TBX2, a Novel Regulator of Labour.

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.

Nifedipine versus atosiban for threatened preterm birth (APOSTEL III): a multicentre, randomised controlled trial.

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).

Maternal lipid profile and the relation with spontaneous preterm delivery: a systematic review.

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.

Evaluation of strategies regarding management of imminent preterm delivery before 32 weeks of gestation: a regional cohort study among 1375 women in the Netherlands.

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.

Nifedipine versus atosiban in the treatment of threatened preterm labour (Assessment of Perinatal Outcome after Specific Tocolysis in Early Labour: APOSTEL III-Trial).

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 ≤ 10 mm or 2) a cervical length of 11-30 mm and a positive Fibronectin test or 3) ruptured membranes will be randomly allocated to treatment with nifedipine or atosiban. Primary outcome is a composite measure of severe neonatal morbidity and mortality. Secondary outcomes will be time to delivery, gestational age at delivery, days on ventilation support, neonatal intensive care (NICU) admittance, length admission in neonatal intensive care, total days in hospital until 3 months corrected age, convulsions, apnoea, asphyxia, proven meningitis, pneumothorax, maternal side effects and costs. Furthermore, an economic evaluation of the treatment will be performed. Analysis will be by intention to treat principle. The power calculation is based on an expected 10% difference in the prevalence of adverse neonatal outcome. This implies that 500 women have to be randomised (two sided test, ß 0.2 at alpha 0.05). DISCUSSION: This trial will provide evidence on the optimal drug of choice in acute tocolysis in threatening preterm labour. CLINICAL TRIAL REGISTRATION: NTR2947, date of registration: June 20th 2011.

Reproductive Outcomes of Women with Turner Syndrome Undergoing Oocyte Vitrification: A Retrospective Multicenter Cohort Study.

BACKGROUND: Turner syndrome (TS) is accompanied with premature ovarian insufficiency. Oocyte vitrification is an established method to preserve fertility. However, data on the oocyte yield in women with TS who vitrify their oocytes and the return rate to utilize the oocytes are scarce. METHODS: Retrospective multicenter cohort study. Data was collected from medical records of women with TS who started oocyte vitrification between 2010 and 2021. RESULTS: Thirty-three women were included. The median cumulative number of vitrified oocytes was 20 per woman. Complications occurred in 4% of the cycles. Significant correlations were found between the cumulative number of vitrified oocytes and AMH (r = 0.54 and p < 0.01), AFC (r = 0.49 and p < 0.01), percentage of 46,XX cells (r = 0.49 and p < 0.01), and FSH (r = -0.65 and p < 0.01). Spontaneous (n = 8) and IVF (n = 2) pregnancies occurred in 10 women ± three years after vitrification. So far, none of the women have returned to utilize their vitrified oocytes. CONCLUSIONS: Oocyte vitrification is a feasible fertility preservation option for women with TS, particularly in those with 46,XX cell lines or sufficient ovarian reserve. Multiple stimulation cycles are recommended to reach an adequate number of vitrified oocytes for pregnancy. It is too early to draw conclusions about the utilization of vitrified oocytes in women with TS.

Cardiovascular biochemical risk factors among women with spontaneous preterm delivery.

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.

Cardiovascular disease risk in women with premature ovarian insufficiency: A systematic review and meta-analysis.

AIMS: The purpose of this review was to assess the relationship between premature ovarian insufficiency (POI), defined as natural menopause <40 years, and risk of ischaemic heart disease (IHD), stroke and overall cardiovascular disease (CVD). METHODS AND RESULTS: We performed a systematic search in PubMed (1966-2012), EMBASE (1980-2012). Studies were included if they were prospective, follow-up>3 years, assessment of age menopause <40 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. CONCLUSION: 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.

Cardiovascular disease risk in women with a history of spontaneous preterm delivery: A systematic review and meta-analysis.

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.

Relationship between recurrent miscarriage and early preterm delivery and recurrent events in patients with manifest vascular disease: The SMART study.

