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BACKGROUND Polycystic ovary syndrome (PCOS) is associated with cardiometabolic disease, but recent systematic reviews and meta-analyses of longitudinal studies that quantify these associations are lacking. OBJECTIVE AND RATIONALE Is PCOS a risk factor for cardiometabolic disease? SEARCH METHODS We searched from inception to September 2019 in MEDLINE and EMBASE using controlled terms (e.g. MESH) and text words for PCOS and cardiometabolic outcomes, including cardiovascular disease (CVD), stroke, myocardial infarction, hypertension (HT), type 2 diabetes (T2D), metabolic syndrome and dyslipidaemia. Cohort studies and case–control studies comparing the prevalence of T2D, HT, fatal or non-fatal CVD and/or lipid concentrations of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and triglycerides (TGs) between women with and without PCOS of ≥18 years of age were eligible for this systematic review and meta-analysis. Studies were eligible regardless of the degree to which they adjusted for confounders including obesity. Articles had to be written in English, German or Dutch. Intervention studies, animal studies, conference abstracts, studies with a follow-up duration less than 3 years and studies with less than 10 PCOS cases were excluded. Study selection, quality assessment (Newcastle–Ottawa Scale) and data extraction were performed by two independent researchers. OUTCOMES Of the 5971 identified records, 23 cohort studies were included in the current systematic review. Women with PCOS had increased risks of HT (risk ratio (RR): 1.75, 95% CI 1.42 to 2.15), T2D (RR: 3.00, 95% CI 2.56 to 3.51), a higher serum concentration of TC (mean difference (MD): 7.14 95% CI 1.58 to 12.70 mg/dl), a lower serum concentration of HDL-C (MD: −2.45 95% CI −4.51 to −0.38 mg/dl) and increased risks of non-fatal cerebrovascular disease events (RR: 1.41, 95% CI 1.02 to 1.94) compared to women without PCOS. No differences were found for LDL-C (MD: 3.32 95% CI −4.11 to 10.75 mg/dl), TG (MD 18.53 95% CI −0.58 to 37.64 mg/dl) or coronary disease events (RR: 1.78, 95% CI 0.99 to 3.23). No meta-analyses could be performed for fatal CVD events due to the paucity of mortality data. WIDER IMPLICATIONS Women with PCOS are at increased risk of cardiometabolic disease. This review quantifies this risk, which is important for clinicians to inform patients and to take into account in the cardiovascular risk assessment of women with PCOS. Future clinical trials are needed to assess the ability of cardiometabolic screening and management in women with PCOS to reduce future CVD morbidity.

Background and Objectives: Therapeutic interventions targeting molecular factors involved in the transition from uterine quiescence to overt labour are not substantially reducing the rate of spontaneous preterm labour. The identification of novel rational therapeutic targets are essential to prevent the most common cause of neonatal mortality. Based on our previous work showing that Tbx2 (T-Box transcription factor 2) is a putative upstream regulator preceding progesterone withdrawal in mouse myometrium, we now investigate the role of TBX2 in human myometrium. Materials and Methods: RNA microarray analysis of (A) preterm human myometrium samples and (B) myometrial cells overexpressing TBX2 in vitro, combined with subsequent analysis of the two publicly available datasets of (C) Chan et al. and (D) Sharp et al. The effect of TBX2 overexpression on cytokines/chemokines secreted to the myometrium cell culture medium were determined by Luminex assay. Results: Analysis shows that overexpression of TBX2 in myometrial cells results in downregulation of TNFα- and interferon signalling. This downregulation is consistent with the decreased expression of cytokines and chemokines of which a subset has been previously associated with the inflammatory pathways relevant for human labour. In contrast, CXCL5 (C-X-C motif chemokine ligand 5), CCL21 and IL-6 (Interleukin 6), previously reported in relation to parturition, do not seem to be under TBX2 control. The combined bioinformatical analysis of the four mRNA datasets identifies a subset of upstream regulators common to both preterm and term labour under control of TBX2. Surprisingly, TBX2 mRNA levels are increased in preterm contractile myometrium. Conclusions: We identified a subset of upstream regulators common to both preterm and term labour that are activated in labour and repressed by TBX2. The increased TBX2 mRNA expression in myometrium collected during a preterm caesarean section while in spontaneous preterm labour compared to tissue harvested during iatrogenic preterm delivery does not fit the bioinformatical model. We can only explain this by speculating that the in vivo activity of TBX2 in human myometrium depends not only on the TBX2 expression levels but also on levels of the accessory proteins necessary for TBX2 activity.

