has revealed that these analgesics induced a spectrum of abnormalities within early developing structures, ranging from cell death to a decline in differentiating glomeruli density. These results warrant caution for the use of these medicines during the first trimester of pregnancy., (© 2021 Federation of American Societies for Experimental Biology.)

Tumor necrosis factor-alpha (TNF-α) is a multifunctional Th1 cytokine and one of the most important inflammatory cytokines. In pregnancy, TNF-α influences hormone synthesis, placental architecture, and embryonic development. It was also shown that increased levels of TNF-α are associated with pregnancy loss and preeclampsia. Increased TNF-α levels in complicated pregnancy draw attention to trophoblast biology, especially migratory activity, syncytialisation, and endocrine function. Additionally, elevated TNF-α levels may affect the maternal-fetal relationship by altering the secretory profile of placental immunomodulatory factors, which in turn affects maternal immune cells. There is growing evidence that metabolic/pro-inflammatory cytokines can program early placental functions and growth in the first trimester of pregnancy. Furthermore, early pregnancy placenta has a direct impact on fetal development and maternal immune system diseases that release inflammatory (e.g., TNF-α) and immunomodulatory factors, such as chronic inflammatory rheumatic, gastroenterological, or dermatological diseases, and may result in an abnormal release of cytokines and chemokines in syncytiotrophoblasts. Pregnancy poses a challenge in the treatment of chronic disease in patients who plan to have children. The activity of the disease, the impact of pregnancy on the course of the disease, and the safety of pharmacotherapy, including anti-rheumatic agents, in pregnancy should be considered.

Many first trimester sporadic miscarriages are unexplained and the role of environmental exposures is unknown. The present aim was to study if levels of Perfluoroalkyl substances (PFASs) in early pregnancy are associated with unexplained, sporadic first trimester miscarriage. The study was performed within the Swedish SELMA pregnancy cohort. Seventy-eight women with non-recurrent first trimester miscarriage were included and 1449 women were available as live birth controls. Eight PFASs were measured in first trimester serum. A doubling of perfluorooctanoic acid (PFOA) exposure, corresponding to an inter-quartile increase, was associated with an odds ratio (95%CI) for miscarriage of 1.48 (1.09-2.01) when adjusting for parity, age and smoking. Analyses per quartiles of PFOA exposure indicated a monotonic dose response association with miscarriage. A similar, but not significant, pattern was observed for perfluorononanoic acid (PFNA). For other PFAS, there were no associations with miscarriage. We have previously shown associations between early pregnancy PFAS exposures and preeclampsia, as well as lower birth weight. Now we report an association between PFOA and miscarriage within the same cohort, which may suggest shared but unknown mechanisms. The study can only represent a period of early placentation and clinical pregnancy loss during the second half of the first trimester.

Context: Large, longitudinal studies on androgen levels in pregnant women with polycystic ovary syndrome (PCOS) are lacking. While metformin has a mild androgen-lowering effect in non-pregnant women with PCOS, its effects on maternal androgen levels in pregnancy are less well understood., Objective: To describe androgen patterns in pregnant women with PCOS and in healthy control women, and to explore the potential effects of metformin on maternal androgen levels in PCOS., Design and Setting: A post hoc analysis from a randomized, placebo-controlled, multicenter study carried out at 11 secondary care centers and a longitudinal single-center study on healthy pregnant women in Norway., Participants: A total of 262 women with PCOS and 119 controls., Intervention: The participants with PCOS were randomly assigned to metformin (2 g daily) or placebo, from first trimester to delivery., Main Outcome Measures: Androstenedione (A4), testosterone (T), sex-hormone binding globulin (SHBG), and free testosterone index (FTI) at 4 time points in pregnancy., Results: Women with PCOS versus healthy controls had higher A4, T, and FTI, and lower SHBG at all measured time points in pregnancy. In the overall cohort of women with PCOS, metformin had no effect on A4, T, SHBG, and FTI. In subgroup analyses, metformin reduced A4 (P = 0.019) in nonobese women. Metformin also reduced A4 (P = 0.036), T (P = 0.023), and SHBG (P = 0.010) levels through pregnancy in mothers with a male fetus., Conclusion: Metformin had no effect on maternal androgens in PCOS pregnancies. In subgroup analyses, a modest androgen-lowering effect was observed in nonobese women with PCOS. In PCOS women carrying a male fetus, metformin exhibited an androgen-lowering effect., (© Endocrine Society 2020.)

Medication abortion, also referred to as medical abortion, is a safe and effective method of providing abortion. Medication abortion involves the use of medicines rather than uterine aspiration to induce an abortion. The U.S. Food and Drug Administration (FDA)-approved medication abortion regimen includes mifepristone and misoprostol. The purpose of this document is to provide updated evidence-based guidance on the provision of medication abortion up to 70 days (or 10 weeks) of gestation. Information about medication abortion after 70 days of gestation is provided in other ACOG publications ().

This study aimed to determine the effects of prenatal exposure to angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs), particularly when exposure is limited to the first trimester of pregnancy, on adverse maternal and neonatal outcomes. A systematic search was performed on four databases, that is, PubMed, Scopus, Web of Science, and Cochrane Library, to identify relevant articles published up to December 31, 2019. Included studies were limited to original investigations assessing the association between prenatal exposure to ACEIs/ARBs and adverse pregnancy outcomes. Odds ratios were used as a summary effect measure. Pooled-effect estimates of each outcome were calculated by the random-effects meta-analysis. The main outcomes included overall and specific congenital malformations, low birth weight, miscarriage, elective termination of pregnancy, stillbirth, and preterm delivery. Of 19 included articles involving a total of 4 163 753 pregnant women, 13 studies reported an increased risk of, at least, one adverse pregnancy outcome in pregnant women who were exposed to ACEIs/ARBs. Meta-analysis revealed a significant association between overall congenital malformations and first trimester-only exposure to ACEIs/ARBs (OR = 1.94, 95% CI = 1.71-2.21, P < .0001). Cardiovascular malformations, miscarriage, and stillbirth also provided a significant relation with ACEI/ARB exposure. In conclusion, prenatal exposure to ACEIs/ARBs in the first trimester of pregnancy was found to be associated with an increased risk of adverse pregnancy outcomes. Women of reproductive age should be aware of the potential teratogenic risks of these drugs if they become pregnant., (© 2020 The Authors. Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd.)

Medication abortion, also referred to as medical abortion, is a safe and effective method of providing abortion. Medication abortion involves the use of medicines rather than uterine aspiration to induce an abortion. The U.S. Food and Drug Administration (FDA)-approved medication abortion regimen includes mifepristone and misoprostol. The purpose of this document is to provide updated evidence-based guidance on the provision of medication abortion up to 70 days (or 10 weeks) of gestation. Information about medication abortion after 70 days of gestation is provided in other ACOG publications ().

