Core Outcome Set for GROwth restriction: deVeloping Endpoints (COSGROVE).

BACKGROUND: Foetal growth restriction (FGR) refers to a foetus that does not reach its genetically predetermined growth potential. It is well recognised that growth-restricted foetuses are at increased risk of stillbirth, foetal compromise, early neonatal death and neonatal morbidity. Later in life, they are prone to health problems, including increased risk of cardiovascular diseases and neurodevelopmental disorders. Interventions for preventing and treating FGR have been studied in many trials, but evidence is often difficult to synthesise and compare because of differences in the selection and definition of outcomes. To enable future trials to measure similar, meaningful outcomes, we are developing two core outcome sets (COS) - one for prevention and the other for treatment of FGR. METHODS: We will review the literature to identify previously reported outcomes. An international panel of relevant stakeholders who have experience of FGR (parent or carer of a baby that was growth restricted, health professional involved in the care of mothers and babies affected by FGR, a person with expertise in FGR research) will rate the importance of each of those outcomes in a series of three sequential online rounds of a Delphi study. Participants will be able to add items to the proposed list in round 1. A final face-to-face consensus meeting will be held with representatives of each stakeholder group at which a final list of outcomes for inclusion in the COS will be agreed. DISCUSSION: The development of COSs in FGR will ensure the collection and reporting of a minimum dataset agreed by stakeholder consensus and will reduce inconsistencies in the reporting of outcomes across relevant trials. Such standardisation in the reporting of outcomes will improve synthesis of evidence and generalisability of knowledge in the future by reducing heterogeneity in outcomes between trials and thus improve the results of systematic reviews and meta-analyses. Ultimately, we hope that the COSs will lead to an improvement in the quality of evidence-based clinical practice, enhance patient care, and improve the quality and consistency of research. TRIAL REGISTRATION: Not applicable. This study is registered in the Core Outcome Measures for Effectiveness (COMET) database

Paternal obesity is associated with IGF2 hypomethylation in newborns: results from a Newborn Epigenetics Study (NEST) cohort

Data from epidemiological and animal model studies suggest that nutrition during pregnancy may affect the health status of subsequent generations. These transgenerational effects are now being explained by disruptions at the level of the epigenetic machinery. Besides in vitro environmental exposures, the possible impact on the reprogramming of methylation profiles at imprinted genes at a much earlier time point, such as during spermatogenesis or oogenesis, has not previously been considered. In this study, our aim was to determine associations between preconceptional obesity and DNA methylation profiles in the offspring, particularly at the differentially methylated regions (DMRs) of the imprinted Insulin-like Growth Factor 2 (IGF2) gene

Elevated maternal lipids in early pregnancy are not associated with risk of intrapartum caesarean in overweight and obese nulliparous women

Background: Maternal overweight and obesity are associated with slower labour progress and increased caesarean delivery for failure to progress. Obesity is also associated with hyperlipidaemia and cholesterol inhibits myometrial contractility in vitro. Our aim was, among overweight and obese nulliparous women, to investigate 1. the role of early pregnancy serum cholesterol and 2. clinical risk factors associated with first stage caesarean for failure to progress at term. Methods: Secondary data analysis from a prospective cohort of overweight/obese New Zealand and Australian nullipara recruited to the SCOPE study. Women who laboured at term and delivered vaginally (n=840) or required first stage caesarean for failure to progress (n=196) were included. Maternal characteristics and serum cholesterol at 14–16 weeks’ of gestation were compared according to delivery mode in univariable and multivariable analyses (adjusted for BMI, maternal age and height, obstetric care type, induction of labour and gestation at delivery ≥41 weeks). Results: Total cholesterol at 14–16 weeks was not higher among women requiring first stage caesarean for failure to progress compared to those with vaginal delivery (5.55 ± 0.92 versus 5.67 ± 0.85 mmol/L, p= 0.10 respectively). Antenatal risk factors for first stage caesarean for failure to progress in overweight and obese women were BMI (adjusted odds ratio [aOR (95% CI)] 1.15 (1.07-1.22) per 5 unit increase, maternal age 1.37 (1.17-1.61) per 5 year increase, height 1.09 (1.06-1.12) per 1cm reduction), induction of labour 1.94 (1.38-2.73) and prolonged pregnancy ≥41 weeks 1.64 (1.14-2.35). Conclusions: Elevated maternal cholesterol in early pregnancy is not a risk factor for first stage caesarean for failure to progress in overweight/obese women. Other clinically relevant risk factors identified are: increasing maternal BMI, increasing maternal age, induction of labour and prolonged pregnancy ≥41 weeks’ of gestation.Elaine M Fyfe, Karen S Rivers, John MD Thompson, Kamala PL Thiyagarajan, Katie M Groom, Gustaaf A Dekker, Lesley ME McCowan and On behalf of the SCOPE consortiu