Objective: To determine whether women delivering preterm have unfavorable cardiovascular profiles as compared with women who deliver at term. Methods: A prospective observational cohort study enrolled 165 women with spontaneous preterm delivery (sPTD) at 24 +0 and 36 +6 gestational weeks in three perinatal care centers in The Netherlands between August 2012 and August 2014. Total cholesterol, triglycerides, high-density lipoprotein (HDL)-cholesterol, low-density lipoprotein (LDL)-cholesterol, apolipoprotein, glucose, and homocysteine were measured within 24 hours after delivery. Lipids and cardiovascular biochemical risk factors were compared between women with sPTD and an external comparison group of 30 women with term delivery via analysis of covariance. Results: Mean gestational age at delivery was 30.7 ± 3.6 weeks in the sPTD group and 40.3 ± 1.3 weeks in the reference group. Data were adjusted for body mass index, age, and center. As compared with the reference group, total cholesterol and LDL-cholesterol levels were lower and glucose levels were higher among women with sPTD. Conclusion: An association between sPTD and unfavorable lipids and cardiovascular biochemical risk factors was not established. The higher levels of glucose in the sPTD group might be due to increased insulin resistance, which is associated with a higher risk of sPTD.

BACKGROUND: It is unknown whether an unfavorable (atherogenic) lipid profile and homocysteine level, which could supersede clinical cardiovascular disease, is also associated with an increased risk of spontaneous preterm delivery (sPTD). A systematic review of studies assessing the lipid profile and homocysteine value of women with sPTD compared to women with term delivery in pre-pregnancy and during pregnancy. METHODS: A systematic search of peer-reviewed articles published between January 1980 and May 2014 was performed using MEDLINE, EMBASE and the Cochrane database. We included case-control and cohort studies that examined triglycerides, high/low density lipoprotein cholesterol, total cholesterol and homocysteine in women with sPTD. Articles were subdivided in pre-pregnancy, first, second and third trimester. Of 708 articles reviewed for eligibility, 14 met our inclusion criteria. RESULTS AND CONCLUSION: Nine cohort studies and five case-control studies were analyzed, reporting on 1466 cases with sPTD and 11296 controls with term delivery. The studies suggest a possible elevated risk of sPTD in woman with high TG levels, no association of high and low density lipoprotein cholesterol with the risk of sPTD was found. High homocysteine levels are associated with sPTD in the second trimester. The role of triglycerides and homocysteine in sPTD should be explored further.

The purpose of this review was to assess the relationship between premature ovarian insufficiency (POI), defined as natural menopause40 years, and risk of ischaemic heart disease (IHD), stroke and overall cardiovascular disease (CVD).We performed a systematic search in PubMed (1966-2012), EMBASE (1980-2012). Studies were included if they were prospective, follow-up3 years, assessment of age menopause40 years, and incident cases of fatal or nonfatal IHD, stroke, or overall CVD. Relative risks (RRs) and 95% confidence interval (CI) were pooled using a random-effect model. Overall, 10 observational studies were identified, comprising 190,588 women (follow-up 4-37 years) with 9440 events (2026 events for IHD (seven studies) and 6438 events for stroke (seven studies) and 976 for total CVD (two studies). POI was assessed by questionnaire and incident cases through certification and event registers. POI was related to an increased risk of developing or dying from IHD (hazard ratio (HR) 1.69, 95% CI 1.29-2.21, p = 0.0001) and total CVD (HR 1.61, 95% CI 1.22-2.12, p = 0.0007). No relation was found for stroke (HR 1.03, 0.88-1.19, p = 0.74). We found no evidence for heterogeneity.POI is an independent though modest risk factor of IHD and overall CVD but not of stroke. Because of the limited impact of POI on CVD risk compared to classical cardiovascular risk factors, it is unlikely that POI will be implemented as modifier of cardiovascular risk classification.