Our goal was determine the effects of dydrogesterone supplementation to reduce the incidence of preeclampsia (PE) in early pregnancy (from 6 to 20 weeks of gestation). A total of 406 pregnant women were involved into the study. The Study group enrolled 169 women, supplemented with dydrogesterone at a dose of 30 mg/d 6-20 weeks of gestation compared with the control group (237 subjects) - without dydrogesterone supplementation. The women were randomized by age, race, obstetrics complications, and their somatic history. The use of dydrogesterone in early pregnancy - before 20 weeks of gestation (at a dose of 30 mg/d) with high-risk factors of PE contributed to a statistically significant reduction in the frequency of this complication (13.1% and 71.4%, p  < .001). It was seen, that women who took dydrogesterone developed significantly less such disorders like hypertension (3.2% and 71.2%, p  < .001), proteinuria (0.0% and 66.18%, p  < .001), fetal growth retardation syndrome (2.2% and 21.58%, p  < .001), destroy of uteri-placenta velocity (3.2% and 21.58%, p  < .001), preterm labor (8.6% and 53.95%, p  < .001). Dydrogesterone supplementation in the first and second period of pregnancy (from 6 to 20 weeks of gestation) significantly reduced the incidence of PE in women with higher risk pregnancy.

Introduction: During pregnancy, maternal cortisol levels are increased 3-fold by the third trimester. The enzyme 11β-hydroxysteroid dehydrogenase (11β-HSD, isoforms 1 and 2) regulates the balance between cortisol and cortisone levels. Perfluoroalkyl substances (PFAS) have been reported to inhibit 11β-HSD1 and more potently 11β-HSD2, which could lead to reduced levels of cortisol and more extensively cortisone., Aim: The aim of this work is to investigate a possible effect of early pregnancy PFAS exposure on late pregnancy activity of 11β-HSD1 and 11β-HSD2 assessed by cortisol and cortisone levels in diurnal urine (dU) and blood samples., Methods: This study is part of the prospective cohort study, Odense Child Cohort (OCC). A total of 1628 pregnant women had serum (S) concentrations of 5 PFAS (perfluorooctanoic acid [PFOA], perfluorooctane sulfonic acid [PFOS], perfluorohexane sulfonic acid [PFHxS], perfluorononanoic acid [PFNA], and perfluorodecanoic acid (PFDA)) measured in the first trimester (median gestational week, GW 11). dU cortisol and cortisone (n = 344) and S-cortisol (n = 1048) were measured in the third trimester (median GW 27)., Results: In multiple regression analyses, a 2-fold increase in S-PFOS was significantly associated with lower dU-cortisone (β = -9.1%, P < .05) and higher dU-cortisol/dU-cortisone (dU-C/C) (β = 9.3%, P < .05). In crude models, a doubling in PFOS, PFOA, PFHxS, and PFNA concentrations were associated with a significant increase in S-cortisol; however, these associations became insignificant after adjustment., Conclusion: Early pregnancy maternal S-PFAS were inversely associated with late pregnancy dU-cortisone, indicating reduced activity of 11β-HSD2., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Study Question: Does HIV protease inhibitor (PI)-based combination antiretroviral therapy (cART) initiated at periconception affect key events in early pregnancy, i.e. decidualization and spiral artery remodeling?, Summary Answer: Two PIs, lopinavir and darunavir, currently offered as cART options in HIV-positive pregnancies were evaluated, and we found that lopinavir-based cART, but not darunavir-based cART, impaired uterine decidualization and spiral artery remodeling in both human ex vivo and mouse in vivo experimental models., What Is Known Already: Early initiation of cART is recommended for pregnant women living with HIV. However, poor birth outcomes are frequently observed in HIV-positive pregnancies exposed to PI-based cART, especially when it is initiated prior to conception. The correlation between early initiation of PI-cART and adverse birth outcomes is poorly understood, due to lack of data on the specific effects of PI-cART on the early stages of pregnancy involving uterine decidualization and spiral artery remodeling., Study Design, Size, Duration: Lopinavir and darunavir were evaluated in clinically relevant combinations using an ex vivo human first-trimester placenta-decidua explant model, an in vitro human primary decidual cell culture system, and an in vivo mouse pregnancy model. The first-trimester (gestational age, 6-8 weeks) human placenta-decidua tissue was obtained from 11 to 15 healthy women undergoing elective termination of pregnancy. C57Bl/6 female mice (four/treatment group) were administered either lopinavir-cART, darunavir-cART or water by oral gavage once daily starting on the day of plug detection until sacrifice., Participants/materials, Setting, Methods: Human: Spiral artery remodeling was assessed by immunohistochemical analysis of first-trimester placenta-decidua explant co-culture system. Trophoblast migration was measured using a placental explant culture. A primary decidual cell culture was used to evaluate the viability of immune cell populations by flow cytometry. Soluble factors, including biomarkers of decidualization and angiogenesis, were quantified by ELISA and Luminex assay using decidua-conditioned media. Mouse: In the mouse pregnancy model, gestational day 6.5 or 9.5 implantation sites were used to assess decidualization, spiral artery remodeling and uterine natural killer (uNK) cell numbers by immunohistochemistry. Transcription factor STAT3 was assayed by immunohistochemistry in both human decidua and mouse implantation sites., Main Results and the Role of Chance: Lopinavir-cART, but not darunavir-cART, impaired uterine decidualization and spiral artery remodeling in both experimental models. Lopinavir-cART treatment was also associated with selective depletion of uNK cells, reduced trophoblast migration and defective placentation. The lopinavir-associated decidualization defects were attributed to a decrease in expression of transcription factor STAT3, known to regulate decidualization. Our results suggest that periconceptional initiation of lopinavir-cART, but not darunavir-cART, causes defective maturation of the uterine endometrium, leading to impairments in spiral artery remodeling and placentation, thus contributing to the poor birth outcomes., Large Scale Data: N/A., Limitations, Reasons for Caution: The human first-trimester placenta/decidua samples could only be obtained from healthy females undergoing elective termination of pregnancy. As biopsy is the only way to obtain first-trimester decidua from pregnant women living with HIV on PI-cART, ethics approval and participant consent are difficult to obtain. Furthermore, our animal model is limited to the study of cART and does not include HIV. HIV infection is also associated with immune dysregulation, inflammation, alterations in angiogenic factors and complement activation, all of which could influence decidual and placental vascular remodeling and modify any cART effects., Wider Implications of the Findings: Our findings provide mechanistic insight with direct clinical implications, rationalizing why the highest adverse birth outcomes are reported in HIV-positive pregnancies exposed to lopinavir-cART from conception. We demonstrate that dysregulation of decidualization is the mechanism through which lopinavir-cART, but not darunavir-cART, use in early pregnancy leads to poor birth outcomes. Although lopinavir is no longer a first-line regimen in pregnancy, it remains an alternate regimen and is often the only PI available in low resource settings. Our results highlight the need for reconsidering current guidelines recommending lopinavir use in pregnancy and indicate that lopinavir should be avoided especially in the first trimester, whereas darunavir is safe to use and should be the preferred PI in pregnancy.Further, in current times of the COVID-19 pandemic, lopinavir is among the top drug candidates which are being repurposed for inclusion in clinical trials world-over, to assess their therapeutic potential against the dangerous respiratory disease. Current trials are also testing the efficacy of lopinavir given prophylactically to protect health care workers and people with potential exposures. Given the current extraordinary numbers, these might include women with early pregnancies, who may or may not be cognizant of their gestational status. This is a matter of concern as it could mean that women with early pregnancies might be exposed to this drug, which can cause decidualization defects. Our findings provide evidence of safety concerns surrounding lopinavir use in pregnancy, that women of reproductive age considering participation in such trials should be made aware of, so they can make a fully informed decision., Study Funding/competing Interest(s): This work was supported by funding from the Canadian Institutes of Health Research (CIHR) (PJT-148684 and MOP-130398 to L.S.). C.D. received support from CIHR Foundation (FDN143262 to Stephen Lye). S.K. received a TGHRI postdoctoral fellowship. The authors declare that there are no conflicts of interest. L.S. reports personal fees from ViiV Healthcare for participation in a Women and Transgender Think Tank., (© The Author(s) 2020. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: Current guidelines suggest that granisetron is an optional treatment for nausea and vomiting in pregnancy (NVP) despite lack of evidence to support fetal safety. We aimed to determine the association between early pregnancy exposure to granisetron and fetal/neonatal outcomes., Design: Medical records of patients treated for NVP during the first and second trimester between June 2013 to September 2015 were reviewed. Patients were asked to participate in the study by answering a detailed questionnaire regarding newborn's health and complementary data. Pregnancy outcomes of patients exposed to granisetron were compared with those of patients who were not exposed to granisetron., Results: 100 Granisetron exposed pregnancies were compared with 108 granisetron unexposed pregnancies. Exposure to granisetron occurred in the first trimester in 88 patients (94 fetuses). Maternal characteristics, history of anomalies in first degree relatives, co-exposure to other substances and extent of prenatal sonographic surveillance were comparable between both groups. Miscarriage rate was significantly lower among granisetron exposed patients compared to controls (0 vs 5.5 %, respectively, p = 0.03). Three major malformations were identified prenatally or postnatally in each of the groups (2.77 % Vs 2.83 %, p = 1). The rate of major malformations was similar between exposed and unexposed fetuses even after excluding second trimester exposure (3.2 % vs. 2.83 %, respectively p = 1). Mean gestational age at delivery, mean newborn weight and incidence of small for gestation age, were not significantly different between the groups., Conclusion: Granisetron exposure was not associated with increased risk for minor or major fetal anomalies. This study provides preliminary reassurance regarding the safety of in-utero exposure to granisetron., (Copyright © 2019. Published by Elsevier B.V.)

