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Purpose: To determine the feasibility of a randomized controlled trial of delayed umbilical cord clamping in preterm infants., Methods: Following informed consent, women between 24 to 32 weeks gestation experiencing imminent preterm birth were randomly assigned to either an immediate cord clamping (ICC) or delayed cord clamping (DCC) group. Umbilical cord clamping directions were 0-15 s for the ICC group and 30-45 s for the DCC group. Information regarding recruitment rate and trial compliance was collected. Neonatal outcomes of intraventricular hemorrhage (IVH), sepsis, anemia, and hyperbilirubinemia were also compared between the two groups. This trial was registered at https://clinicaltrials.gov/. (ClinicalTrials.gov Identifier: NCT00562536)., Results: Thirty-eight women were recruited in total, 19 each to the ICC and DCC groups respectively. The study recruitment rate was 33% and study compliance rate was 97%. The average time for cord clamping was 5.4 s in the ICC group and 39.7 s in the DCC group ( p  < .05). The incidence of IVH and sepsis was the same in both groups (16 and 11% respectively). Thirty-seven percent of the ICC group and 21% of the DCC group required a blood transfusion. Hyperbilirubinemia requiring phototherapy occurred in 37% of the ICC group and 26% of the DCC group., Conclusion: This study demonstrates that a trial of a short delay in umbilical cord clamping (30-45 s) is feasible for women and physicians. Larger scale studies of long term outcomes are warranted.

Animal research strongly suggests that a single dose of antenatal corticosteroids (ACS) is as effective as a double dose to mature preterm lungs; however, a human randomized controlled trial (RCT) is urgently needed. From August to November 2020, we conducted an online survey of Canadian parents of preterm infants. Survey respondents watched a parent-to-parent video introducing an RCT to study whether the standard double dose of ACS is non-inferior to a single dose (and matching placebo). Approximately two-thirds of respondents reported they were either likely or very likely to participate in the RCT, indicating high parental interest in and support for such a trial., (Crown Copyright © 2021. Published by Elsevier Inc. All rights reserved.)

Objective: This study aimed to evaluate the published data on the effect of cannabis use in perimenopausal and postmenopausal women to alleviate menopausal symptoms, insomnia and anxiety., Methods: Databases searched included Ovid MEDLINE, PubMed, Ovid Embase, Web of Science, Scopus, CINAHL, PsycINFO, Cochrane, LILACS and AMED. Selected studies assessed perimenopausal or postmenopausal women, cannabis use impact and menopausal symptoms., Results: A total of 564 studies were retrieved. Three studies met the inclusion criteria. One study controlled for participant cannabis use and reported on the effects of cannabis and placebo cigarette smoking on mood in 10 postmenopausal women. Another study assessed associations between drug use with hot flashes and insomnia in 120 HIV-infected women and found that menopausal status and cannabis use was crudely associated with the presence of hot flashes. The last study evaluated expectancies of 115 menopausal patients who endorsed lifetime cannabis use and reported that women expected cannabis to improve depression, anxiety, hot flashes and problems with sleep. None of these studies assessed quality of life as an outcome., Conclusion: There is a paucity of literature on the impact of cannabis use in menopause. Research into cannabis consumption in menopause is essential, as it is frequently used to alleviate symptoms without evidence of its benefits.

Background: Data on the optimal gestational weight gain in twin pregnancies are limited. As a result, the Institute of Medicine currently provides only provisional recommendations on gestational weight gain in this population., Objective: This study aimed to identify the optimal range of gestational weight gain in twin pregnancies and to estimate the association between inappropriate gestational weight gain and adverse pregnancy outcomes., Study Design: This was a retrospective cohort study of all women with twin pregnancies that were followed up in a single, tertiary center between 2000 and 2014. We used 2 approaches to identify the optimal range of gestational weight gain: a statistical approach (the interquartile range of gestational weight gain in low-risk pregnancies with normal outcomes) and an outcome-based approach (by identifying thresholds of gestational weight gain below or above which the rate of adverse outcomes increases). The primary outcome was preterm birth. Associations of gestational weight gain below or above the normal range with the study outcomes were estimated using logistic regression analysis and were expressed as adjusted odds ratio with 95% confidence intervals. These associations were stratified by prepregnancy body mass index group., Results: A total of 1274 women with twin pregnancies met the study criteria: 43 were classified as underweight, 777 were normal weight, 278 were overweight, and 176 were obese. Our estimates of the optimal gestational weight gain range were similar to those recommended by the Institute of Medicine except for the obese category, in which our optimal gestational weight gain range at 37 weeks (9.3-16.3 kg) was lower than in the provisional Institute of Medicine recommendations (11.3-19.1 kg). Nearly half of our cohort experienced inappropriate gestational weight gain: 30% (n=381) gained weight below and 17% (n=216) gained weight above current Institute of Medicine recommendations. In the normal weight group, gestational weight gain below recommendations was associated with an increased risk of preterm birth and birthweight at the <10th centile and with a reduction in the risk of hypertensive disorders, whereas gestational weight gain above recommendations was associated with an increased risk of hypertensive disorders and a reduction in the risk of birthweight at the <10th centile. Associations were less consistent in the overweight and obese groups., Conclusion: These findings identify gestational weight gain as a potentially modifiable risk factor for preterm birth and other pregnancy complications in twin gestations. Further prospective studies are needed to determine whether interventions aimed at optimizing gestational weight gain can improve the outcomes of these high-risk pregnancies., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objectives: Rates of age-associated severe maternal morbidity (SMM) have increased in Canada, and an association with neighbourhood income is well established. Our aim was to examine SMM trends according to neighbourhood material deprivation quintile, and to assess whether neighbourhood deprivation effects are moderated by maternal age., Design, Setting and Participants: A population-based retrospective cohort study using linked administrative databases in Ontario, Canada. We included primiparous women with a live birth or stillbirth at ≥20 weeks' gestational age., Primary Outcome: SMM from pregnancy onset to 42 days postpartum. We calculated SMM rate differences (RD) and rate ratios (RR) by neighbourhood material deprivation quintile for each of four 4-year cohorts from 1 April 2002 to 31 March 2018. Log-binomial multivariable regression adjusted for maternal age, demographic and pregnancy-related variables., Results: There were 1 048 845 primiparous births during the study period. The overall rate of SMM was 18.0 per 1000 births. SMM rates were elevated for women living in areas with high material deprivation. In the final 4-year cohort, the RD between women living in high vs low deprivation neighbourhoods was 3.91 SMM cases per 1000 births (95% CI: 2.12 to 5.70). This was higher than the difference observed during the first 4-year cohort (RD 2.09, 95% CI: 0.62 to 3.56). SMM remained associated with neighbourhood material deprivation following multivariable adjustment in the pooled sample (RR 1.16, 95% CI: 1.11 to 1.21). There was no evidence of interaction with maternal age., Conclusion: SMM rate increases were more pronounced for primiparous women living in neighbourhoods with high material deprivation compared with those living in low deprivation areas. This raises concerns of a widening social gap in maternal health disparities and highlights an opportunity to focus risk reduction efforts toward disadvantaged women during pregnancy and postpartum., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Conflicting reports of increases and decreases in rates of preterm birth (PTB) and stillbirth in the general population during the COVID-19 pandemic have surfaced. The objective of our study was to conduct a living systematic review and meta-analyses of studies reporting pregnancy and neonatal outcomes by comparing the pandemic and pre-pandemic periods., Material and Methods: We searched PubMed and Embase databases, reference lists of articles published up until 14 May 2021 and included English language studies that compared outcomes between the COVID-19 pandemic time period and pre-pandemic time periods. Risk of bias was assessed using the Newcastle-Ottawa scale. We conducted random-effects meta-analysis using the inverse variance method., Results: Thirty-seven studies with low-to-moderate risk of bias, reporting on 1 677 858 pregnancies during the pandemic period and 21 028 650 pregnancies during the pre-pandemic period, were included. There was a significant reduction in unadjusted estimates of PTB (28 studies, unadjusted odds ratio [uaOR] 0.94, 95% confidence [CI] 0.91-0.98) but not in adjusted estimates (six studies, adjusted OR [aOR] 0.95, 95% CI 0.80-1.13). The reduction was noted in studies from single centers/health areas (uaOR 0.90, 95% CI 0.86-0.94) but not in regional/national studies (uaOR 0.99, 95% CI 0.95-1.03). There was reduction in spontaneous PTB (five studies, uaOR 0.89, 95% CI 0.82-0.98) and induced PTB (four studies, uaOR 0.90, 95% CI 0.81-1.00). There was no reduction in PTB when stratified by gestational age <34, <32 or <28 weeks. There was no difference in stillbirths between the pandemic and pre-pandemic time periods (21 studies, uaOR 1.08, 95% CI 0.94-1.23; four studies, aOR 1.06, 95% CI 0.81-1.38). There was an increase in birthweight (six studies, mean difference 17 g, 95% CI 7-28 g) during the pandemic period. There was an increase in maternal mortality (four studies, uaOR 1.15, 95% CI 1.05-1.26), which was mostly influenced by one study from Mexico. There was significant publication bias for the outcome of PTB., Conclusions: The COVID-19 pandemic time period may be associated with a reduction in PTB; however, referral bias cannot be excluded. There was no difference in stillbirth between the pandemic and pre-pandemic period., (© 2021 Nordic Federation of Societies of Obstetrics and Gynecology.)

