Exposure of human fetal kidneys to mild analgesics interferes with early nephrogenesis.

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.

The Role of TNF-α and Anti-TNF-α Agents during Preconception, Pregnancy, and Breastfeeding.

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.

Periconceptional exposure to lopinavir, but not darunavir, impairs decidualization: a potential mechanism leading to poor birth outcomes in HIV-positive pregnancies.

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.

Alcohol Intake in Early Pregnancy and Spontaneous Preterm Birth: A Cohort Study.

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.

Alcohol Intake in Early Pregnancy and Risk of Attention-Deficit/Hyperactivity Disorder in Children Up to 19 Years of Age: A Cohort Study.

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.

The role of progestogen supplementation (dydrogesterone) in the prevention of preeclampsia.

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.

The uteroplacental contact zone cytokine influence on NK cell cytotoxicity to trophoblasts.

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-1ß, IL-6, IFNγ, IL-4, TGFß, bFGF, and also through increasing the cytotoxic potential of NK cells in case of IL-1ß, IFNγ, IL-8, TGFß, 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.

Associations of maternal quitting, reducing, and continuing smoking during pregnancy with longitudinal fetal growth: Findings from Mendelian randomization and parental negative control studies.

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.

PFOS Modulates Interactive Epigenetic Regulation in First-Trimester Human Trophoblast Cell Line HTR-8/SVneo.

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/SVneo) 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.

Detecting Neurodevelopmental Effects of Early-Gestation Ethanol Exposure: A Nonhuman Primate Model of Ethanol Drinking During Pregnancy.

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.

Identifying signals of potentially harmful medications in pregnancy: use of the double false discovery rate method to adjust for multiple testing.

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.

NOD1 modulates decidual stromal cell function to maintain pregnancy in the early trimester.

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-1ß (interleukin 1 beta) secretion but decreased their invasion capacity. In addition, several cytokines such as IL-1ß, 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.

The Other Side of the Curtain.

In this narrative medicine essay, a newly minted pediatric critical care physician learns firsthand what holistic medical care is from the love and attention she received during a hospitalization for mediastinal lymphoma.

Evaluation of behavioral problems after prenatal dexamethasone treatment in Swedish children and adolescents at risk of congenital adrenal hyperplasia.

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.

Pregnancy in Patients With Chronic Myeloid Leukemia.

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.

Nifedipine Prevents Apoptosis of Alcohol-Exposed First-Trimester Trophoblast Cells.

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 Ca2+ . We previously found that acute EtOH exposure increases trophoblast apoptosis due to signaling from both intracellular and extracellular Ca2+ . Therefore, nifedipine, a Ca2+ 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 Ca2+ channel blocker nifedipine for 1 hour before exposure to 50 mM EtOH for an additional hour. Intracellular Ca2+ 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 Ca2+ 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.

Trends in prescription drug use during pregnancy and postpartum in Norway, 2005 to 2015.

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.

First-trimester artemisinin derivatives and quinine treatments and the risk of adverse pregnancy outcomes in Africa and Asia: A meta-analysis of observational studies.