Background: Limited research has addressed whether maternal alcohol intake in early pregnancy increases the risk of spontaneous preterm birth. In the current study, we examined how alcohol binge drinking and weekly alcohol intake in early pregnancy were associated with spontaneous preterm birth in a contemporary cohort of Danish women., Methods: We included 15,776 pregnancies of 14,894 women referred to antenatal care at Copenhagen University Hospital, Denmark, between 2012 and 2016. Self-reported alcohol intake in early pregnancy was obtained from a Web-based questionnaire completed prior to the women's first visit at the department. Information on spontaneous preterm birth was extracted from the Danish Medical Birth Register. Adjusted hazard ratios (aHRs) with 95% confidence intervals (CIs) of spontaneous preterm birth according to self-reported alcohol binge drinking and weekly intake of alcohol in early pregnancy were derived from Cox regression., Results: Women reporting 1, 2, and ≥ 3 binge drinking episodes had an aHR for spontaneous preterm birth of 0.88 (95% CI 0.68 to 1.14), 1.34 (95% CI 0.98 to 1.82), and 0.93 (95% CI 0.62 to 1.41), respectively, compared to women with no binge drinking episodes. Women who reported an intake of ≥ 1 drink per week on average had an aHR for spontaneous preterm birth of 1.09 (95% CI 0.63 to 1.89) compared to abstainers. When restricting to nulliparous women or cohabiting women with ≥ 3 years of higher education, this estimate was 1.28 (95% CI 0.69 to 2.40) and 1.20 (95% CI 0.67 to 2.15), respectively., Conclusion: We found no evidence that maternal alcohol intake in early pregnancy was associated with a higher risk of spontaneous preterm birth, neither for alcohol binge drinking nor for a low average weekly intake of alcohol., (© 2019 by the Research Society on Alcoholism.)

Background: Little is known about maternal alcohol intake in early pregnancy and the risk of attention-deficit/hyperactivity disorder (ADHD) in children beyond 5 years of age. We examined the association between alcohol binge drinking and weekly alcohol intake in early pregnancy and the risk of ADHD in children followed from birth to 19 years of age., Methods: We included 48,072 children born between 1998 and 2012, whose mothers participated in the Aarhus Birth Cohort. Maternal alcohol intake was obtained from a self-administered questionnaire completed in early pregnancy. ADHD diagnoses were retrieved from the Danish Psychiatric Central Research Register and the Danish National Patient Register. Crude hazard ratio and adjusted hazard ratio (aHR) of ADHD according to alcohol binge drinking or weekly intake of alcohol were calculated using the Cox regression., Results: Compared to children of women with no binge drinking episodes, we observed an aHR for ADHD of 0.91 (95% CI 0.76 to 1.08), 0.73 (95% CI 0.56 to 0.96), and 0.77 (95% CI 0.57 to 1.06) among children of women reporting 1, 2, and 3 or more binge drinking episodes, respectively. Among children of women drinking <1 drink per week, 1 drink per week, 2 drinks per week, and 3 or more drinks per week, we observed an aHR for ADHD of 0.87 (95% CI 0.74 to 1.03), 0.63 (95% CI 0.40 to 0.98), 1.30 (95% CI 0.89 to 1.92), and 0.78 (95% CI 0.38 to 1.59), respectively, when compared to children of women not drinking on a weekly basis., Conclusion: We found no evidence that binge drinking or low alcohol intake in early pregnancy was associated with the risk of ADHD in children., (© 2019 by the Research Society on Alcoholism.)

Objective: The present study was to estimate the role of cytokines for trophoblast death in NK cells presence., Methods: This study involves assessment of NK-92 line NK cell cytotoxic activity against JEG-3 line cells, in presence of cytokines. We also assessed the effect of secretory placenta products on NK cell cytotoxic activity toward JEG-3 line cells., Results: Uteroplacental contact zone cytokines are able to enhance trophoblast mortality both by themselves in case of IL-1β, IL-6, IFNγ, IL-4, TGFβ, bFGF, and also through increasing the cytotoxic potential of NK cells in case of IL-1β, IFNγ, IL-8, TGFβ, and GM-CSF. PLGF decreases NK cell cytotoxicity for trophoblasts. Secretory products of first trimester placenta enhance NK cell cytotoxic potential for trophoblasts., Conclusions: Cytokines of the uteroplacental contact zone can appear a mechanism ensuring trophoblast mortality dynamics throughout pregnancy.