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 <14 weeks), recurrent miscarriage (≥3 miscarriages) and early preterm delivery (gestational age 14-32 weeks)) and cardiovascular morbidity and mortality were estimated using multivariable adjusted hazard ratios. RESULTS: During a mean follow-up of 5.0 years, 80 women had a recurrent cardiovascular event, of which 28 were fatal. A history of recurrent miscarriage was associated with an increased risk for a recurrent cardiovascular event (hazard ratio 4.3 95% confidence interval 1.7--10.9). In addition, early preterm delivery was related to a 4.1 (95% confidence interval 1.5--11.3) fold increased risk of cardiovascular death in women with previous cardiovascular disease. No statistically significant relationships were found for less than three miscarriages. CONCLUSIONS: In women with previous cardiovascular disease, an obstetric history of recurrent miscarriage is associated with an increased risk of recurrent cardiovascular morbidity and early preterm delivery with cardiovascular mortality.

Cardiovascular risk management after reproductive and pregnancy-related disorders: A Dutch multidisciplinary evidence-based guideline.

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.

Earlier Age of Onset of Chronic Hypertension and Type 2 Diabetes Mellitus After a Hypertensive Disorder of Pregnancy or Gestational Diabetes Mellitus.

A prospective cohort study was conducted to assess the impact of a history of hypertensive disorder of pregnancy (HDP) or gestational diabetes mellitus (GDM) on the risk and age of onset of hypertension, type 2 diabetes mellitus (T2D), and cardiovascular disease (CVD) later in life, independent of hypertension and T2D. Between 1993 and 1997, 22 265 ever-pregnant women were included from the European Prospective Investigation into Cancer and Nutrition-NL study, aged 20 to 70 years at baseline. Details on complications of pregnancy and known hypertension were obtained by questionnaire. Blood pressure was measured at enrollment. Participants were followed for the occurrence of CVD events. Data were analyzed using ANCOVA, multivariable logistic regression, and Cox proportional hazard (with HDP and GDM as time-dependent variables for T2D and CVD) models. At enrollment, women with a HDP reported diagnosis of hypertension 7.7 years earlier (95% confidence interval [CI] 6.9-8.5) and women with GDM reported diagnosis of T2D 7.7 years earlier (95% CI 5.8-9.6) than women without pregnancy complications. After adjustment for potential confounders, HDP was associated with presence of hypertension at enrollment (odds ratio 2.12, 95% CI 1.98-2.28) and onset of CVD later in life (hazard ratio 1.21, 95% CI 1.10-1.32). After including the intermediates hypertension and T2D in the model, the risk of CVD later in life decreased (hazard ratio 1.09, 95% CI 1.00-1.20). GDM was associated with an increased risk of developing T2D later in life (hazard ratio 3.68, 95% CI 2.77-4.90), but not with risk of CVD. HDP and GDM have a substantial impact on the risk of CVD and are potentially important indicators for preventive cardiovascular risk management.

Evaluation of antenatal corticosteroid prescribing patterns among 984 women at risk for preterm delivery.

OBJECTIVE: To evaluate the prescribing patterns of the first antenatal corticosteroids (ACS) course in our tertiary referral centre from 2005 until 2010. STUDY DESIGN: 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. RESULTS: 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. CONCLUSIONS: 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.

[Preeclampsia as cardiovascular risk factor]. / Pre-eclampsie als cardiovasculaire risicofactor.

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.

Neonatal side effects of maternal labetalol treatment in severe preeclampsia.

OBJECTIVE: 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. STUDY DESIGN: 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 (RR

Menstrual cycle and its disorders in women with congenital heart disease.

OBJECTIVES: To investigate the age at menarche, the prevalence of menstrual cycle (interval) disorders, and determinants in women with congenital heart disease (CHD). DESIGN: Using two CHD registries, 1802 (82%) of the 2196 women with CHD contacted (aged 18-58 years) provided written informed consent. After exclusion of patients with genetic disorders known to be associated with menstrual cycle disorders, 1593 eligible patients remained. Interviews by telephone and reviews of medical records were conducted. RESULTS: Overall, the age at menarche was slightly increased in women with CHD (13.3 vs. 13.1 years in the general population), mainly attributable to an increased prevalence of primary amenorrhea (n = 147; 9.2%). Other menstrual cycle disorders were documented: secondary amenorrhea (n = 181, 11.4%), polymenorrhea (n = 103, 6.5%), oligomenorrhea (n = 90, 5.6%), and menorrhagia (n = 117, 6.5%). The occurrence of these disorders also depended on the presence of cyanotic heart disease, surgical status, the number of surgical interventions, and the severity of CHD. DISCUSSION: Menstrual cycle disturbances, in particular primary amenorrhea, were frequently observed in this population. Patients with complex (cyanotic) heart disease needing repeated surgical interventions prior to menarche are especially at risk.