BACKGROUND: Animal embryotoxicity data, and the scarcity of safety data in human pregnancies, have prevented artemisinin derivatives from being recommended for malaria treatment in the first trimester except in lifesaving circumstances. We conducted a meta-analysis of prospective observational studies comparing the risk of miscarriage, stillbirth, and major congenital anomaly (primary outcomes) among first-trimester pregnancies treated with artemisinin derivatives versus quinine or no antimalarial treatment. METHODS AND FINDINGS: Electronic databases including Medline, Embase, and Malaria in Pregnancy Library were searched, and investigators contacted. Five studies involving 30,618 pregnancies were included; four from sub-Saharan Africa (n = 6,666 pregnancies, six sites) and one from Thailand (n = 23,952). Antimalarial exposures were ascertained by self-report or active detection and confirmed by prescriptions, clinic cards, and outpatient registers. Cox proportional hazards models, accounting for time under observation and gestational age at enrollment, were used to calculate hazard ratios. Individual participant data (IPD) meta-analysis was used to combine the African studies, and the results were then combined with those from Thailand using aggregated data meta-analysis with a random effects model. There was no difference in the risk of miscarriage associated with the use of artemisinins anytime during the first trimester (n = 37/671) compared with quinine (n = 96/945; adjusted hazard ratio [aHR] = 0.73 [95% CI 0.44, 1.21], I2 = 0%, p = 0.228), in the risk of stillbirth (artemisinins, n = 10/654; quinine, n = 11/615; aHR = 0.29 [95% CI 0.08-1.02], p = 0.053), or in the risk of miscarriage and stillbirth combined (pregnancy loss) (aHR = 0.58 [95% CI 0.36-1.02], p = 0.099). The corresponding risks of miscarriage, stillbirth, and pregnancy loss in a sensitivity analysis restricted to artemisinin exposures during the embryo sensitive period (6-12 wk gestation) were as follows: aHR = 1.04 (95% CI 0.54-2.01), I2 = 0%, p = 0.910; aHR = 0.73 (95% CI 0.26-2.06), p = 0.551; and aHR = 0.98 (95% CI 0.52-2.04), p = 0.603. The prevalence of major congenital anomalies was similar for first-trimester artemisinin (1.5% [95% CI 0.6%-3.5%]) and quinine exposures (1.2% [95% CI 0.6%-2.4%]). Key limitations of the study include the inability to control for confounding by indication in the African studies, the paucity of data on potential confounders, the limited statistical power to detect differences in congenital anomalies, and the lack of assessment of cardiovascular defects in newborns. CONCLUSIONS: Compared to quinine, artemisinin treatment in the first trimester was not associated with an increased risk of miscarriage or stillbirth. While the data are limited, they indicate no difference in the prevalence of major congenital anomalies between treatment groups. The benefits of 3-d artemisinin combination therapy regimens to treat malaria in early pregnancy are likely to outweigh the adverse outcomes of partially treated malaria, which can occur with oral quinine because of the known poor adherence to 7-d regimens. REVIEW REGISTRATION: PROSPERO CRD42015032371.

Placental DAPK1 and autophagy marker LC3B-II are dysregulated by TNF-α in a gestational age-dependent manner.

Autophagy, a cell-survival process responsible for degradation of protein aggregates and damaged organelles, is increasingly recognized as another mechanism essential for human placentation. A substantial body of experiments suggests inflammation and oxidative stress as the underlying stimuli for altered placental autophagy, giving rise to placenta dysfunction and pregnancy pathologies. Here, the hypothesis is tested whether or not pro-inflammatory cytokines interleukin (IL)-6 and tumor necrosis factor (TNF)-α are able to influence the expression profile of autophagy genes in human first-trimester villous placenta. Autophagy-focused qPCR arrays identified substantial downregulation of death-associated protein kinase 1 (DAPK1) in first-trimester placental explants in response to IL-6 and TNF-α, respectively. Immunohistochemistry of placental explants detected considerable DAPK1 staining in placental macrophages, villous cytotrophoblasts and less intense in the syncytiotrophoblast. Both immunohistochemistry and Western blot showed decreased DAPK1 protein in TNF-α-treated placental explants compared to control. On cellular level, DAPK1 expression decreased in SGHPL-4 trophoblasts in response to TNF-α. Observed changes in the expression profile of autophagy-related genes were reflected by significantly decreased lipidation of autophagy marker microtubule-associated protein light chain 3 beta (LC3B-II) in first trimester placental explants in response to TNF-α. Analysis of TNF-α-treated term placental explants showed decreased DAPK1 protein, whereas in contrast to first-trimester LC3B expression and lipidation increased. Immunohistochemistry of placental tissues from early-onset preeclampsia (PE) showed less DAPK1 staining, when compared to controls. Accordingly, DAPK1 mRNA and protein were decreased in primary trophoblasts isolated from early-onset PE, while LC3B-I and -II were increased. Results from this study suggest that DAPK1, a regulator of apoptosis, autophagy and programmed necrosis, decreases in human placenta in response to elevated maternal TNF-α, irrespective of gestational age. In contrast, TNF-α differentially regulates levels of autophagy marker LC3B in human placenta over gestation.

Use of antibiotics during pregnancy and the risk of major congenital malformations: a population based cohort study.

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.