Background: Maternal smoking during pregnancy is an established risk factor for low infant birth weight, but evidence on critical exposure windows and timing of fetal growth restriction is limited. Here we investigate the associations of maternal quitting, reducing, and continuing smoking during pregnancy with longitudinal fetal growth by triangulating evidence from 3 analytical approaches to strengthen causal inference., Methods and Findings: We analysed data from 8,621 European liveborn singletons in 2 population-based pregnancy cohorts (the Generation R Study, the Netherlands 2002-2006 [n = 4,682]) and the Born in Bradford study, United Kingdom 2007-2010 [n = 3,939]) with fetal ultrasound and birth anthropometric measures, parental smoking during pregnancy, and maternal genetic data. Associations with trajectories of estimated fetal weight (EFW) and individual fetal parameters (head circumference, femur length [FL], and abdominal circumference [AC]) from 12-16 to 40 weeks' gestation were analysed using multilevel fractional polynomial models. We compared results from (1) confounder-adjusted multivariable analyses, (2) a Mendelian randomization (MR) analysis using maternal rs1051730 genotype as an instrument for smoking quantity and ease of quitting, and (3) a negative control analysis comparing maternal and mother's partner's smoking associations. In multivariable analyses, women who continued smoking during pregnancy had a smaller fetal size than non-smokers from early gestation (16-20 weeks) through to birth (p-value for each parameter < 0.001). Fetal size reductions in continuing smokers followed a dose-dependent pattern (compared to non-smokers, difference in mean EFW [95% CI] at 40 weeks' gestation was -144 g [-182 to -106], -215 g [-248 to -182], and -290 g [-334 to -247] for light, moderate, and heavy smoking, respectively). Overall, fetal size reductions were most pronounced for FL. The fetal growth trajectory in women who quit smoking in early pregnancy was similar to that of non-smokers, except for a shorter FL and greater AC around 36-40 weeks' gestation. In MR analyses, each genetically determined 1-cigarette-per-day increase was associated with a smaller EFW from 20 weeks' gestation to birth in smokers (p = 0.01, difference in mean EFW at 40 weeks = -45 g [95% CI -81 to -10]) and a greater EFW from 32 weeks' gestation onwards in non-smokers (p = 0.03, difference in mean EFW at 40 weeks = 26 g [95% CI 5 to 47]). There was no evidence that partner smoking was associated with fetal growth. Study limitations include measurement error due to maternal self-report of smoking and the modest sample size for MR analyses resulting in unconfounded estimates being less precise. The apparent positive association of the genetic instrument with fetal growth in non-smokers suggests that genetic pleiotropy may have masked a stronger association in smokers., Conclusions: A consistent linear dose-dependent association of maternal smoking with fetal growth was observed from the early second trimester onwards, while no major growth deficit was found in women who quit smoking early in pregnancy except for a shorter FL during late gestation. These findings reinforce the importance of smoking cessation advice in preconception and antenatal care and show that smoking reduction can lower the risk of impaired fetal growth in women who struggle to quit., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: DAL has received support from several national and international government and charitable funders, and from Medtronic Ltd and Roche Diagnostics for research unrelated to that presented here. The other authors report no conflicts.

Objective: To contribute in closing the current gap in literature that holistically examines sociocultural influences on perinatal drug dependency. This article draws from social network theory and structural violence to qualitatively consider the contextual components of addiction and substance use during pregnancy, which purposefully moves away from situating this issue from solely being within the contexts of pathologized disorders or products of social inequalities., Design: Face-to-face semi-structured interviews with drug-dependent pregnant women identified during a reproductive environmental health consultation., Setting: Interviews were conducted at a university hospital in southeastern Spain between October 2015 and June 2016., Participants: 10 pregnant women with confirmed perinatal substance use and/or drug dependency., Findings: The sociocultural perspective offers a useful lens by which providers can understand the reasons for initial substance use and progress of multi-drug dependency as way of individually tailoring intervention strategies for expecting mothers. This perspective draws from the frameworks of social network analysis (SNA) and structural violence to dialectically examine drug dependency in this unique patient population not to be solely an individual occurrence, but rather a combination of macro and micro-level factors at play., Key Conclusions: The sociocultural approach in examining maternal health allows for the holistic exploration of the already taboo and symbolically paradoxical phenomenon of drug dependency in pregnant women., Implications for Practice: The "Hoja Verde" and similar perinatal screening methods that comprehensively assess for the potential of environmental risks can be a key instrument in the practice of preventing developmental issues of children as early as pregnancy and into adolescence., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Introduction: The study aimed to detect factors predicting a successful pharmacological induction of first-trimester miscarriage., Material and Methods: A prospective, cohort research was conducted at the 1st Department of Obstetrics and Gynecology, Medical University of Warsaw, between years 2011-2015. 642 women diagnosed with first trimester miscarriage qualified for pharmacological induction with misoprostol were included in the study. Each patient underwent repeatable doses of 800mcg misoprostol vaginally. The endpoint was complete excretion of all tissues, with no need to perform surgical curettage. Type of miscarriage, gravidity, parity, number of doses, time of drug administration and side effects were analysed as possible factors influencing the results. The statistical analysis was performed with STATISTICA 10.0 software., Results: The percentage of successful miscarriage induction was 83.6%. Two main factors corresponded with successful pharmacological treatment in regression analysis: number of administered doses (adjusted OR 1.64; 95% CI 1.18-2.29) and week of gestation (aOR 1.22; 95%CI 1.03-1.44). The success of the pharmacological induction of miscarriage was significantly decreased if the woman had a history of caesarean section (aOR 0.34; 95% CI 0.2-0.57). 2.2% of patients experienced benign side effects of the therapy., Conclusions: Pharmacological induction is an effective and safe treatment method of first trimester abortion in the majority of cases. The knowledge of factors influencing the efficacy of misoprostol may help clinicians in proper counselling and individualisation of therapy.

Organic compounds have been linked to adverse pregnancy complications. Perfluorooctanesulfonic acid (PFOS), a man-made fluorosurfactant and global pollutant, has been shown to induce oxidative stress in various cell types. Oxidative stress plays a key role in leading several placental diseases including preeclampsia (PE), gestational diabetes, spontaneous abortion, preterm labor, and intrauterine growth restriction. Recently, epigenetic regulation such as histone modifications, DNA methylation, and microRNAs (miRNAs), are shown to be associated with oxidative stress as well as pregnancy complications such as PE. However, whether PFOS exerts its detrimental effects in the placenta through epigenetics remains to be unveiled. Therefore, we aimed to investigate the effect of PFOS-induced reactive oxygen species (ROS) generation in first trimester human trophoblast cell line (HTR-8/SV neo ) and whether epigenetic regulation is involved in this process. When treated with a range of PFOS doses at 24 and 48 h, even at 10 μM, it significantly increased the ROS production and decreased gene and protein expression, respectively, of the DNA methyltransferases DNMT1 ( p < 0.001; p < 0.05), DNMT3A ( p < 0.001; p < 0.05), and DNMT3B ( p < 0.01; p < 0.01) and the sirtuins, for example, SIRT1 ( p < 0.001; p < 0.001) and SIRT3 ( p < 0.001; p < 0.05), while reducing global DNA methylation ( p < 0.01) and increasing protein lysine acetylation ( p < 0.001) as compared to vehicle controls. Interestingly, PFOS (10 μM) significantly increased miR29-b ( p < 0.01), which has been previously reported to be associated with PE. The observed epigenetic effects were shown to be dependent on the expression of miR-29b, as knockdown of miR-29b significantly alters the gene and protein expression of DNMT1, DNMT3A, DNMT3B, SIRT1, and SIRT3 and ROS production as well as global DNA methylation and protein acetylation. This study provides for the first time a novel insight into PFOS-induced ROS generation via regulation of sets of the interactive epigenetic circuit in the placenta, which may lead to pregnancy complications.