Analytical techniques capable of determining the spatial distribution and quantity (mass and/or particle number) of engineered nanomaterials in organisms are essential for characterizing nano-bio interactions and for nanomaterial risk assessments. Here, we combine the use of dynamic secondary ion mass spectrometry (dynamic SIMS) and single particle inductively coupled mass spectrometry (spICP-MS) techniques to determine the biodistribution and quantity of gold nanoparticles (AuNPs) ingested by Caenorhabditis elegans. We report the application of SIMS in image depth profiling mode for visualizing, identifying, and characterizing the biodistribution of AuNPs ingested by nematodes in both the lateral and z (depth) dimensions. In parallel, conventional- and sp-ICP-MS quantified the mean number of AuNPs within the nematode, ranging from 2 to 36 NPs depending on the size of AuNP. The complementary data from both SIMS image depth profiling and spICP-MS provides a complete view of the uptake, translocation, and size distribution of ingested NPs within Caenorhabditis elegans., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier B.V.)

Background: Zika virus (ZIKV) has generated global interest in the last five years mostly due to its resurgence in the Americas between 2015 and 2016. It was previously thought to be a self-limiting infection causing febrile illness in less than one quarter of those infected. However, a rise in birth defects amongst children born to infected pregnant women, as well as increases in neurological manifestations in adults has been demonstrated. We systemically reviewed the literature to understand clinical manifestations and health outcomes in adults globally., Methods: This review was registered prospectively with PROPSERO (CRD 42018096558). We systematically searched for studies in six databases from inception to the end of September 2020. There were no language restrictions. Critical appraisal was completed using the Joanna Briggs Institute Critical Appraisal Tools., Findings: We identified 73 studies globally that reported clinical outcomes in ZIKV-infected adults, of which 55 studies were from the Americas. For further analysis, we considered studies that met 70% of critical appraisal criteria and described subjects with confirmed ZIKV. The most common symptoms included: exanthema (5,456/6,129; 89%), arthralgia (3,809/6,093; 63%), fever (3,787/6,124; 62%), conjunctivitis (2,738/3,283; 45%), myalgia (2,498/5,192; 48%), headache (2,165/4,722; 46%), and diarrhea (337/2,622; 13%). 36/14,335 (0.3%) of infected cases developed neurologic sequelae, of which 75% were Guillain-Barré Syndrome (GBS). Several subjects reported recovery from peak of neurological complications, though some endured chronic disability. Mortality was rare (0.1%) and hospitalization (11%) was often associated with co-morbidities or GBS., Conclusions: The ZIKV literature in adults was predominantly from the Americas. The most common systemic symptoms were exanthema, fever, arthralgia, and conjunctivitis; GBS was the most prevalent neurological complication. Future ZIKV studies are warranted with standardization of testing and case definitions, consistent co-infection testing, reporting of laboratory abnormalities, separation of adult and pediatric outcomes, and assessing for causation between ZIKV and neurological sequelae., Competing Interests: The authors have declared that no competing interests exist.

Objective: Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are the most commonly used medications for mood and anxiety disorders in women. Many women need to continue or initiate these medications during pregnancy, but there is concern about potential withdrawal effects in the newborn, referred to as neonatal abstinence syndrome (NAS). The reason why some infants remain asymptomatic while others are affected has not been elucidated. The objective of this study was to examine whether genetic differences in maternal drug metabolism influence the incidence of NAS., Methods: Women who took Selective serotonin reuptake inhibitors s/SNRIs during pregnancy were recruited from obstetrical clinics. DNA was extracted from saliva samples for genetic analyses of cytochrome P450 (CYP) enzyme polymorphisms. Delivery and NAS data were collected from electronic medical records., Results: Ninety-five women participated. The overall NAS rate was 16.2%. Mild NAS was seen in 13.8% of neonates and severe NAS, in 2%. One-quarter (25%) of the neonates with mild withdrawal symptoms were born to mothers with polymorphisms associated with slower metabolism of their particular antidepressant, but this association was not statistically significant., Conclusion: Importantly, the overall rate of NAS in our study was lower than previously reported. Maternal CYP polymorphisms did not affect the rate of NAS in neonates exposed to SSRIs/SNRIs in utero. This study lends added assurance to patients requiring SSRIs or SNRIs during pregnancy., (Copyright © 2020 The Society of Obstetricians and Gynaecologists of Canada/La Société des obstétriciens et gynécologues du Canada. Published by Elsevier Inc. All rights reserved.)

Background: Meaningful performance measurement requires indicators to be scientifically robust and strategically focused. For many circumpolar states, indicators aligned with national strategies may ignore the priorities of northern, remote, or Indigenous populations. The aim of this project was to identify contextually appropriate performance indicators for maternity care in circumpolar regions., Methods: Fourteen maternity care and health systems experts participated in a modified Delphi consensus process. The list of proposed indicators was derived from a previously published scoping review. Fourteen participants rated each proposed indicator according to importance, circumpolar relevance, validity, and reliability and suggested additional indicators for consideration., Results: Consensus was achieved after two rounds, as measured by a Cronbach's alpha of 0.87. Eleven indicators, many of which represented physical health outcomes, were ranked highly on all four criteria. Twenty-nine additional indicators, largely focused on social determinants of health, health care responsiveness, and accessibility, were identified for further research. Travel for care, cultural safety and upstream structural determinants of health were identified as important themes., Conclusions: This study identified the important gaps between current performance measurement strategies and the context and values that permeate maternal-child health in circumpolar regions. The indicators identified in this study provide an important foundation for ongoing work. We recommend that future work encompass an appreciation for the intersectoral nature of social, structural, and colonial determinants of maternal-child health in circumpolar regions.

Background: The umbilical artery (UA) Doppler pulsatility index is used clinically to detect elevated feto-placental vascular resistance. However, this metric is confounded by variation in fetal cardiac function and is only moderately predictive of placental pathology. Our group developed a novel ultrasound methodology that measures wave reflections in the UA, thereby isolating a component of the Doppler signal that is specific to the placenta. The present study examined whether wave reflections in the UA are predictive of placental vascular pathology., Methods: Standard clinical Doppler ultrasound of the UAs was performed in 241 pregnant women. Of these, 40 women met narrowly defined preset criteria for the control group, 36 had maternal vascular malperfusion (MVM) and 16 had fetal vascular malperfusion (FVM). Using a computational procedure, the Doppler waveforms were decomposed into a pair of forward and backward propagating waves., Findings: Compared to controls, wave reflections were significantly elevated in women with either MVM (p<0.0001) or FVM pathology (p = 0.02). In contrast, the umbilical and uterine artery pulsatility indices were only elevated in the MVM group (p<0.0001) and there were no differences between women with FVM and the controls., Interpretation: The measurement of wave reflections in the UA, combined with standard clinical ultrasound parameters, has the potential to improve the diagnostic performance of UA Doppler to detect placental vascular pathology. Identifying women with FVM pathology is particularly challenging prenatally and future investigations will determine if women at risk of this specific placental disease could benefit from this novel diagnostic technique., Competing Interests: Declaration of Competing Interest The authors have nothing to disclose., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Depression and anxiety impact up to 1 in 5 pregnant and postpartum women worldwide. Yet, as few as 20% of these women are treated with frontline interventions such as evidence-based psychological treatments. Major barriers to uptake are the limited number of specialized mental health treatment providers in most settings, and problems with accessing in-person care, such as childcare or transportation. Task sharing of treatment to non-specialist providers with delivery on telemedicine platforms could address such barriers. However, the equivalence of these strategies to specialist and in-person models remains unproven., Methods: This study protocol outlines the Scaling Up Maternal Mental healthcare by Increasing access to Treatment (SUMMIT) randomized trial. SUMMIT is a pragmatic, non-inferiority test of the comparable effectiveness of two types of providers (specialist vs. non-specialist) and delivery modes (telemedicine vs. in-person) of a brief, behavioral activation (BA) treatment for perinatal depressive and anxiety symptoms. Specialists (psychologists, psychiatrists, and social workers with ≥ 5 years of therapy experience) and non-specialists (nurses and midwives with no formal training in mental health care) were trained in the BA protocol, with the latter supervised by a BA expert during treatment delivery. Consenting pregnant and postpartum women with Edinburgh Postnatal Depression Scale (EPDS) score of ≥ 10 (N = 1368) will be randomized to one of four arms (telemedicine specialist, telemedicine non-specialist, in-person specialist, in-person non-specialist), stratified by pregnancy status (antenatal/postnatal) and study site. The primary outcome is participant-reported depressive symptoms (EPDS) at 3 months post-randomization. Secondary outcomes are maternal symptoms of anxiety and trauma symptoms, perceived social support, activation levels and quality of life at 3-, 6-, and 12-month post-randomization, and depressive symptoms at 6- and 12-month post-randomization. Primary analyses are per-protocol and intent-to-treat. The study has successfully continued despite the COVID-19 pandemic, with needed adaptations, including temporary suspension of the in-person arms and ongoing randomization to telemedicine arms., Discussion: The SUMMIT trial is expected to generate evidence on the non-inferiority of BA delivered by a non-specialist provider compared to specialist and telemedicine compared to in-person. If confirmed, results could pave the way to a dramatic increase in access to treatment for perinatal depression and anxiety., Trial Registration: ClinicalTrials.gov NCT04153864 . Registered on November 6, 2019.