Maternal marijuana use has independent effects on risk for spontaneous preterm birth but not other common late pregnancy complications

Widespread legalisation of marijuana raises safety concerns for its use in pregnancy. This study investigated the association of marijuana use prior to and during pregnancy with pregnancy outcomes in a prospective cohort of 5588 nulliparous women from the international SCOPE study. Women were assessed at 15 ± 1 and 20 ± 1 weeks’ gestation. Cases [278 Preeclampsia, 470 gestational hypertension, 633 small-for-gestational-age, 236 spontaneous preterm births (SPTB), 143 gestational diabetes] were compared separately with 4114 non-cases. Although the numbers are small, continued maternal marijuana use at 20 weeks’ gestation was associated with SPTB independent of cigarette smoking status [adj OR 2.28 (95% CI:1.45–3.59)] and socioeconomic index (SEI) [adj OR 2.17 (95% CI:1.41–3.34)]. When adjusted for maternal age, cigarette smoking, alcohol and SEI, continued maternal marijuana use at 20 weeks’ gestation had a greater effect size [adj OR 5.44 (95% CI 2.44–12.11)]. Our data indicate that increasing use of marijuana among young women of reproductive age is a major public health concern

Metabolic syndrome in pregnancy and risk for adverse pregnancy outcomes: A prospective cohort of nulliparous women

Background: Obesity increases the risk for developing gestational diabetes mellitus (GDM) and preeclampsia (PE), which both associate with increased risk for type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD) in women in later life. In the general population, metabolic syndrome (MetS) associates with T2DM and CVD. The impact of maternal MetS on pregnancy outcomes, in nulliparous pregnant women, has not been investigated. Methods and findings: Low-risk, nulliparous women were recruited to the multi-centre, international prospective Screening for Pregnancy Endpoints (SCOPE) cohort between 11 November 2004 and 28 February 2011. Women were assessed for a range of demographic, lifestyle, and metabolic health variables at 15 ± 1 weeks’ gestation. MetS was defined according to International Diabetes Federation (IDF) criteria for adults: waist circumference ≥80 cm, along with any 2 of the following: raised trigycerides (≥1.70 mmol/l [≥150 mg/dl]), reduced high-density lipoprotein cholesterol (<1.29 mmol/l [<50 mg/dl]), raised blood pressure (BP) (i.e., systolic BP ≥130 mm Hg or diastolic BP ≥85 mm Hg), or raised plasma glucose (≥5.6 mmol/l). Log-binomial regression analyses were used to examine the risk for each pregnancy outcome (GDM, PE, large for gestational age [LGA], small for gestational age [SGA], and spontaneous preterm birth [sPTB]) with each of the 5 individual components for MetS and as a composite measure (i.e., MetS, as defined by the IDF). The relative risks, adjusted for maternal BMI, age, study centre, ethnicity, socioeconomic index, physical activity, smoking status, depression status, and fetal sex, are reported. A total of 5,530 women were included, and 12.3% (n = 684) had MetS. Women with MetS were at an increased risk for PE by a factor of 1.63 (95% CI 1.23 to 2.15) and for GDM by 3.71 (95% CI 2.42 to 5.67). In absolute terms, for PE, women with MetS had an adjusted excess risk of 2.52% (95% CI 1.51% to 4.11%) and, for GDM, had an adjusted excess risk of 8.66% (95% CI 5.38% to 13.94%). Diagnosis of MetS was not associated with increased risk for LGA, SGA, or sPTB. Increasing BMI in combination with MetS increased the estimated probability for GDM and decreased the probability of an uncomplicated pregnancy. Limitations of this study are that there are several different definitions for MetS in the adult population, and as there are none for pregnancy, we cannot be sure that the IDF criteria are the most appropriate definition for pregnancy. Furthermore, MetS was assessed in the first trimester and may not reflect pre-pregnancy metabolic health status. Conclusions: We did not compare the impact of individual metabolic components with that of MetS as a composite, and therefore cannot conclude that MetS is better at identifying women at risk. However, more than half of the women who had MetS in early pregnancy developed a pregnancy complication compared with just over a third of women who did not have MetS. Furthermore, while increasing BMI increases the probability of GDM, the addition of MetS exacerbates this probability. Further studies are required to determine if individual MetS components act synergistically or independently