We sought to explore the functions and modulated factors of NOD1 in normal decidual stromal cells (DSCs) derived from the first trimester pregnancy and whether existed different expression of NOD1 between normal and unexplained recurrent pregnancy loss (URPL) in DSCs. Twenty-six patients with normal pregnancies that required abortion and 12 URPL patients at first trimester were enrolled for the study. As a result, we found lower levels of NOD1 in the DSCs derived from URPL compared with those from normal early trimester pregnancy. Furthermore, increased NOD1 expression in the normal DSCs induced apoptosis and increased monocyte chemotactic protein-1 (MCP-1) and IL-1β (interleukin 1 beta) secretion but decreased their invasion capacity. In addition, several cytokines such as IL-1β, tumour necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ), and interleukin-17 (IL-17) were present at the maternal-fetal interface in RPL and were found to regulate NOD1 expression in primary DSCs. Our study indicates that RPL may be associated with NOD1 aberrant expression in DSCs, which plays a significant role in maintaining pregnancy via infection control and regulation of immune responses that might affect the pregnancy outcome. We expect that our results will bring more comprehensively understanding about the connection between NOD1 and RPL for researchers., (© 2019 John Wiley & Sons, Ltd.)

This study aimed to assess characteristics of pregnant women taking antiepileptic drugs with inadequate folic acid intake. This cross-sectional study examined pregnant women taking antiepileptic drugs who were registered in the Japanese Drug Information Institute in Pregnancy (JDIIP) database between October 2005 and December 2016. Participants were classified into two groups according to when they started folic acid supplementation (before pregnancy: 'adequate', after pregnancy or never: 'inadequate'). Logistic regression analysis was performed to investigate factors associated with inadequate folic acid intake. Of 12,794 registrants, 468 pregnant women were taking antiepileptics during the first trimester. Of these, we analysed data from 456 women who had no missing data. As a result, inadequate folic acid intake was noted among 83.3% of them, suggesting that the current level of folic acid intake is insufficient overall. Younger age, smoking, alcohol drinking, multiparity, unplanned pregnancy, and being prescribed AEDs by paediatric or psychiatric departments were independent factors associated with inadequate folic acid intake. As planned pregnancy was the strongest factor, healthcare professionals should ensure that childbearing women taking antiepileptics are informed of the importance of planned pregnancy. In addition, healthcare professionals must gain a better understanding of folic acid intake, as the prevalence of adequate intake differed according to which departments prescribed antiepileptic drugs.

Study Objective: The potential for maternal antidepressant use to influence the risk of spontaneous abortion, one of the most important adverse pregnancy outcomes, is not clear. We aimed to assess whether first trimester antidepressant exposure was associated with an increased risk of spontaneous abortion., Design: Community-based prospective cohort study (Right from the Start)., Setting: Eight metropolitan areas in North Carolina, Tennessee, and Texas., Participants: A total of 5451 women (18 years of age or older) who were planning to conceive or were pregnant (before 12 weeks of completed gestation) and were enrolled in the study between 2000 and 2012; of those women, 223 used antidepressants (selective serotonin reuptake inhibitors [SSRIs] only [170], SSRIs and non-SSRIs [9], and non-SSRIs only [44]) during their first trimester, and 5228 did not (never users). Measurements and Main Results First trimester antidepressant use was determined during a first trimester telephone interview. Spontaneous abortion was self-reported and verified by medical records. The association of first trimester antidepressant use and spontaneous abortion was assessed by using Cox proportional hazard regression. Among the 5451 women enrolled, 223 (4%) reported first trimester antidepressant use, and 659 (12%) experienced a spontaneous abortion. SSRIs were the most common class of antidepressants used (179 [80%]). Compared with women who never used antidepressants during the first trimester of pregnancy, women who reported antidepressant use were 34% (adjusted hazard ratio [aHR] 1.34, 95% confidence interval [CI] 0.97-1.85) more likely to experience a spontaneous abortion after adjusting for covariates. Women who reported ever using SSRIs were 45% (aHR 1.45, 95% CI 1.02-2.06) more likely to experience a spontaneous abortion compared with never users. When time of loss relative to the time of interview was taken into consideration, the association between first trimester SSRI use and spontaneous abortion was significant only among those with losses before the interview (aHR 1.49, 95% CI 1.04-2.13) but was not significant among those with losses after the interview (aHR 0.43, 95% CI 0.06-3.15)., Conclusion: The association between use of first trimester antidepressants, particularly SSRI use, and spontaneous abortion was significant only among women whose exposure status was assessed after loss. In this instance, reporting bias may create a spurious association. Future studies should take the timing of data collection relative to the timing of loss into consideration., (© 2019 Pharmacotherapy Publications, Inc.)

Exposures to endocrine disrupting chemicals and metals are near ubiquitous worldwide, and their potential impact on children is a major public health concern. This pilot study was designed to characterize exposures to phthalates, phenols and metals among pregnant women in the first trimester, and to examine associations with fetal biometrics and birth weight. A total of 41 chemicals and elements were analyzed in urine from 56 mothers with full-term newborns from the Michigan Mother-Infant Pairs study. Bivariate analyses identified predictors of exposure biomarkers. Associations between birth weight, Fenton z-scores and second trimester fetal biometrics with toxicants were examined via multivariable linear regression. An average of 30 toxicants were detected in maternal urine. Fast food consumption was associated with several phthalate metabolites, phenols and metals, and canned food consumption with bisphenol F (P &lt;0.05). Mono (3-carboxypropyl) phthalate was significantly associated with higher birth weight and Fenton z-score while the opposite was observed for bisphenol S. Estimated femur length from ultrasonography was significantly inversely associated with arsenic, barium and lead. While limited by sample size, this study is one of the first to evaluate birth outcomes with respect to emerging endocrine disrupting chemicals and to examine associations between toxicants and fetal biometrics. Exposure assessment was provided by the National Institute of Environmental Health Sciences' Children's Health Exposure Analysis Resource (NIEHS CHEAR), a resource available to children's studies with the goal of combining data across cohorts in an effort to characterize the impact of toxicants on child health from birth and beyond.

This report is about a female child born to a multiple sclerosis mother who continued fingolimod during her first trimester of pregnancy. The child was born with normal full-term delivery but showed neurodevelopmental retardation in the following years. it is recommended that multiple sclerosis patients undergoing treatment with fingolimod use contraceptive methods for at least two months after discontinuation of the medication., (Copyright © 2019. Published by Elsevier B.V.)