Mammalian brain circuits are wired by dynamic formation and remodeling during development to produce a balance of excitatory and inhibitory synapses. Synaptic regulation is mediated by a complex network of proteins including immunoglobulin (Ig)- class cell adhesion molecules (CAMs), structural and signal-transducing components at the pre- and post-synaptic membranes, and the extracellular protein matrix. This review explores the current understanding of developmental synapse regulation mediated by L1 and NCAM family CAMs. Excitatory and inhibitory synapses undergo formation and remodeling through neuronal CAMs and receptor-ligand interactions. These responses result in pruning inactive dendritic spines and perisomatic contacts, or synaptic strengthening during critical periods of plasticity. Ankyrins engage neural adhesion molecules of the L1 family (L1-CAMs) to promote synaptic stability. Chondroitin sulfates, hyaluronic acid, tenascin-R, and linker proteins comprising the perineuronal net interact with L1-CAMs and NCAM, stabilizing synaptic contacts and limiting plasticity as critical periods close. Understanding neuronal adhesion signaling and synaptic targeting provides insight into normal development as well as synaptic connectivity disorders including autism, schizophrenia, and intellectual disability., 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 Duncan, Murphy and Maness.)

Introduction: Women living with HIV experience more adverse birth outcomes; the mechanisms are not fully understood. We examined placenta morphology and associations with birth outcomes in a Canadian cohort of women living with HIV (HIV + ) on antiretroviral therapy (ART) from conception and HIV-uninfected (HIV - ) women., Methods: Term placentas from 94 women (40 HIV - , 54 HIV + ) were studied. Trimmed placenta weight was collected. Placenta digital photos were used to compute morphometric parameters. Regression models investigated associations between log-transformed placenta parameters and birth outcomes., Results: We observed a trend towards lower placenta weight and smaller placenta area in the HIV + group, both of which were significantly associated with small for gestational age births. HIV + serostatus was associated with 6-fold (95%CI 2-20) greater odds of having placenta area in the lowest quartile (<236 cm 2 ). Cord marginality (distance from the edge) was significantly lower in the HIV + group (p = 0.004), with 35% of placenta having an abnormal (marginal or velamentous) cord insertion vs. 12.5% in the HIV - group (p = 0.01). Velamentous cord insertion was seen in 13% of placentas in the HIV + vs. 0% in HIV - group (p = 0.02). A significant correlation between cord marginality and placenta thickness was observed in the HIV - group, with a more marginal cord being associated with a thicker placenta. This correlation was not observed in the HIV + group. HIV + placentas exposed to protease inhibitors were significantly less circular compared to the HIV - group (p = 0.03)., Conclusion: Our data suggest that HIV/ART exposure affects placenta morphology and is associated with higher rates of abnormal cord insertion., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective: To examine the dose-dependent effect of maternal vitamin D during pregnancy on blood pressure from mid-to-late gestation within the context of a randomized, placebo-controlled trial of vitamin D supplementation in Bangladesh (n = 1298)., Methods: Healthy women without hypertension were enrolled at 17-24 weeks gestation and randomized to one of four vitamin D doses during pregnancy: placebo, 4200, 16 800 or 28 000 IU/week. This substudy examined 1257 women with blood pressure measured at enrollment with at least one other timepoint (measurements included at 24 weeks, 30 weeks, and weekly from 36 weeks until delivery). Effects of vitamin D on SBP or DBP were analyzed using mixed-effects models., Results: Vitamin D did not have an effect on SBP or DBP at 24 or 30 weeks; blood pressure was higher at 36 weeks for the highest dose versus placebo [mean difference (95% CI) mmHg: SBP = 2.3 (0.9-3.7); DBP = 1.9 (0.7-3.0)]. The differences in changes in SBP and DBP between vitamin D groups and placebo across intervals were small (P > 0.10), but the difference for 28 000 IU/week versus placebo was the highest from 30 to 36 weeks [SBP 0.2 (-0.1 to 0.5) and DBP 0.2 (-0.0 to 0.4) mmHg]., Conclusion: Vitamin D supplementation starting mid-pregnancy did not affect SBP or DBP until late gestation, and then only at the highest dose. These results do not support the clinical use of vitamin D in pregnancy to lower maternal blood pressure.

Objective: Our objective was to systematically review randomized and quasi-randomized trials on the neonatal and maternal effects of lower doses of antenatal corticosteroids (<24 mg of betamethasone or dexamethasone) compared with standard double doses of antenatal corticosteroids (24 mg of betamethasone or dexamethasone) administered to women at risk of preterm delivery., Data Sources: Medline, Embase, CINAHL, Web of Science, Cochrane CENTRAL, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform, and the Australia New Zealand Clinical Trials Registry were searched from inception to December 8, 2019., Study Selection: A total of 2401 titles, abstracts, and protocols were independently screened by two reviewers, and subsequently 113 full-text articles were reviewed., Data Extraction: Our primary outcomes were perinatal death and severe respiratory distress syndrome., Data Synthesis: We identified one large in-progress trial comparing 11.4 mg versus 22.8 mg betamethasone and one published randomized controlled trial that compared a lower dose of dexamethasone (16 mg) to a standard dose of betamethasone (24 mg). The only relevant data from the published trial suggests minor changes in fetal heart rate variability between baseline and 24- to 48-hour follow-up between the two groups. Data for other outcomes had to be excluded due to the administration of weekly courses of antenatal corticosteroids., Conclusions: Randomized trial data comparing lower doses of antenatal corticosteroids to standard double doses are scarce. Given concerns regarding current antenatal corticosteroids dosing patterns, there is an urgent need for randomized controlled trials examining lower versus standard double doses of antenatal corticosteroids., (Copyright © 2020 The Society of Obstetricians and Gynaecologists of Canada/La Société des obstétriciens et gynécologues du Canada. Published by Elsevier Inc. All rights reserved.)

Background: Maternally administered corticosteroids are routinely used to accelerate fetal lung maturation in pregnancies at risk of early preterm delivery. Although, among the subgroup with growth restriction, a majority show a temporary improvement in umbilical artery Doppler waveforms that may be sustained up to 7 days, a minority will acutely decompensate in response to corticosteroids in association with deteriorating umbilical and fetal Doppler waveforms. The basis for such acute Doppler changes is presently unknown. Our group has developed a noninvasive ultrasound methodology to measure wave reflections in the umbilical artery and have established that wave reflection metrics are sensitive to structural changes in the placental vasculature and to acute changes in vascular tone. Using this approach, we demonstrated in healthy pregnant mice that fetoplacental vascular resistance decreased in betamethasone-treated mice compared with saline-treated controls., Objective: This study aimed to investigate the effects of betamethasone administration on the wave reflection metrics in a mouse model of fetal growth restriction and to compare these findings with equivalent measurements in human fetuses., Study Design: Pregnant CD-1 mice were housed from embryonic day 14.5 to embryonic day 17.5 in either a normoxic (21% O 2 , n=24) or hypoxic environment (11% O 2 , n=22), the latter being an established mouse model of fetal growth restriction. To investigate the effect of maternally administered betamethasone on the fetoplacental vasculature, ultrasound imaging was performed at baseline and 4 hours after treatment (either betamethasone or sterile saline). Umbilical artery wave reflection metrics were compared between the groups and for the effect of fetal sex. In addition, a cohort of 10 pregnant women with elevated umbilical artery pulsatility index and evidence of fetal growth restriction and 6 controls were imaged before and after corticosteroid administration., Results: In the mouse model, after betamethasone administration, the female fetuses from the hypoxia group showed a 15% increase in umbilical artery diameter, a 98% increase in umbilical artery blood flow, and a 27% decrease in umbilical artery reflection coefficient, whereas the males from the hypoxia group showed no substantial changes. In agreement with our mouse findings, umbilical artery reflections were found to be larger in human growth-restricted fetuses than controls in women at risk of preterm birth., Conclusion: Our studies provide insight into the mechanism whereby the human growth-restricted fetus may exhibit a temporary favorable fetoplacental vascular response to maternally administered corticosteroids. Further investigations are needed to understand why the male growth-restricted fetus seems unable to mount this favorable vascular response., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Antibiotic drug discovery has been an essential field of research since the early 1900s, but the threat from infectious bacteria has only increased over the decades because of the emergence of widespread multidrug resistance. In this review, we discuss the recent advances in natural product, computational and medicinal chemistry that have reinvigorated the field of antibiotic drug discovery while giving perspective on how easily, both in cost and in expertise, these methods can be implemented by other researchers with the goal of increasing the number of scientists contributing to this public health crisis.