Adherence to adjuvant endocrine therapy among breast cancer survivors: a systematic review and meta-synthesis of the qualitative literature using grounded theory

Purpose: Numerous studies have examined non-adherence to adjuvant endocrine therapy in women recovering from breast cancer, but none provide a comprehensive theory to explain the challenges of long-term medication-taking and resilience needed to continue. The aim of this study was to source, appraise, and synthesise data from existing qualitative studies to develop an in-depth explanatory model of non-adherence and discontinuation of hormonal medication among breast cancer survivors. Methods: A comprehensive search of databases and the literature identified 24 eligible qualitative studies published 2010-2019. Quotations (n= 801) listed within these papers and the original author interpretations were synthesised using NVivo, and grounded theory methodology. Results: At the beginning, knowledge about adjuvant endocrine therapy, trust in doctors, and worries and expectations, mean agreeing to medication is the only viable option, akin to a Hobson’s choice. Thereafter, women’s ability to deal with medication side-effects, knowledge, and support received affect their decision to continue, akin to a horned dilemma where giving up the medication risks cancer recurrence, and continuing means reduced contentment. Women stopping medication altogether question treatment necessity, search for normalcy, and prioritise quality of life. Conclusion: Shared experiences and understandings were uncovered by examining commonalities in existing publications. The core category explained the difficulties women face with the initial decision to accept long-term endocrine therapy and then the everyday challenges of continuing or deciding to stop treatment early. An educational tool to inform survivors and health professionals about these challenges could potentially improve women’s experience on treatment and in turn their adherence

Use of antihypertensive medications in pregnancy and the risk of adverse perinatal outcomes: McMaster Outcome Study of Hypertension In Pregnancy 2 (MOS HIP 2)

BACKGROUND: Uncertainty remains about the potential harmful effects of antihypertensive therapy on the developing fetus, especially for beta-blockers (βb). METHODS: We prospectively enrolled all singleton women with a blood pressure ≥ 140/90 mm Hg during pregnancy. The main analysis included 1948 women with all forms of hypertension and compared the use of βb drugs, non-βb drugs or a combination of both, to no treatment. The primary study outcome was a composite of the diseases of prematurity, need for assisted ventilation for greater than 1 day, or perinatal death. A sub-group analysis evaluated the four treatment options among 583 singleton women with chronic hypertension before 20 weeks gestation. RESULTS: In the main analysis, no association was observed between βb use and the primary composite outcome [adjusted odds ratio (OR) 1.4, 95% CI 0.9–2.2], while an association was seen with non-βb therapy (OR 5.0, 95% CI 2.6–9.6) and combination therapy (OR 2.9, 95% CI 1.8–4.7). In the sub-group of 583 women with hypertension before 20 weeks, use of a non-βb drug (OR 4.9, 95% CI 1.7–14.2) or combination therapy (OR 2.9. 95% CI 1.1–7.7) was significantly associated with the primary composite outcome, while βb monotherapy was not (OR 1.4, 95% CI 0.6–3.4). CONCLUSIONS: Maternal use of antihypertensive medications other than βbs was associated with both major perinatal morbidity and mortality, while βb monotherapy was not. The combined use of βb and non-βb medications demonstrated the strongest association. Before definitive conclusions can be drawn, a large multicentre randomized controlled trial is needed to address the issues of both maternal efficacy and fetal safety with the use of one or more antihypertensive agents in pregnancy