Adequate invasion and complete remodelling of the maternal spiral arteries by the invading extravillous trophoblasts are the major determinants of a successful pregnancy. Increase in oxidative stress during pregnancy has been linked to the reduction in trophoblast invasion and incomplete conversion of the maternal spiral arteries, resulting in pregnancy complications such as pre-eclampsia, intrauterine growth restriction, and spontaneous miscarriages resulting in foetal/maternal mortality. The use of antioxidant therapy (vitamin C and E) and other preventative treatments (such as low dose aspirin) have been ineffective in preventing pre-eclampsia. Also, as the majority of antihypertensive drugs pose side effects, choosing an appropriate treatment would depend upon the efficacy and safety of mother/foetus. Since pre-eclampsia is mainly linked to placental oxidative stress, new diet-based antioxidants can be of use to prevent this condition. The antioxidant properties of flavonoids (naturally occurring phenolic compounds which are ubiquitously distributed in fruits and vegetables) have been well documented in non-trophoblast cells. Therefore, this study aimed to investigate the effects of flavonoids (quercetin, hesperidin) and their metabolites (Quercetin 3-O-β-glucuronide and hesperetin), either alone or in combination, on first trimester trophoblast cell line HTR-8/SVneo during oxidative stress. The data obtained from this study indicate that selected flavonoids, their respective metabolites significantly reduced the levels of reduced glutathione (p < 0.0001) during HR-induced oxidative stress. These flavonoids also inhibited the activation of pro-apoptotic kinases (p38 MAPK and c-Jun N-terminal kinase) during HR-induced phosphorylation. In addition, they enhanced spheroid stem-like cell generation from HTR8/SVneo cells, aiding their invasion. Our data suggest that dietary intake of food rich in quercetin or hesperidin during early pregnancy can significantly improve trophoblast (placenta) health and function against oxidative stress., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Increased inflammation and abnormal placentation are common features of a wide spectrum of pregnancy-related disorders such as intra uterine growth restriction, preeclampsia and preterm birth. The inflammatory response of the human placenta has been mostly investigated in relation to cytokine release, but the direct molecular consequences on trophoblast differentiation have not been investigated. This study measured the general effects of LPS on both extravillous and villous trophoblast physiology, and the involvement of the transcription factors PPARγ and NF-κB, specifically using 1 st trimester explants and HTR-8/ SVneo cell line models. While both proteins are known for their roles in inflammatory pathways, PPARγ has been identified as an important molecule in trophoblast differentiation, suggesting its potential role in mediating a crosstalk between inflammation and trophoblast differentiation. Here, LPS (1 µg/ml) exposure of first trimester placental villous explants resulted in secretion of inflammatory cytokines, induction of apoptosis and reduction in trophoblast cell proliferation. Additionally, LPS significantly reduced expression of the trophoblast differentiation proteins GCM1 and β-hCG, and increased invasion of the extravillous trophoblast. Activation of PPARγ by Rosiglitazone (10 µM) reversed the LPS-mediated effects on inflammatory cytokine release, trophoblast apoptosis and proliferation compared to controls. Lastly, markers of trophoblast differentiation and invasion reverted to control levels upon activation of PPARγ and concomitant inhibition of NF-κB (either by Rosiglitazone or NF-κB specific inhibitor), revealing a new role for NF-κB in trophoblast invasion. This study reveals a novel PPARγ - NF-κB axis that coordinates inflammatory and differentiation pathways in the human placenta. The ability to reverse trophoblast-associated inflammation with Rosiglitazone offers promise that the PPARγ - NF-κB pathway could one day provide a therapeutic target for placental dysfunction associated with both inflammation and abnormal trophoblast differentiation.

Aims: Surveillance of medication use in pregnancy is essential to identify associations between first trimester medications and congenital anomalies (CAs). Medications in the same Anatomical Therapeutic Chemical classes may have similar effects. We aimed to use this information to improve the detection of potential teratogens in CA surveillance data., Methods: Data on 15 058 malformed fetuses with first trimester medication exposures from 1995-2011 were available from EUROmediCAT, a network of European CA registries. For each medication-CA combination, the proportion of the CA in fetuses with the medication was compared to the proportion of the CA in all other fetuses in the dataset. The Australian classification system was used to identify high-risk medications in order to compare two methods of controlling the false discovery rate (FDR): a single FDR applied across all combinations, and a double FDR incorporating groupings of medications., Results: There were 28 765 potential combinations (523 medications × 55 CAs) for analysis. An FDR cut-off of 50% resulted in a reasonable effective workload, for which single FDR gave rise to eight medication signals (three high-risk medications) and double FDR 50% identified 16 signals (six high-risk). Over a range of FDR cut-offs, double FDR identified more high-risk medications as signals, for comparable effective workloads., Conclusions: The double FDR method appears to improve the detection of potential teratogens in comparison to the single FDR, while maintaining a low risk of false positives. Use of double FDR is recommended in routine signal detection analyses of CA data., (© 2018 The British Pharmacological Society.)

Background: Gestational ethanol (EtOH) exposure is associated with multiple developmental abnormalities, collectively termed fetal alcohol spectrum disorder (FASD). While the majority of women abstain from EtOH following knowledge of pregnancy, one contributing factor to the high FASD prevalence is that pregnancy is not detected until 4 to 6 weeks. Thus, EtOH consumption continues during the initial stages of fetal development., Methods: An experimental protocol is described in which rhesus macaques self-administer 1.5 g/kg/d EtOH (or isocaloric maltose dextrin) prior to pregnancy and through the first 60 days of a 168-day gestation term. Menstrual cycles were monitored, including measurements of circulating estradiol and progesterone levels. The latency to consume 1.5 g/kg EtOH and blood EtOH concentration (BEC) was measured., Results: Twenty-eight fetuses (14 EtOH and 14 controls) were generated in this study. EtOH did not affect menstrual cycles or the probability of successful breeding. No EtOH-induced gross adverse effects on pregnancy were observed. Individual variability in latency to complete drinking translated into variability in BEC, measured 90 minutes following session start. Drinking latencies in controls and EtOH drinkers were longer in the second gestational month than in the first. All pregnancies reached the planned experimental time point of G85, G110, or G135, when in utero MRIs were performed, fetuses were delivered by caesarean section, and brains were evaluated with ex vivo procedures, including slice electrophysiology. Fetal tissues have been deposited to the Monkey Alcohol Tissue Research Resource., Conclusions: This FASD model takes advantage of the similarities between humans and rhesus macaques in gestational length relative to brain development, as well as similarities in EtOH self-administration and metabolism. The daily 1.5 g/kg dose of EtOH through the first trimester does not influence pregnancy success rates. However, pregnancy influences drinking behavior during the second month of pregnancy. Future publications using this model will describe the effect of early-gestation EtOH exposure on anatomical and functional brain development at subsequent gestational ages., (© 2018 by the Research Society on Alcoholism.)