Objective: To determine whether preterm birth in a twin pregnancy increases the risk of subsequent preterm birth (PTB) in a singleton pregnancy and to identify predictors for singleton PTB in women with previous twin PTB. Method: A retrospective cohort study of women with prior twin birth followed by a singleton birth in two tertiary referral centres between 2000 and 2016 was conducted. Rate of PTB in subsequent singleton pregnancy was compared between women who experienced previous preterm versus term twin birth. Analysis was further stratified by gestational age at twin and singleton birth, etiology for PTB and chorionicity in the twin pregnancy. Results: A total of 378 women met the inclusion criteria, of whom 252 (66.7%) experienced PTB in the index twin pregnancy. The overall rate of PTB in the subsequent singleton pregnancy was 11.6% (44/378). Women with prior twin PTB had a higher rate of PTB in the subsequent singleton pregnancy compared with women with prior term twin birth (17.5 versus 6.3%, p  = .003, or 3.12, 95%-CI 1.42-6.85), mainly due to a higher rate of late singleton preterm birth (13.1 versus 4.0%, p  = .005). Findings of higher odds of PTB in the subsequent singleton pregnancy was limited to women who gave birth before 34 0/7 weeks in the twin pregnancy and was related to the degree of prematurity (prior twin PTB at 30 0/7 -33 6/7  weeks: OR 3.09, 95%-CI 1.12-8.51; prior twin PTB at <30 0/7  weeks: OR 5.8, 95%-CI 2.46-13.68). The association between previous twin PTB and subsequent singleton PTB was limited to women with prior spontaneous twin PTB (OR 3.34, 95%-CI 1.50-7.45). Conclusion: Women with a history of spontaneous PTB in a twin pregnancy are at increased odds of PTB in subsequent singleton pregnancies compared to women with prior term twin birth, and the risk is related to the severity of prematurity in the index twin pregnancy.

Genome-wide chromatin state underlies gene expression potential and cellular function. Epigenetic features and nucleosome positioning contribute to the accessibility of DNA, but widespread regulators of chromatin state are largely unknown. Our study investigates how coordination of ANP32E and H2A.Z contributes to genome-wide chromatin state in mouse fibroblasts. We define H2A.Z as a universal chromatin accessibility factor, and demonstrate that ANP32E antagonizes H2A.Z accumulation to restrict chromatin accessibility genome-wide. In the absence of ANP32E, H2A.Z accumulates at promoters in a hierarchical manner. H2A.Z initially localizes downstream of the transcription start site, and if H2A.Z is already present downstream, additional H2A.Z accumulates upstream. This hierarchical H2A.Z accumulation coincides with improved nucleosome positioning, heightened transcription factor binding, and increased expression of neighboring genes. Thus, ANP32E dramatically influences genome-wide chromatin accessibility through subtle refinement of H2A.Z patterns, providing a means to reprogram chromatin state and to hone gene expression levels.

Background: Although metformin is increasingly being used in women with type 2 diabetes during pregnancy, little data exist on the benefits and harms of metformin use on pregnancy outcomes in these women. We aimed to investigate the effects of the addition of metformin to a standard regimen of insulin on neonatal morbidity and mortality in pregnant women with type 2 diabetes., Methods: In this prospective, multicentre, international, randomised, parallel, double-masked, placebo-controlled trial, women with type 2 diabetes during pregnancy were randomly assigned from 25 centres in Canada and four in Australia to receive either metformin 1000 mg twice daily or placebo, added to insulin. Randomisation was done via a web-based computerised randomisation service and stratified by centre and pre-pregnancy BMI (<30 kg/m 2 or ≥30 kg/m 2 ) in a ratio of 1:1 using random block sizes of 4 and 6. Women were eligible if they had type 2 diabetes, were on insulin, had a singleton viable pregnancy, and were between 6 and 22 weeks plus 6 days' gestation. Participants were asked to check their fasting blood glucose level before the first meal of the day, before the last meal of the day, and 2 h after each meal. Insulin doses were adjusted aiming for identical glucose targets (fasting glucose <5·3 mmol/L [95 mg/dL], 2-h postprandial glucose <6·7 mmol/L [120 mg/dL]). Study visits were done monthly and patients were seen every 1-4 weeks as was needed for standard clinical care. At study visits blood pressure and bodyweight were measured; patients were asked about tolerance to their pills, any hospitalisations, insulin doses, and severe hypoglycaemia events; and glucometer readings were downloaded to the central coordinating centre. Participants, caregivers, and outcome assessors were masked to the intervention. The primary outcome was a composite of fetal and neonatal outcomes, for which we calculated the relative risk and 95% CI between groups, stratifying by site and BMI using a log-binomial regression model with an intention-to-treat analysis. Secondary outcomes included several relevant maternal and neonatal outcomes. The trial was registered with ClinicalTrials.gov, NCT01353391., Findings: Between May 25, 2011, and Oct 11, 2018, we randomly assigned 502 women, 253 (50%) to metformin and 249 (50%) to placebo. Complete data were available for 233 (92%) participants in the metformin group and 240 (96%) in the placebo group for the primary outcome. We found no significant difference in the primary composite neonatal outcome between the two groups (40% vs 40%; p=0·86; relative risk [RR] 1·02 [0·83 to 1·26]). Compared with women in the placebo group, metformin-treated women achieved better glycaemic control (HbA 1c at 34 weeks' gestation 41·0 mmol/mol [SD 8·5] vs 43·2 mmol/mol [-10]; 5·90% vs 6·10%; p=0·015; mean glucose 6·05 [0·93] vs 6·27 [0·90]; difference -0·2 [-0·4 to 0·0]), required less insulin (1·1 units per kg per day vs 1·5 units per kg per day; difference -0·4 [95% CI -0·5 to -0·2]; p<0·0001), gained less weight (7·2 kg vs 9·0 kg; difference -1·8 [-2·7 to -0·9]; p<0·0001) and had fewer caesarean births (125 [53%] of 234 in the metformin group vs 148 [63%] of 236 in the placebo group; relative risk [RR] 0·85 [95% CI 0·73 to 0·99]; p=0·031). We found no significant difference between the groups in hypertensive disorders (55 [23%] in the metformin group vs 56 [23%] in the placebo group; p=0·93; RR 0·99 [0·72 to 1·35]). Compared with those in the placebo group, metformin-exposed infants weighed less (mean birthweight 3156 g [SD 742] vs 3375 g [742]; difference -218 [-353 to -82]; p=0·002), fewer were above the 97th centile for birthweight (20 [9%] in the metformin group vs 34 [15%] in the placebo group; RR 0·58 [0·34 to 0·97]; p=0·041), fewer weighed 4000 g or more at birth (28 [12%] in the metformin group vs 44 [19%] in the placebo group; RR 0·65 [0·43 to 0·99]; p=0·046), and metformin-exposed infants had reduced adiposity measures (mean sum of skinfolds 16·0 mm [SD 5·0] vs 17·4 [6·2] mm; difference -1·41 [-2·6 to -0·2]; p=0·024; mean neonatal fat mass 13·2 [SD 6·2] vs 14·6 [5·0]; p=0·017). 30 (13%) infants in the metformin group and 15 (7%) in the placebo group were small for gestational age (RR 1·96 [1·10 to 3·64]; p=0·026). We found no significant difference in the cord c-peptide between groups (673 pmol/L [435] in the metformin group vs 758 pmol/L [595] in the placebo group; p=0·10; ratio of means 0·88 [0·72 to 1·02]). The most common adverse event reported was gastrointestinal (38 events in the metformin group and 38 events in the placebo group)., Interpretation: We found several maternal glycaemic and neonatal adiposity benefits in the metformin group. Along with reduced maternal weight gain and insulin dosage and improved glycaemic control, the lower adiposity and infant size measurements resulted in fewer large infants but a higher proportion of small-for-gestational-age infants. Understanding the implications of these effects on infants will be important to properly advise patients who are contemplating the use of metformin during pregnancy., Funding: Canadian Institutes of Health Research, Lunenfeld-Tanenbaum Research Institute, University of Toronto., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objective Data: The purpose of this study was to conduct a systematic review and meta-analyses of literature regarding the risk of preterm birth in singleton pregnancies after a preterm twin birth., Study: We conducted a literature search of Embase, Ovid Medline, and Cochrane from inception until February 28, 2019. Studies that evaluated women with a previous twin birth followed by a singleton birth were included., Study Appraisal and Synthesis Methods: Data were abstracted in duplicate, and summary odds ratios and confidence intervals were calculated with the use of random effects model. Risk of bias was assessed with the use of the Newcastle-Ottawa Scale, and quality of evidence was evaluated with the use of the Grades of Recommendation, Assessment, Development, and Evaluation approach. The primary outcome was a preterm singleton birth (<37 weeks gestational age); secondary outcomes included risk of late preterm birth (34-36+6 weeks gestation), preterm birth between 30 and 33+6 weeks gestation, and preterm birth at <30 weeks gestation. Subanalysis of risk of singleton preterm birth after spontaneous twin birth was also performed. A priori, the protocol was developed and registered with PROSPERO (2016; registration number: CRD42017053382)., Results: We included 8 cohort studies at low risk-of-bias met inclusion criteria for the systematic review and 6 for the meta-analysis. Compared with women with previous term twin births, women who had previous preterm (<37 weeks gestation) twin births were at increased odds of preterm singleton birth in subsequent pregnancy (odds ratio, 4.34; 95% confidence interval, 2.83-6.65). Gestational age at birth of previous twin pregnancy was an effect modifier. Compared with previous term twin births, the odd ratios of subsequent preterm singleton birth were 2.13 (95% confidence interval, 1.21-3.74) if twins were born between 34 and 36+6 weeks gestation, 5.18 (95% confidence interval, 2.78-9.64) if twins were born between 30 and 33+6 weeks gestation, and 9.78 (95% confidence interval, 4.99-18.98) if twins were born at <30 weeks gestation. A similar trend was seen for the risk of singleton preterm birth after spontaneous twin preterm birth., Conclusion: A history of preterm twin birth is associated with higher odds of subsequent preterm singleton birth. The odds increase with decreasing gestational age of previous twin birth., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Selective catalysis at the molecular level represents a cornerstone of chemical synthesis. However, it still remains an open question how to elevate tunable catalysis to larger length scales to functionalize whole polymer chains in a selective manner. We now report a hydrazone-linked tetrahedron with wide openings, which acts as a catalyst to size-selectively functionalize polydisperse polymer mixtures. Our experimental and computational evidence supports a dual role of the hydrazone-linked tetrahedron. To accelerate functionalization of the polymer substrates, the tetrahedron (i) unfolds the polymer substrates and/or breaks the polymer aggregates as well as (ii) enables target sites (amino groups) on the polymers to coordinate with catalytic units (triglyme) attached to the tetrahedron. With the tetrahedron as the catalyst, we find that the reactivity of the shorter polymers increases selectively. Our findings enable the possibility to engineer hydrolytically stable molecular polyhedra as organocatalysts for size-selective polymer modification., Competing Interests: DECLARATION OF INTERESTS The authors have no competing financial interests to declare. N.D. is currently a graduate student at Yale University (New Haven, CT). K.E.M. is currently employed at the University of North Carolina, Asheville (Asheville, NC). S.C.R is currently a postdoctoral researcher at the University of Southern Mississippi (Hattiesburg, MS). J.P.C. is currently employed as a Scientist at Integrity Industrial Ink Jet Integration, LLC (West Lebanon, NH). However, N.D., K.E.M., S.C.R., and J.P.C performed the work for this paper at the University of Vermont (Burlington, VT). Some of the authors have also filed a provisional patent application ([INSERT PATENT NUMBER ONCE THE PROVISIONAL APPLICATION HAS BEEN FILED]) related to this work.