The effect of hypertensive disorders in pregnancy on small for gestational age and stillbirth: a population based study

BACKGROUND: Hypertensive disorders in pregnancy are leading causes of maternal, fetal and neonatal morbidity and mortality worldwide. However, studies attempting to quantify the effect of hypertension on adverse perinatal outcomes have been mostly conducted in tertiary centres. This population-based study explored the frequency of hypertensive disorders in pregnancy and the associated increase in small for gestational age (SGA) and stillbirth. METHODS: We used information on all pregnant women and births, in the Canadian province of Nova Scotia, between 1988 and 2000. Pregnancies were excluded if delivery occurred < 20 weeks, if birthweight was < 500 grams, if there was a high-order multiple pregnancy (greater than twin gestation), or a major fetal anomaly. RESULTS: The study population included 135,466 pregnancies. Of these, 7.7% had mild pregnancy-induced hypertension (PIH), 1.3% had severe PIH, 0.2% had HELLP (hemolysis, elevated liver enzymes, low platelets), 0.02% had eclampsia, 0.6% had chronic hypertension, and 0.4% had chronic hypertension with superimposed PIH. Women with any hypertension in pregnancy were 1.6 (95% CI 1.5–1.6) times more likely to have a live birth with SGA and 1.4 (95% CI 1.1–1.8) times more likely to have a stillbirth as compared with normotensive women. Adjusted analyses showed that women with gestational hypertension without proteinuria (mild PIH) and with proteinuria (severe PIH, HELLP, or eclampsia) were more likely to have infants with SGA (RR 1.5, 95% CI 1.4–1.6 and RR 3.2, 95% CI 2.8–3.6, respectively). Women with pre-existing hypertension were also more likely to give birth to an infant with SGA (RR 2.5, 95% CI 2.2–3.0) or to have a stillbirth (RR 3.2, 95% CI 1.9–5.4). CONCLUSIONS: This large, population-based study confirms and quantifies the magnitude of the excess risk of small for gestational age and stillbirth among births to women with hypertensive disease in pregnancy

Detecting Instability in Animal Social Networks: Genetic Fragmentation Is Associated with Social Instability in Rhesus Macaques

The persistence of biological systems requires evolved mechanisms which promote stability. Cohesive primate social groups are one example of stable biological systems, which persist in spite of regular conflict. We suggest that genetic relatedness and its associated kinship structure are a potential source of stability in primate social groups as kinship structure is an important organizing principle in many animal societies. We investigated the effect of average genetic relatedness per matrilineal family on the stability of matrilineal grooming and agonistic interactions in 48 matrilines from seven captive groups of rhesus macaques. Matrilines with low average genetic relatedness show increased family-level instability such as: more sub-grouping in their matrilineal groom network, more frequent fighting with kin, and higher rates of wounding. Family-level instability in multiple matrilines within a group is further associated with group-level instability such as increased wounding. Stability appears to arise from the presence of clear matrilineal structure in the rhesus macaque group hierarchy, which is derived from cohesion among kin in their affiliative and agonistic interactions with each other. We conclude that genetic relatedness and kinship structure are an important source of group stability in animal societies, particularly when dominance and/or affilative interactions are typically governed by kinship