Background: A growing number of young women are exposed to statins during their first trimester of pregnancy. The goal of this study is to examine if first trimester statin exposure is associated with an increase in risk of fetal congenital cardiac anomalies., Methods: In a cohort of 379,238 pregnancies, we examined the risk of fetal congenital cardiac anomalies in association with maternal exposure to statin therapy during the first trimester of pregnancy using logistic regression models and propensity score matching methods., Results: 280 women were exposed to statins. Congenital cardiac anomalies were present in 14 (5.0%) of pregnancies exposed to statin and 5282 (1.4%) of non-exposed pregnancies. First-trimester statin exposure was associated with an increased risk of ventricular septal defect (adjusted odds ratio [OR] 3.3, 95% confidence interval [CI]l 1.8-6.0, p < 0.001). This association was confirmed in an analysis using a propensity score-matched cohort (OR 4.7, 95% CI 2.0-10.8, p < 0.001)., Conclusions: Exposure to statins during the first trimester of pregnancy is associated with fetal ventricular septal defect., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Purpose: To explore trends in use of maternal medication 3 months prior to, during and 3 months after pregnancy., Methods: Data on births from the Medical Birth Registry of Norway were linked to the Norwegian Prescription Database, identifying women's use of medications around pregnancy. All women giving birth in Norway during 2005 to 2015 (638 532 singleton births to 414 567 women) were included. Proportions of pregnant women using different medications in association with pregnancy, and annual relative change in medication use during 2005 to 2015, were calculated., Results: In Norway, 60% of pregnant women used prescription medications during pregnancy (2005-15), increasing from 57% in 2005 to 62% in 2015. The annual relative increase was 0.9% (95% CI: 0.8-1.0). In the first trimester, approximately 17% of the women used medications regarded as potentially teratogenic during 2005 to 2015, increasing from 15% to 19%. Overall, this proportion was higher in the first than in the second (8.9%) and third (8.0%) trimesters, and higher than in the 3 months after pregnancy (14%). The annual relative increase of medications regarded as potentially teratogenic in the first trimester was 2.5% (95% CI: 2.3-2.7)., Conclusions: The proportion of women using potentially teratogenic medications in the first trimester of pregnancy have increased during the last decade. Clinicians need to be aware of the possibility of pregnancy when prescribing potentially teratogenic medication to women of fertile age and focus this in the consultations. The increasing trends call for the need of routine surveillance of adverse birth outcomes linked to medication use in pregnancy., (© 2018 John Wiley & Sons, Ltd.)

Introduction: Nimesulide is the most prescribed non-steroidal anti-inflammatory drug in Italy, and it is currently marketed in about 50 countries worldwide. The association between the use of nimesulide in early pregnancy and the risk of birth defects was investigated in a large cohort of pregnant women from Italy., Methods: Data were from the healthcare utilization databases of the Italian region of Lombardy. The cohort of 353,081 newborns occurring in Lombardy during the period 2005-2010 was investigated. Exposure to nimesulide during the first trimester of pregnancy, and congenital malformations detected at presentation and within 90 days after birth (outcome), were investigated. Exposure-outcome association was measured by the ratio between the prevalence of congenital malformations among users and non-users of nimesulide. Propensity score stratification was used to control for potential confounders, including maternal medical comorbidities, concomitant medications and sociodemographic characteristics., Results: The 627 (0.18%) women who filled prescriptions for nimesulide in the first trimester of pregnancy had a 2.6-fold risk of having children with congenital urinary tract anomalies compared to those who did not (adjusted prevalence ratio 2.6; 95% CI 1.2-5.7). Weaker and non-significant evidence for congenital malformations as a whole was found (adjusted prevalence ratio 1.2, 95% CI 0.9-1.6)., Conclusion: Our study suggests that the use of nimesulide in early pregnancy may result in a greater risk of having births with congenital urinary tract anomalies., Funding: This study was funded by grants from the Italian Ministry of the Education, University and Research ('Fondo d'Ateneo per la Ricerca' portion, year 2015).

Problem: The development of the placenta and its functions are sensitive to infection and stress, which can activate the hypothalamic-pituitary-adrenal axis. Adrenally produced glucocorticoids are the body's primary mediators of the inflammatory and stress response. Although the glucocorticoid receptor (GR) is expressed in all human villous trophoblast tissue, the effect of glucocorticoids on placentation is not well understood., Method of Study: Using microarray analysis, we identified the glucocorticoid-regulated transcriptional profile in the immortalized first-trimester extravillous trophoblast cell line Swan.71 (Sw.71)., Results: The synthetic glucocorticoid dexamethasone significantly regulated 3829 genes, including genes associated with cell movement, growth, and survival. SERPINE1, an inhibitor of trophoblast invasion, was induced by glucocorticoids in Sw.71 cells and is associated with the pathogenesis of preeclampsia. Glucocorticoid treatment induced recruitment of activated polymerase II and GR to the SERPINE1 promoter, suggesting a mechanism for transcriptional regulation. Functionally, glucocorticoid treatment inhibited cell proliferation, migration, and invasion., Conclusion: These findings suggest that glucocorticoids regulate extravillous trophoblast functions by altering the gene expression profile, which may contribute to the pathogenesis of reproductive disorders such as preeclampsia and IUGR., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: This study was designed to investigate the effect of nicotine on serum progesterone and estradiol levels as possible cause of abortion during first trimester of gestation in female Wistar rats., Methods: Fourteen female rats with regular estrous cycles in the same phase of cycle were divided into two groups (Control and Nicotine-treated) with each group receiving 1ml of distilled water and 1mg/kg of nicotine respectively for the first seven days of pregnancy (GD1-7). The animals were sacrificed on the 8th day and blood samples were collected for hormonal analyses. Ovaries and uteruses were excised, weighed, and prepared for histological study., Results: This study revealed a significant decrease in serum progesterone and estradiol levels in the nicotine-treated group when compared to controls. The histological findings equally showed degeneration in the cytoarchitecture of the ovary of the nicotine-treated group., Conclusion: The observed hormonal imbalances and alteration in the cytoarchitecture of the ovary caused by nicotine in the first trimester of pregnancy may result in abortion during this period.

Estimates suggest that nearly 30% of patients diagnosed with chronic myeloid leukemia (CML) are aged <49 years, with approximately half being women. For many of these women, childbearing concerns are a major factor as they initiate treatment with tyrosine kinase inhibitors, which are known to be teratogenic. During her presentation at the NCCN 23rd Annual Conference, Dr. Berman identified the challenges in helping women undergoing treatment for CML who want to have children, and emphasized the importance of an individualized and multidisciplinary approach to management. In addition, she encouraged NCCN to create a pregnancy registry of this patient population to enable clinicians to collect firm data to guide clinical decision-making., (Copyright © 2018 by the National Comprehensive Cancer Network.)

Dexamethasone (DEX) is used to prevent prenatal virilization in female fetuses with congenital adrenal hyperplasia (CAH). Since treatment has to be started before the genotype of the fetus is known, 7 out of 8 fetuses will be exposed to DEX without benefit. Previously, we have observed negative effects on cognition and behavior in DEX treated children. Here we evaluated neuropsychological functions, psychopathology and autistic traits in non-CAH DEX-treated adults exposed during the first trimester of fetal life (duration 6.2 ± 2.2 weeks). Cognitive functions, psychopathology and autistic traits were compared between DEX-treated subjects (n = 23) and non-exposed controls (n = 58). Cognitive outcome was also evaluated longitudinally for DEX-treated participants. We used neuropsychological tests (Wechsler Scales and the Stroop Interference Test) and questionnaires assessing executive functions (the Barkley Deficit in Executive Functioning Scale), psychopathology (the Montgomery Åsberg Depression Ratings Scale, the Hospital Anxiety and Depression Scale, the Liebowitz Social Anxiety Scale) and autistic traits (Autism Quota). We did not observe any significant differences in cognition, psychopathology or autistic traits between DEX-treated individuals and population controls. A significant improvement in verbal working memory (p = 0.038) and in impulse inhibition (p = 0.011) was seen when subjects were evaluated longitudinally. In summary, first-trimester DEX-exposed adult individuals do not show any significant neuropsychological deficits nor an increase in anxiety, depression or autistic traits, compared with a control group from the general population. The results also suggest that the observed deficits in executive functioning during childhood may improve with time., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Introduction: The prevalence of chronic hypertension is increasing in pregnant women. Beta-blockers are among the most prevalent anti-hypertensive agents used in early pregnancy., Objective: The objective of this study was to investigate whether first-trimester use of beta-blockers increases the risk of specific congenital anomalies in offspring., Methods: A population-based case-malformed control study was conducted in 117,122 registrations of congenital anomalies from 17 European Concerted Action on Congenital Anomalies and Twins (EUROCAT) registries participating in EUROmediCAT with data for all or part of the period between 1995 and 2013. Associations previously reported in the literature (signals) were tested and an exploratory analysis was performed to identify new signals. Odds ratios of exposure to any beta-blocker or to a beta-blocker subgroup were calculated for each signal anomaly compared with two control groups (non-chromosomal, non-signal anomalies and chromosomal anomalies). The exploratory analyses were performed for each non-signal anomaly compared with all the other non-signal anomalies., Results: The signals from the literature (congenital heart defects, oral clefts, neural tube defects and hypospadias) were not confirmed. Our exploratory analysis revealed that multi-cystic renal dysplasia had significantly increased odds of occurring after maternal exposure to combined alpha- and beta-blockers (adjusted odds ratio 3.8; 95% confidence interval 1.3-11.0)., Conclusion: Beta-blocker use in the first trimester of pregnancy was not found to be associated with a higher risk of specific congenital anomalies in the offspring, but a new signal between alpha- and beta-blockers and multi-cystic renal dysplasia was found. Future large epidemiological studies are needed to confirm or refute our findings.