The profiling of DNA methylation modifications in peripheral blood has significant potential to determine risk factors for human disease. Little is known concerning the sensitivity of DNA methylation profiles to ex vivo sample handling. Here, we studied typical conditions prior to sample storage associated with cord blood samples obtained from clinical investigations using reduced representation bisulfite sequencing. We examined both whole blood collected shortly after birth and dried blood spots, a potentially important source of neonatal blood for investigation of the DNA methylome and the Developmental Origins of Health and Disease in human cohorts because they are routinely collected during clinical care. Samples were matched across different time conditions, as they were from the same cord blood samples obtained from the same individuals. Maintaining whole blood ex vivo up to 24 h (4°C) or dried blood spots up to 7 days (room temp.) had little effect on DNA methylation profiles. Minimal differences were detected between cord blood immediately frozen and dried blood spots. Our results indicate that DNA methylation profiles are resilient to ex vivo sample handling conditions prior to storage. These data will help guide future human studies focused toward determination of DNA methylation modifications in whole blood., (Copyright © 2020 Sasaki, Kim, Murphy and Matthews.)

This study sought to perform a systematic review of adverse events reported with the use of cabergoline for postpartum lactation inhibition or suppression in women aged 15 to 50. Following registration with PROSPERO (CRD42017049894), a comprehensive search of the Ovid databases Medline, Embase, and CENTRAL, along with PubMed, was conducted from January 1, 1985 to January 25, 2018. All study designs investigating cabergoline use for postpartum lactation inhibition or suppression in women aged 15 to 50 were included. A total of 695 articles were retrieved, and 25 articles were eligible for inclusion. Adverse events were then reported in terms of frequency, with percentages calculated according to the total number of women exposed to the intervention. A bias assessment of the articles was also performed. Among a total of 757 women, 108 adverse events were observed in 96 women (14.2%). The most common adverse events were dizziness (35 of 757), headache (30 of 757), and nausea or vomiting (19 of 757). These events were described as short-lived, self-resolving, and dose dependent. One pharmacovigilance study reported 29 "serious" events from a total of 175 events in 72 case reports, which included thromboembolic and neurologic events. Four case studies specifically addressed the psychiatric population, with one half reporting psychiatric symptoms following administration of cabergoline. In conclusion, this systematic review demonstrates that adverse events were generally benign and tolerable following the administration of cabergoline. However, pharmacovigilance data reveal that vigilance is still needed given the occurrence of rare but serious events., (Copyright © 2019 The Society of Obstetricians and Gynaecologists of Canada/La Société des obstétriciens et gynécologues du Canada. Published by Elsevier Inc. All rights reserved.)

The objective of this study is to determine whether maternal antidepressant use during pregnancy influences uteroplacental hemodynamics, thereby affecting fetal growth and gestational age at delivery. The secondary aim was to determine the incidence of neonatal abstinence syndrome (NAS) among infants exposed to antidepressant medications. The charts of women who received obstetrical care and had a history of depression from January 2014 to December 2016 at Mount Sinai Hospital in Toronto, Canada, were reviewed. Exclusion criteria were substance abuse; narcotic or lithium use at the time of delivery.In total, 205 women met the inclusion criteria (92 took antidepressants; 113 women did not). There were no significant differences in umbilical artery pulsatility index (PI), gestational age at delivery, or birth weight when comparing women based on antidepressant use. A small proportion (18%) of neonates had mild withdrawal symptoms; one baby had a score (≥ 8) consistent with severe NAS. In women with a history of depression, there was no difference in uteroplacental hemodynamics as measured by third trimester Doppler ultrasonography when comparing women who took antidepressant medication versus those who did not. The large majority of babies who were exposed to antidepressants in utero did not show withdrawal symptoms. These results lend support for the relative safety of antidepressants during pregnancy.

Background: Depression in pregnancy negatively affects maternal-child health. Transcranial direct current stimulation (tDCS), a non-invasive brain stimulation treatment for depression, has not been evaluated in pregnancy., Objective: To conduct a pilot randomized controlled trial (RCT) to evaluate tDCS for antenatal depression., Methods: In this pilot RCT in Toronto, Ontario (October 2014 to December 2016), adult pregnant women 14-32 weeks gestation with major depressive disorder who had declined antidepressant medication were considered for inclusion. Participants were randomly assigned 1:1 to tDCS or sham-control. Active tDCS comprised 30-min sessions of 2 mAmp direct current delivered over the dorsolateral prefrontal cortex, 5 days per week, for 3 weeks. Sham was administered similarly, but with current turned off after 30 s. Main outcomes were feasibility, acceptability, and protocol adherence. Maternal Montgomery Asperg Depression Rating Scale (MADRS) was measured post-treatment and at 4 and 12 weeks postpartum., Results: Of 20 women randomized, 16 completed treatment and provided data (124 tDCS, 122 sham sessions). Views of treatment were positive with no serious adverse events. Post-treatment estimated marginal mean MADRS scores were 11.8 (standard error, SE 2.66) for tDCS and 15.4 (SE 2.51) for sham (p = 0.34). At 4 weeks postpartum, 75.0% of tDCS women were remitted versus 12.5% sham-control (p = 0.04)., Conclusions: Results support proceeding to a definitive RCT to evaluate tDCS for antenatal depression. The preliminary efficacy estimates immediately post-treatment and in the postpartum, are encouraging with respect to the potential use of tDCS to improve treatment rates in this population. The trial was registered at: clinical trials.gov (NCT02116127)., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: This study sought to compare the pregnancy and postpartum self-reported mood and mental health status of women who conceived with assisted reproductive technology (ART) with those of women who conceived spontaneously., Methods: In this prospective cohort study, 1176 pregnant women from prenatal clinics in the Ontario Birth Study were enrolled. In the pregnancy and the postpartum period, women who conceived with ART, including in vitro fertilization and intrauterine insemination, were compared with women who conceived spontaneously regarding depression and anxiety at 12-16 weeks and 24-28 weeks gestation and 6-10 weeks postpartum. The following main outcome measures were used: Edinburgh Postnatal Depression Scale, two-item Patient Health Questionnaire, State Trait Anxiety Inventory six-item scale, and two-item Generalized Anxiety Disorder scale (Canadian Task Force Classification II-2)., Results: Women who conceived with ART demonstrated a decreased likelihood of depression compared with women who spontaneously conceived (SC) at 24-28 weeks gestation (Edinburgh Postnatal Depression Scale: ART 3.6% vs. SC 15%; P < 0.01; two-item Patient Health Questionnaire: ART 0.0% vs. SC 4.0%; P = 0.027), as well as decreased perceived stress (mean score: ART 3.25 vs. SC 4.02; P < 0.01). Women in the ART group also had a lower percentage of positive two-item Generalized Anxiety Disorder scores (ART 2.7% vs. SC 7.5%; P = 0.049). There was no difference in self-reported depression, anxiety, or perceived stress between groups at 12-16 weeks gestation or at 6-10 weeks postpartum., Conclusion: Women who conceived using ART reported decreased rates of depressive symptoms, perceived stress, and generalized anxiety during the second trimester of pregnancy compared with women who had SC pregnancies, and both groups experienced similar mental health status earlier in gestation and in the postpartum period., (Copyright © 2019 The Society of Obstetricians and Gynaecologists of Canada/La Société des obstétriciens et gynécologues du Canada. Published by Elsevier Inc. All rights reserved.)