Item does not contain fulltext BACKGROUND: In women with threatened preterm birth, delay of delivery by 48 h allows antenatal corticosteroids to improve neonatal outcomes. For this reason, tocolytics are often administered for 48 h; however, there is no consensus about which drug results in the best maternal and neonatal outcomes. In the APOSTEL III trial we aimed to compare the effectiveness and safety of the calcium-channel blocker nifedipine and the oxytocin inhibitor atosiban in women with threatened preterm birth. METHODS: We did this multicentre, randomised controlled trial in ten tertiary and nine teaching hospitals in the Netherlands and Belgium. Women with threatened preterm birth (gestational age 25-34 weeks) were randomly assigned (1:1) to either oral nifedipine or intravenous atosiban for 48 h. An independent data manager used a web-based computerised programme to randomly assign women in permuted block sizes of four, with groups stratified by centre. Clinicians, outcome assessors, and women were not masked to treatment group. The primary outcome was a composite of adverse perinatal outcomes, which included perinatal mortality, bronchopulmonary dysplasia, sepsis, intraventricular haemorrhage, periventricular leukomalacia, and necrotising enterocolitis. Analysis was done in all women and babies with follow-up data. The study is registered at the Dutch Clinical Trial Registry, number NTR2947. FINDINGS: Between July 6, 2011, and July 7, 2014, we randomly assigned 254 women to nifedipine and 256 to atosiban. Primary outcome data were available for 248 women and 297 babies in the nifedipine group and 255 women and 294 babies in the atosiban group. The primary outcome occurred in 42 babies (14%) in the nifedipine group and in 45 (15%) in the atosiban group (relative risk [RR] 0.91, 95% CI 0.61-1.37). 16 (5%) babies died in the nifedipine group and seven (2%) died in the atosiban group (RR 2.20, 95% CI 0.91-5.33); all deaths were deemed unlikely to be related to the study drug. Maternal adverse events did not differ between groups. INTERPRETATION: In women with threatened preterm birth, 48 h of tocolysis with nifedipine or atosiban results in similar perinatal outcomes. Future clinical research should focus on large placebo-controlled trials, powered for perinatal outcomes. FUNDING: ZonMw (the Netherlands Organisation for Health Research and Development).

Background Increasing evidence suggests a relation between having had spontaneous preterm delivery and cardiovascular disease in the future. We performed a systematic review and meta-analysis to assess the relation between a history of spontaneous preterm delivery and risk of ischaemic heart disease (IHD), stroke or overall cardiovascular disease (CVD). Methods We carried out a systematic search in Medline (from 1966 to 17 July 2014) and Embase (from 1980 to 17 July 2014). We included studies with a cohort design assessing the relation between spontaneous preterm delivery and fatal or nonfatal IHD, stroke, or overall CVD. IHD, stroke and CVD were assessed through linkage with national registries. Hazard ratios (HRs) were pooled using a random-effects model. Results Of the 10 cohort studies included; sample sizes ranged from 3706 to 923,686 women and follow-up ranged from 12-35 years. Spontaneous preterm delivery was related to an increased risk of developing or dying from IHD (HR 1.38, 95% confidence interval (CI) 1.22-1.57), stroke (HR 1.71, 95% CI 1.53-1.91) and overall CVD (relative risk (HR) 2.01, 95% CI 1.52-2.65). All studies found a positive effect, although substantial between-study heterogeneity was found for IHD and CVD. Conclusion Spontaneous preterm delivery is an independent risk factor for the development of IHD, stroke and overall CVD.

Labetalol is often used in severe preeclampsia (PE). Hypotension, bradycardia and hypoglycemia are feared neonatal side effects, but may also occur in (preterm) infants regardless of labetalol exposure. We analyzed the possible association between intrauterine labetalol exposure and such side effects.From 1 January 2003 through 31 March 2008, all infants from mothers suffering severe PE admitted to one tertiary care center were included. Severe PE was defined according to the International Society for the Study of Hypertension in Pregnancy (ISSHP) criteria. Infants exposed to labetalol in utero (labetalol infants) were compared with infants, who were not exposed to labetalol (controls). Neonatal records were reviewed for hypotension (RRmean gestational age in weeks), bradycardia (heartrate100/min) and hypoglycaemia (glucose2.7 mmol/L) in the first 48 postnatal hours.Of 109 infants, 55 had been exposed to labetalol, whereas 54 were not (controls). Gestational age at delivery and birthweight were similar in both groups (31.8 vs. 32.8 weeks (p=0.06) and 1510 vs. 1639 grams (p=0.25), respectively for the labetalol vs. control group). Hypotension occurred significantly more in conjunction with labetalol exposure (16, (29.1%) vs. 4 (7.4%); p=0.003), irrespective of the route of administration. Patent ductus arteriosus (PDA) was present in 9 (56%) of hypotensive labetalol infants compared to 1 (24%) infant in the hypotensive control group (NS). In a multivariate regression model, labetalol exposure, the need for intubation and PDA appeared independently associated with hypotension (P0.001). Hypoglycemia occurred in 26 (47.3%) of labetalol infants and in 23 (42.6%) of control infants (p=0.62). Bradycardia occurred in 4 (7.3%) of labetalol infants and in 1 (1.9%) of control infants (p=0.18). Hypoglycemia was more common in premature infants (n=45 (48,9%) vs. n=4 (23.5%), p=0.05) in both labetalol and control infants.Hypotension is more common after maternal labetalol exposure, regardless of the dosage and route of administration. The need for intubation and the presence of a PDA also play a role. Hypoglycemia is a very common finding in this population and is merely related to prematurity and independent of labetalol exposure as was the incidental occurrence of bradycardia. These findings on the neonatal side effects of maternal labetalol treatment in preeclampsia underline the importance of frequent blood glucose and blood pressure measurements in the first days of life, especially in intubated preterm infants with a PDA.