Prenatal dexamethasone (DEX) treatment in congenital adrenal hyperplasia (CAH) is effective in reducing virilization in affected girls, but potential long-term adverse effects are largely unknown. In this report we intended to explore potential side effects of DEX therapy to enhance the adequacy of future risk benefit analyses of DEX treatment. We investigated the long-term effects of first trimester prenatal DEX treatment on behavioral problems and temperament in children and adolescents aged 7-17 years. The study included 34 children and adolescents, without CAH, who had been exposed to DEX during the first trimester and 67 untreated controls. Standardized parent-completed questionnaires were used to evaluate adaptive functioning and behavioral/emotional problems (CBCL), social anxiety (SPAI-C-P), and temperament (EAS) in the child. Self-reports were used to assess the children's perception of social anxiety (SASC-R). No statistically significant differences were found between DEX-treated and control children and adolescents, suggesting that, in general, healthy children treated with DEX during early fetal life are well adjusted., (Copyright © 2017. Published by Elsevier Inc.)

The use of prescription psychostimulants during pregnancy has been increasing in recent years. One large and 3 small studies have recently examined the risk of major congenital malformations following the use of methylphenidate and amphetamines during the first trimester of pregnancy. The broad findings of these studies are that first trimester gestational exposure to methylphenidate or amphetamines is associated with an increased risk of major congenital malformations but the associations are no longer statistically significant after adjusting analyses for confounding variables; that first trimester exposure to amphetamines is not associated with an increased risk of cardiovascular malformations; and that first trimester exposure to methylphenidate may increase the risk of cardiovascular malformations. A closer look at the data on the last-mentioned finding, however, suggests that the statistical significance of the finding is in doubt and that even if the finding is statistically significant, it is probably not clinically significant. Furthermore, all the findings emerged from observational studies that cannot exclude confounding by indication and other sources of confounding. A reasonable conclusion, therefore, is that there is no evidence, at present, to suggest that methylphenidate and amphetamines are teratogenic. Nevertheless, because absence of evidence of risk is not evidence of absence of risk, the benefits of continuing psychostimulant medication during pregnancy should be weighed against potential risks in an individualized and shared decision-making process., (© Copyright 2018 Physicians Postgraduate Press, Inc.)

Background: Maternal alcohol abuse leading to fetal alcohol spectrum disorder (FASD) includes fetal growth restriction (FGR). Ethanol (EtOH) induces apoptosis of human placental trophoblast cells, possibly disrupting placentation and contributing to FGR in FASD. EtOH facilitates apoptosis in several embryonic tissues, including human trophoblasts, by raising intracellular Ca 2+ . We previously found that acute EtOH exposure increases trophoblast apoptosis due to signaling from both intracellular and extracellular Ca 2+ . Therefore, nifedipine, a Ca 2+ channel blocker that is commonly administered to treat preeclampsia and preterm labor, was evaluated for cytoprotective properties in trophoblast cells exposed to alcohol., Methods: Human first-trimester chorionic villous explants and the human trophoblast cell line HTR-8/SVneo (HTR) were pretreated with 12.5 to 50 nM of the Ca 2+ channel blocker nifedipine for 1 hour before exposure to 50 mM EtOH for an additional hour. Intracellular Ca 2+ concentrations were monitored in real time by epifluorescence microscopy, using fluo-4-AM. Apoptosis was assessed by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), accumulation of cytoplasmic cytochrome c, and cleavage rates of caspase 3 and caspase 9., Results: The increase in intracellular Ca 2+ upon exposure to EtOH in both villous explants and HTR cells was completely blocked (p < 0.05) when pretreated with nifedipine, accompanied by inhibition of EtOH-induced release of cytochrome c, caspase activities, and TUNEL., Conclusions: This study indicates that nifedipine can interrupt the apoptotic pathway downstream of EtOH exposure and could provide a novel strategy for future interventions in women with fetuses at risk for FASD., (Copyright © 2017 by the Research Society on Alcoholism.)

Aims: Few studies have investigated the link between individual antibiotics and major congenital malformations (MCMs) including specific malformations owing to small sample size. We aimed to quantify the association between exposure to gestational antibiotic and the risk of MCMs., Methods: Using the Quebec pregnancy cohort (1998-2008), we included a total of 139 938 liveborn singleton alive whose mothers were covered by the "Régie de l'assurance maladie du Québec" drug plan for at least 12 months before and during pregnancy. Antibiotic exposure was assessed in the first trimester and MCMs were identified within the first year of life., Results: After adjusting for potential confounders, clindamycin exposure was associated with an increased risk of MCMs (aOR 1.34, 95% CI 1.02-1.77, 60 exposed cases), musculoskeletal system malformations (aOR 1.67, 95% CI 1.12-2.48, 29 exposed cases) and ventricular/atrial septal defect (aOR 1.81, 95% CI 1.04-3.16, 13 exposed cases). Doxycycline exposure increased the risk of circulatory system malformation, cardiac malformations and ventricular/atrial septal defect (aOR 2.38, 95% CI 1.21-4.67, 9 exposed cases; aOR 2.46, 95% CI 1.21-4.99, 8 exposed cases; aOR 3.19, 95% CI 1.57-6.48, 8 exposed cases, respectively). Additional associations were seen with quinolone (1 defect), moxifloxacin (1 defect), ofloxacin (1 defect), macrolide (1 defect), erythromycin (1 defect) and phenoxymethylpenicillin (1 defect). No link was observed with amoxicillin, cephalosporins and nitrofurantoin. Similar results were found when penicillins were used as the comparator group., Conclusions: Clindamycin, doxycycline, quinolones, macrolides and phenoxymethylpenicillin in utero exposure were linked to organ-specific malformations. Amoxicillin, cephalosporins and nitrofurantoin were not associated with MCMs., (© 2017 The British Pharmacological Society.)