Antenatal corticosteroids are often administered to women at risk of preterm birth to accelerate fetal lung development; however, there is evidence that this treatment may adversely affect placental function in some fetuses. Our group has recently demonstrated that wave reflections in the umbilical artery (UA), measured using high-frequency ultrasound, are sensitive to placental vascular abnormalities. In the present study, we used this approach to investigate the effect of maternal administration of betamethasone, a clinically relevant corticosteroid, on the feto-placental vasculature of the mouse. Fetuses were assessed at embryonic day (E)15.5 and E17.5 in C57BL6/J mice. At both gestational ages, the UA diameter, UA blood flow, and the wave reflection coefficient were significantly elevated in the betamethasone-treated mice compared to vehicle-treated controls. These observations support the interpretation that placental vascular resistance dropped with betamethasone treatment to an extent that could not be explained by vasodilation of the UA alone. Consistent with clinical studies, the effect of betamethasone on UA end-diastolic velocity was heterogeneous. Our results suggest that UA wave reflections are more sensitive to acute changes in placental vascular resistance compared with the UA pulsatility index, and this technique may have clinical application to identify a favorable placental vascular response to fetal therapies such as antenatal corticosteroids, where the fetal heart rate is likely to vary., (© The Author(s) 2019. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Tyrosine hydroxylase is the key enzyme controlling the synthesis of the catecholamines including dopamine. The breakdown of dopamine into toxic compounds has been suggested to have a key role in the degeneration of the dopaminergic neurons in Parkinson's disease. Humans are unique in containing four isoforms of tyrosine hydroxylase, but understanding of the role of these isoforms under normal conditions and in disease states is limited. The aim of this work was to determine the level and distribution of the four human isoforms in tissues from healthy controls and patients with Parkinson's disease. The results show that isoform 1 and isoform 2 are the major tyrosine hydroxylase isoforms in human brain, but that tyrosine hydroxylase isoform 2 is more abundant in the substantia nigra than the tyrosine hydroxylase isoform 1. The two minor isoforms, isoform 3 and isoform 4, are expressed at a proportionally higher level in the terminal field regions (caudate and putamen) compared to the substantia nigra. There was a selective loss of tyrosine hydroxylase isoform 1 in Parkinson's disease compared to age-matched controls and a corresponding increase in the proportion of tyrosine hydroxylase isoform 2. Phosphorylation of serine 40 was significantly increased in caudate, putamen and ventral tegmental area, but not in the substantia nigra, in Parkinson's disease brain. These results show a selective sparing of tyrosine hydroxylase isoform 2 in Parkinson's disease. Isoform 2 exhibits a reduced capacity for activation compared to isoform 1, which may account for the selective sparing of cells expressing isoform 2 in Parkinson's disease. Surviving neurons in Parkinson's disease brain exhibit a substantial increase in tyrosine hydroxylase phosphorylation consistent with a compensatory mechanism of increased dopamine synthesis in the terminal field regions., (Crown Copyright © 2019. Published by Elsevier Inc. All rights reserved.)

Objective: To compare maternal blood endotoxin activity (EA) in women with preterm premature rupture of membranes (PPROM) with gestational age (GA) matched controls; to evaluate serial EA till birth in PPROM and its correlation with latency to delivery. Methods: We followed singleton preterm pregnancies from admission with PPROM until birth. Uncomplicated, GA-matched pregnancies served as controls. Demographics, birth and neonatal outcomes were collected. EA (EAA™) was assessed serially in PPROM and at study entry in controls. EA was compared using Mann Whitney and Wilcoxon tests, p value <.05 was considered significant. Results: We recruited 20 cases of PPROM and 20 controls. Demographics were similar between groups. Mean GA of PPROM was 29.0 ± 2.2 weeks and median latency was 7.5 (IQR 14.1) weeks. Median EA at admission following PPROM was significantly elevated over controls (0.43 (0.18) versus 0.36 (0.2); p  < .02). Overall there was no difference in median EA at admission and in labor (0.43 (0.18) versus 0.33 (0.21); p  = .2) following PPROM. However, on comparing cases with latency to delivery ≤7 days ( n  = 10) versus >7 days ( n  = 10), there was a significant drop in EA in the latter group (0.44 (0.2) versus 0.34 (0.2); p  < .004). Conclusions: EA in PPROM represents a promising biomarker in predicting the clinical evolution of preterm birth.

Premature prelabor rupture of the membranes (PPROM) causes one-third of preterm births worldwide and is most likely caused by subclinical intrauterine infection and/or inflammation. We proposed that women with systemic inflammation at the time of PPROM would have shorter latency. Peripheral blood samples were collected from 20 singleton pregnant women with PPROM between 23 ± 1 and 33 ± 6 weeks. The first sample was drawn within 48 hours of admission, followed by weekly blood draws until delivery. Pregnancies complicated with acute chorioamnionitis, preeclampsia, intrauterine growth restriction, obesity, substance abuse, and chronic maternal disease were excluded. Twenty uncomplicated, gestational age-matched pregnancies served as controls. Plasma concentration of 39 cytokines was measured longitudinally using Luminex assays to investigate their value as predictive biomarkers of latency. Women with PPROM exhibited significantly lower plasma concentration of interferon-γ-inducible protein 10-Chemokine (c-x-c motif; IP10/CXCL10), Chemokine (c-x-c motif) Ligand 9 (MIG/CXCL9), Platelet-derived growth factor BB (PDGFbb), and cutaneous T cell-attracting chemokine, also known as CCL27/CCL27 than controls at admission but significantly elevated interleukin (IL)1RA, tumor necrosis factor α, monocyte chemotactic protein-1/CCL2 at delivery compared to admission. Women with PPROM who delivered within 7 days had significantly lower plasma concentration of anti-inflammatory cytokine IL1RA than those with latency periods >7 days. The IL1RA and endotoxin activity in conjunction with clinical parameters results in excellent prediction of latency to delivery (area under the receiver-operating characteristic curve = 0.91). We concluded that higher levels of anti-inflammatory cytokines in women with PPROM were associated with increased latency until delivery, likely due to counterbalancing of proinflammatory load. When used in conjunction with other predictive characteristics of time until delivery, cytokines may further assist clinical decision-making and optimize pregnancy outcomes in women with PPROM.

Introduction: Perinatology, the study of two individuals that constitute the mother-fetus dyad, poses unique challenges to the conduct of clinical decision analysis (CDA) and economic evaluation (EE) studies. Our objective was systematically to review CDA and model-based EE studies in pregnant women to better understand how these studies have been conducted and reported in perinatology., Material and Methods: MEDLINE, Embase, Scopus, Web of Science and clinicaltrials.gov were searched as of October 2018. The indexing terms "pregnancy", "decision trees", "Markov models" and "economic models" were used. The search was limited to human data and the English language. Two reviewers independently screened titles and abstracts. Data extraction and assessment of reporting quality were performed in duplicate for 10% of studies and reached 100% agreement. The remainder was carried out by a single reviewer. The study protocol was registered with PROSPERO (CRD 42016047206)., Results: Seventy-seven studies met eligibility criteria and fulfilled between 40% and 91% of relevant attributes on the checklist for critical appraisal of CDA models. There was considerable variation in study reporting. A total of 53% of studies included maternal and offspring outcomes, 14% described using weighted means, meta-analyses or health administrative databases to estimate probabilities and 13% considered outcomes over the lifetime of mother and offspring. Patient preferences (utilities) were used in 47% of the studies. Of these, 10% were elicited from healthcare providers alone and not from pregnant women or the public. Of the EE studies, 25% described a societal analytic perspective. Where relevant, 42% described discounting for costs and benefits, and 30% reported using probabilistic and deterministic sensitivity analyses., Conclusions: Despite long-term implications of perinatal decisions to mother and offspring, CDA and model-based EE studies in perinatology frequently do not consider lifetime horizons and patient-preferences for outcomes related to mother and offspring. They also often fail to adhere to guidelines regarding conduct and reporting., (© 2019 Nordic Federation of Societies of Obstetrics and Gynecology.)