BackgroundPreterm birth is the leading cause of neonatal mortality and morbidity in developed countries. Whether continued tocolysis after 48hours of rescue tocolysis improves neonatal outcome is unproven. ObjectivesTo evaluate the effectiveness of maintenance tocolytic therapy with oral nifedipine on the reduction of adverse neonatal outcomes and the prolongation of pregnancy by performing an individual patient data meta-analysis (IPDMA). Search strategyWe searched PubMed, Embase, and Cochrane databases for randomised controlled trials of maintenance tocolysis therapy with nifedipine in preterm labour. Selection criteriaWe selected trials including pregnant women between 24 and 36(6/7)weeks of gestation (gestational age, GA) with imminent preterm labour who had not delivered after 48hours of initial tocolysis, and compared maintenance nifedipine tocolysis with placebo/no treatment. Data collection and analysisThe primary outcome was perinatal mortality. Secondary outcome measures were intraventricular haemorrhage (IVH), necrotising enterocolitis (NEC), infant respiratory distress syndrome (IRDS), prolongation of pregnancy, GA at delivery, birthweight, neonatal intensive care unit admission, and number of days on ventilation support. Pre-specified subgroup analyses were performed. Main resultsSix randomised controlled trials were included in this IPDMA, encompassing data from 787 patients (n=390 for nifedipine; n=397 for placebo/no treatment). There was no difference between the groups for the incidence of perinatal death (risk ratio, RR1.36; 95% confidence interval, 95%CI 0.35-5.33), intraventricular haemorrhage (IVH)gradeII (RR0.65; 95%CI 0.16-2.67), necrotising enterocolitis (NEC) (RR1.15; 95%CI 0.50-2.65), infant respiratory distress syndrome (IRDS) (RR0.98; 95%CI 0.51-1.85), and prolongation of pregnancy (hazard ratio, HR0.74; 95%CI 0.55-1.01). ConclusionMaintenance tocolysis is not associated with improved perinatal outcome and is therefore not recommended for routine practice. Tweetable abstractNifedipine maintenance tocolysis is not associated with improved perinatal outcome or pregnancy prolongation. Tweetable abstract Nifedipine maintenance tocolysis is not associated with improved perinatal outcome or pregnancy prolongation

Item does not contain fulltext BACKGROUND: In the past decades evidence has accumulated that women with reproductive and pregnancy-related disorders are at increased risk of developing cardiovascular disease (CVD) in the future. Up to now there is no standardised follow-up of these women becausee guidelines on cardiovascular risk management for this group are lacking. However, early identification of high-risk populations followed by prevention and treatment of CVD risk factors has the potential to reduce CVD incidence. Therefore, the Dutch Society of Obstetrics and Gynaecology initiated a multidisciplinary working group to develop a guideline for cardiovascular risk management after reproductive and pregnancy-related disorders. METHODS: The guideline addresses the cardiovascular risk consequences of gestational hypertension, preeclampsia, preterm delivery, small-for-gestational-age infant, recurrent miscarriage, polycystic ovary syndrome and premature ovarian insufficiency. The best available evidence on these topics was captured by systematic review. Recommendations for clinical practice were formulated based on the evidence and consensus of expert opinion. The Dutch societies of gynaecologists, cardiologists, vascular internists, radiologists and general practitioners reviewed the guideline to ensure support for implementation in clinical practice. RESULTS: For all reproductive and pregnancy-related disorders a moderate increased relative risk was found for overall CVD, except for preeclampsia (relative risk 2.15, 95% confidence interval 1.76-2.61). CONCLUSION: Based on the current available evidence, follow-up is only recommended for women with a history of preeclampsia. For all reproductive and pregnancy-related disorders optimisation of modifiable cardiovascular risk factors is recommended to reduce the risk of future CVD.