Objective: The objective of this study was to evaluate the feasibility of using text messages to enhance mental health screening and education of women in the immediate postpartum period., Methods: A total of 937 postpartum women were recruited from an obstetrics and gynecology clinic of a large urban hospital. Participants received a text message containing a two-question screen for postpartum depression every two weeks and three text messages per week about postpartum mental health for the first 12 weeks postpartum. Those who screened positive were administered the Edinburgh Postnatal Depression Scale. They were matched with a subset of women who were also assessed with the Edinburgh Postnatal Depression Scale after screening negative for depression with the text messaging screen. At 12 to 13 weeks postpartum, all participants received an online survey assessing satisfaction with the text messages., Results: Of 937 participants, 126 (13%) screened positive. Agreement between the texted screen and the Edinburgh Postnatal Depression Scale was moderate (κ=0.45), with good sensitivity (0.90, 95% confidence interval [95% CI]=0.81-0.96) and specificity (0.82, 95% CI=0.79-0.85). Nine hundred thirty (99%) participants responded to at least one of the six texted screens, whereas 632 (67%) responded to all six. Of the 589 (63%) who responded to the satisfaction survey, 459 (78%) recommended that all women be screened for postpartum depression via text messaging and that all women in the postpartum period be sent information texts about postpartum depression (N=504, 91%)., Conclusions: Using text messaging technology to screen women for postpartum depression and provide information on postpartum mental health appears to be sensitive, feasible, and well accepted.

Background: Infants born preterm compared with infants born at term are at an increased risk of dying and of serious morbidities in early life, and those who survive have higher rates of neurological impairments. It remains unclear whether exposure to repeat courses of prenatal corticosteroids can reduce these risks. This individual participant data (IPD) meta-analysis (MA) assessed whether repeat prenatal corticosteroid treatment given to women at ongoing risk of preterm birth in order to benefit their infants is modified by participant or treatment factors., Methods and Findings: Trials were eligible for inclusion if they randomised women considered at risk of preterm birth who had already received an initial, single course of prenatal corticosteroid seven or more days previously and in which corticosteroids were compared with either placebo or no placebo. The primary outcomes for the infants were serious outcome, use of respiratory support, and birth weight z-scores; for the children, they were death or any neurosensory disability; and for the women, maternal sepsis. Studies were identified using the Cochrane Pregnancy and Childbirth search strategy. Date of last search was 20 January 2015. IPD were sought from investigators with eligible trials. Risk of bias was assessed using criteria from the Cochrane Collaboration. IPD were analysed using a one-stage approach. Eleven trials, conducted between 2002 and 2010, were identified as eligible, with five trials being from the United States, two from Canada, and one each from Australia and New Zealand, Finland, India, and the United Kingdom. All 11 trials were included, with 4,857 women and 5,915 infants contributing data. The mean gestational age at trial entry for the trials was between 27.4 weeks and 30.2 weeks. There was no significant difference in the proportion of infants with a serious outcome (relative risk [RR] 0.92, 95% confidence interval [CI] 0.82 to 1.04, 5,893 infants, 11 trials, p = 0.33 for heterogeneity). There was a reduction in the use of respiratory support in infants exposed to repeat prenatal corticosteroids compared with infants not exposed (RR 0.91, 95% CI 0.85 to 0.97, 5,791 infants, 10 trials, p = 0.64 for heterogeneity). The number needed to treat (NNT) to benefit was 21 (95% CI 14 to 41) women/fetus to prevent one infant from needing respiratory support. Birth weight z-scores were lower in the repeat corticosteroid group (mean difference -0.12, 95%CI -0.18 to -0.06, 5,902 infants, 11 trials, p = 0.80 for heterogeneity). No statistically significant differences were seen for any of the primary outcomes for the child (death or any neurosensory disability) or for the woman (maternal sepsis). The treatment effect varied little by reason the woman was considered to be at risk of preterm birth, the number of fetuses in utero, the gestational age when first trial treatment course was given, or the time prior to birth that the last dose was given. Infants exposed to between 2-5 courses of repeat corticosteroids showed a reduction in both serious outcome and the use of respiratory support compared with infants exposed to only a single repeat course. However, increasing numbers of repeat courses of corticosteroids were associated with larger reductions in birth z-scores for weight, length, and head circumference. Not all trials could provide data for all of the prespecified subgroups, so this limited the power to detect differences because event rates are low for some important maternal, infant, and childhood outcomes., Conclusions: In this study, we found that repeat prenatal corticosteroids given to women at ongoing risk of preterm birth after an initial course reduced the likelihood of their infant needing respiratory support after birth and led to neonatal benefits. Body size measures at birth were lower in infants exposed to repeat prenatal corticosteroids. Our findings suggest that to provide clinical benefit with the least effect on growth, the number of repeat treatment courses should be limited to a maximum of three and the total dose to between 24 mg and 48 mg., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: RJW provided expertise on a legal case for LabCorp for which he received compensation. The case was not related to the topic being presented. He is PI for several studies that CUMC receives grants for including support from commercial entities Natera, Inc.; Sequenom; Illumina, Inc. He does not receive compensation from any of these grants.

Single particle inductively coupled plasma-mass spectrometry (spICP-MS) is an emerging technique capable of simultaneously measuring nanoparticle size and number concentration of metal-containing nanoparticles (NPs) at environmental levels. single particle ICP-MS will become an established measurement method once the metrological quality of the measurement results it produces have been proven incontrovertibly. This Article presents the first validation of spICP-MS capabilities for measuring mean NP size and number size distribution of gold nanoparticles (AuNPs). The validation is achieved by (i) calibration based on the consensus value for particle size derived from six different sizing techniques applied to National Institute of Standards and Technology (NIST) Reference Material (RM) 8013; (ii) comparison with high-resolution scanning electron microscopy (HR-SEM) used as a reference method, which is linked to the International System of Units (SI) through a calibration standard characterized by the NIST metrological atomic force microscope; and (iii) evaluation of the uncertainty associated with the measurement of the mean particle size to enable comparison of the spICP-MS and HR-SEM methods. After establishing HR-SEM and spICP-MS measurement protocols, both methods were used to characterize commercial AuNP suspensions of three different sizes (30, 60, and 100 nm) with four different coatings and surface charge at pH 7. Single particle ICP-MS measurements (corroborated by HR-SEM) revealed the existence of two distinct subpopulations of particles in the number size distributions for four of the 60 nm commercial suspensions, a fact that was not apparent in the measurement results supplied by the vendor using transmission electron microscopy. This finding illustrates the utility of spICP-MS for routine characterization of commercial AuNP suspensions regardless of size or coating.

There are multiple conventions for gestational age notation, which lead to different interpretations of completed weeks. This variability is exemplified by the different gestational age ranges recommended for administration of antenatal corticosteroid prophylaxis. Antenatal corticosteroid prophylaxis is widely recommended for women at risk of preterm delivery up to 34 completed weeks gestation. According to the World Health Organization, 34 completed weeks refers to the time period from the first day of the last menstrual period (day zero) to 34 weeks and 6 days of gestation (i.e., to 34 +6 34 weeks, or 244 days gestation). However, an alternative convention interprets 34 completed weeks as the period from the first day of the last menstrual period to 33 +6 36 weeks' gestation (i.e., 237 days' gestation). These inconsistencies in gestational age notation may have led to different practice recommendations for antenatal corticosteroid prophylaxis worldwide. Agreeing on the World Health Organization notation and interpretation of completed weeks may help promote clear communication within our discipline and more precise and effective knowledge dissemination., (Copyright © 2018 Society of Obstetricians and Gynaecologists of Canada. Published by Elsevier Inc. All rights reserved.)

Objective: To compare glycemic control, quality of life, and pregnancy outcomes of women using insulin pumps and multiple daily injection therapy (MDI) during the Continuous Glucose Monitoring in Women With Type 1 Diabetes in Pregnancy Trial (CONCEPTT)., Research Design and Methods: This was a prespecified analysis of CONCEPTT involving 248 pregnant women from 31 centers. Randomization was stratified for pump versus MDI and HbA 1c . The primary outcome was change in HbA 1c from randomization to 34 weeks' gestation. Key secondary outcomes were continuous glucose monitoring (CGM) measures, maternal-infant health, and patient-reported outcomes., Results: At baseline, pump users were more often in stable relationships ( P = 0.003), more likely to take preconception vitamins ( P = 0.03), and less likely to smoke ( P = 0.02). Pump and MDI users had comparable first-trimester glycemia: HbA 1c 6.84 ± 0.71 vs. 6.95 ± 0.58% (51 ± 7.8 vs. 52 ± 6.3 mmol/mol) ( P = 0.31) and CGM time in target (51 ± 14 vs. 50 ± 13%) ( P = 0.40). At 34 weeks, MDI users had a greater decrease in HbA 1c (-0.55 ± 0.59 vs. -0.32 ± 0.65%, P = 0.001). At 24 and 34 weeks, MDI users were more likely to achieve target HbA 1c ( P = 0.009 and P = 0.001, respectively). Pump users had more hypertensive disorders ( P = 0.011), mainly driven by increased gestational hypertension (14.4 vs. 5.2%; P = 0.025), and more neonatal hypoglycemia (31.8 vs. 19.1%, P = 0.05) and neonatal intensive care unit (NICU) admissions >24 h (44.5 vs. 29.6%; P = 0.02). Pump users had a larger reduction in hypoglycemia-related anxiety ( P = 0.05) but greater decline in health/well-being ( P = 0.02)., Conclusions: In CONCEPTT, MDI users were more likely to have better glycemic outcomes and less likely to have gestational hypertension, neonatal hypoglycemia, and NICU admissions than pump users. These data suggest that implementation of insulin pump therapy is potentially suboptimal during pregnancy., (© 2018 by the American Diabetes Association.)