BACKGROUND: Women with a complication of pregnancy are at increased risk of cardiovascular morbidity and mortality later in life. Yet, information on risk of recurrent events in women with a previous cardiovascular event is lacking. We aimed to assess the relationship between early preterm delivery, (recurrent) miscarriage and the risk for recurrent cardiovascular events in women with manifest vascular disease. METHODS: We included 1014 women with a mean age of 60 years from the SMART study, a prospective ongoing cohort study among subjects with clinically manifest vascular disease. The included women had a history of ≥1 pregnancy and were followed for the occurrence of subsequent vascular events. The relationship between the pregnancy complications ((miscarriage (gestational age

Objective To evaluate the management of imminent preterm delivery with respect to prescription of antenatal corticosteroids (ACS) and referral to a tertiary center. Study Design A retrospective cohort study existing of 1 perinatal center and 9 referring hospitals. All women who received their first dose of ACS in 1 of the 10 hospitals between 24+0 and 32+0 weeks of gestation and/or delivered before 32 weeks of gestation from 2005 until 2010. Patients were identified using the electronic database of hospital pharmacies. Main outcome measures were time interval from administration to delivery for different indications and number of women who were not referred in time to a tertiary center. Results In total, 1375 women received ACS. Main indications were suspected preterm labor (44.7%), preterm prelabor rupture of membranes (15.9%), maternal indication (12.8%), fetal indication (9.2%) and vaginal blood loss (8.4%). Overall, 467 (34.0%) women delivered ≤7 days after ACS administration; 8.7% of women with vaginal blood loss and 54.5% of women with maternal indication. Among the 931 women who received ACS in the secondary hospitals, 452 (48.5%) women were referred to a tertiary hospital and 89 (6.5%) women delivered in a secondary hospital with a gestational age of less than 32 weeks. Conclusion One-third of all women receiving ACS delivered within 7 days and half of the women who received ACS in a secondary hospital were referred to a tertiary center. There seems to be room for improvement regarding the timing of ACS administration and subsequently referral to a tertiary center.

Contains fulltext : 136389.pdf (Publisher’s version ) (Open Access) BACKGROUND: Preterm birth is the most common cause of neonatal morbidity and mortality. Postponing delivery for 48 hours with tocolytics to allow for maternal steroid administration and antenatal transportation to a centre with neonatal intensive care unit facilities is the standard treatment for women with threatening preterm delivery in most centres. However, there is controversy as to which tocolytic agent is the drug of first choice. Previous trials have focused on tocolytic efficacy and side effects, and are probably underpowered to detect clinically meaningfull differences in neonatal outcome. Thus, the current evidence is inconclusive to support a balanced recommendation for clinical practice. This multicenter randomised clinical trial aims to compare nifedipine and atosiban in terms of neonatal outcome, duration of pregnancy and maternal side effects. METHODS/DESIGN: The Apostel III trial is a nationwide multicenter randomised controlled study. Women with threatened preterm labour (gestational age 25 - 34 weeks) defined as at least 3 contractions per 30 minutes, and 1) a cervical length of

Cardiovascular diseases (CVD) are the primary cause of death in women. Guidelines for identifying high-risk individuals have been developed, e.g. the Dutch Guideline on Cardiovascular Risk Management. In the most recent version of this guideline, diabetes mellitus (DM) and rheumatoid arthritis (RA) are cited as cardiovascular risk factors; therefore, individuals with these conditions are identified as being at high risk. As with DM and RA, there is strong evidence that the experience of having a hypertensive disorder during pregnancy is a cardiovascular risk factor. This is particularly the case for early preeclampsia, which constitutes a 7-fold increased risk of ischemic heart disease. However, in the Netherlands, there are no guidelines and there is no consensus on how to screen or treat these women. Trial evidence is therefore urgently needed to substantiate the value of cardiovascular risk management for those women with a history of hypertension during pregnancy.

To evaluate the prescribing patterns of the first antenatal corticosteroids (ACS) course in our tertiary referral centre from 2005 until 2010.We conducted a retrospective cohort study including all women who received ACS between 24(+0) and 34(+0) weeks of gestation. Main outcome measure was the number of women who delivered within 7 d after ACS administration. The time interval from administration to delivery was compared between women with different indications. Furthermore, all women delivering between 24(+0) and 34(+0) weeks of gestation who did not receive ACS were identified.1008 women received ACS, 15 (1.5%) women were lost to follow up. Main indications were suspected preterm labour, preterm prelabour rupture of membranes, maternal indication, foetal indication and vaginal blood loss (VBL). Overall, 447 (45.4%) women delivered ≤7 d after ACS administration. This percentage was 13.6% in women with VBL and 61.5% in women with maternal indication. During the study period, 1267 women delivered before 34 weeks of gestation, 126 (9.9%) women did not receive ACS.The time interval from ACS administration to delivery differs per indication. Women with VBL are most often over treated. The timing of the first ACS course should be improved.