Competing Interests: Competing interests: None declared.

Background: It is unclear whether maternal vitamin D supplementation during pregnancy and lactation improves fetal and infant growth in regions where vitamin D deficiency is common., Methods: We conducted a randomized, double-blind, placebo-controlled trial in Bangladesh to assess the effects of weekly prenatal vitamin D supplementation (from 17 to 24 weeks of gestation until birth) and postpartum vitamin D supplementation on the primary outcome of infants' length-for-age z scores at 1 year according to World Health Organization (WHO) child growth standards. One group received neither prenatal nor postpartum vitamin D (placebo group). Three groups received prenatal supplementation only, in doses of 4200 IU (prenatal 4200 group), 16,800 IU (prenatal 16,800 group), and 28,000 IU (prenatal 28,000 group). The fifth group received prenatal supplementation as well as 26 weeks of postpartum supplementation in the amount of 28,000 IU (prenatal and postpartum 28,000 group)., Results: Among 1164 infants assessed at 1 year of age (89.5% of 1300 pregnancies), there were no significant differences across groups in the mean (±SD) length-for-age z scores. Scores were as follows: placebo, -0.93±1.05; prenatal 4200, -1.11±1.12; prenatal 16,800, -0.97±0.97; prenatal 28,000, -1.06±1.07; and prenatal and postpartum 28,000, -0.94±1.00 (P=0.23 for a global test of differences across groups). Other anthropometric measures, birth outcomes, and morbidity did not differ significantly across groups. Vitamin D supplementation had expected effects on maternal and infant serum 25-hydroxyvitamin D and calcium concentrations, maternal urinary calcium excretion, and maternal parathyroid hormone concentrations. There were no significant differences in the frequencies of adverse events across groups, with the exception of a higher rate of possible hypercalciuria among the women receiving the highest dose., Conclusions: In a population with widespread prenatal vitamin D deficiency and fetal and infant growth restriction, maternal vitamin D supplementation from midpregnancy until birth or until 6 months post partum did not improve fetal or infant growth. (Funded by the Bill and Melinda Gates Foundation; ClinicalTrials.gov number, NCT01924013 .).

Objective: The purpose of this systematic review was to evaluate the efficacy of pretreatment with letrozole prior to either a first- or second-trimester medical termination of pregnancy., Study Design: We searched letrozole, femara, aromatase inhibitors, abortifacient agents, termination of pregnancy and labor induction in MEDLINE, EMBASE, Cochrane Database, Google Scholar and PubMed from inception of each database until September 2015 with no language limitation. A systematic review of all randomized controlled trials (RCTs) was performed where women received either letrozole and misoprostol or placebo and misoprostol for termination of pregnancy. The primary outcome was complete abortion rate, defined as complete evacuation of the products of conception from the uterus. Relative risk with 95% confidence intervals was used to report data., Results: Our systematic review identified 7 studies; 4 RCTs were included in the review. Two RCTs evaluated terminations of pregnancy up to 9 weeks' gestation, while 2 evaluated terminations over 9 weeks' gestation. For each gestational age group, one trial supported an increase in complete abortion rate, while the other showed no difference, with letrozole and misoprostol compared with placebo and misoprostol. Time-to-abortion interval for terminations up to 9 weeks' gestation was not improved with the addition of letrozole to misoprostol. For terminations over 9 weeks' gestation, one trial supported and one trial refuted a decrease in time-to-abortion interval with letrozole and misoprostol. Similarly, for each gestational age group, one study supported a decrease and one study showed no difference in rate of dilation and curettage (D&C) with letrozole and misoprosol. Medication side effects were similar between both treatment groups. There was significant heterogeneity between the trials, and therefore, the results were not meta-analyzed., Conclusions: Some studies and trials report better outcomes (i.e., complete abortion rates, time-to-abortion and D&C rates) in women exposed to letrozole and misoprostol compared to placebo and misoprostol, while other trials demonstrate no difference. Further research exploring letrozole pretreatment prior to medical abortion is required., Implications: This systematic review demonstrated that a combination of letrozole and misoprostol increased the rate of complete abortion compared to misoprostol alone in some studies but not in others; additional well-designed RCT's are needed., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Pregnancy and early childhood represent critical periods that impact health throughout the life-course. The Ontario Birth Study (OBS) is a pregnancy cohort study designed as a platform for research on pregnancy complications, maternal and infant health, and the developmental origins of health and disease., Methods: Pregnant women <17 weeks gestational age were recruited between 2013 and 2015 from antenatal clinics at Mount Sinai Hospital, Toronto, Canada. Life style and diet questionnaires, biospecimens, and clinical data were collected throughout the pregnancy and postpartum period at the time of clinical care. The OBS was integrated into clinical care to reduce participant burden, improve efficiency, and increase research potential., Results: There were 3181 eligible women approached for recruitment and 1374 (43%) participated in the study. Among the 1374 participants, 1272 (93%) delivered a liveborn infant and were followed to 6-10 weeks postpartum. Of the 1272 women who completed the study, 98% had at least one pregnancy blood sample collected, 97% had vaginal swabs collected, 90% completed the prenatal life style questionnaires, and 78% completed the Diet History Questionnaire. Most women (88%) were ≥30 years of age, 55% had no previous children, 24% were overweight or obese pre-pregnancy and 78% of parents had postsecondary education. Most pregnancies were singleton (3% twins), 34% delivered by caesarean section, and 6% preterm (<37 weeks gestation)., Conclusions: The OBS is a contemporary cohort with detailed data including banked biospecimens for studies of pregnancy health and the gene-environment interactions that establish developmental trajectories to health, learning, and social functioning., (© 2018 John Wiley & Sons Ltd.)

Objective: The aims of this study were to examine the prevalence of Celiac disease (CD) in Canadian women with unexplained infertility versus women with an identifiable cause of infertility and to assess the sensitivity of the point-of-care Biocard Celiac Test Kit versus standard serum serologic testing., Methods: In this prospective cohort study, women aged 18 to 44 who were evaluated for infertility between February 2010 and May 2012 at a tertiary academic care fertility clinic in Toronto, ON, were invited to participate. They were categorized as having unexplained infertility (Cases) or infertility secondary to a known cause (Controls). Women on a gluten-free diet or previously diagnosed with CD were excluded. Outcome measures were the Celiac Questionnaire, serum testing for tissue transglutaminase IgA antibody (anti-tTG IgA), serum IgA levels, and Biocard Celiac Test Kit., Results: Of 685 women approached, 1.2% (4/326) with unexplained infertility and 1.1% (4/359) with an identifiable infertility cause were newly found to have CD. Biocard testing revealed the same results as standard serologic IgA and anti-tTG IgA testing., Conclusion: CD was not more common in women with unexplained infertility than those with an identifiable cause of infertility. These results do not support the routine screening of Canadian women with infertility for CD., (Copyright © 2018. Published by Elsevier Inc.)

Purpose: To compare neonatal outcomes of twins delivered <33 weeks' gestation in tertiary centers in Canada according to the mode of birth and presentation., Materials and Methods: This retrospective cohort from the Canadian Neonatal Network database studied preterm twins born from 24 + 0 to 32 + 6 weeks' gestation between 2005 and 2012. Twins were grouped by the mode of birth: both vaginal, combined vaginal/cesarean section (CS), and both CS. Additionally, twins were grouped by the mode of presentation: both vertex, vertex/breech, breech/vertex, and both breech. The primary outcome was a composite of mortality or severe neonatal morbidity (severe neurological injury [intraventricular hemorrhage grade 3/4 or periventricular leukomalacia], bronchopulmonary dysplasia, retinopathy of prematurity, and necrotizing enterocolitis)., Results: Of the 6636 twins, 1934 (29%) were delivered vaginally, 418 (6%) by combined vaginal birth/CS, and 4284 (65%) were born by CS. The composite did not differ between the groups. However, severe neurological injury was decreased (adjusted odds ratio [AOR], 0.77; 95% confidence interval [CI], 0.61-0.98) and respiratory distress syndrome (AOR, 1.34; 95%CI, 1.15-1.56) was increased when both the twins were delivered by CS., Conclusions: Preterm twin infants born via CS experienced less severe neurological injury when compared to those delivered vaginally, but had an increase in respiratory distress syndrome.