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Exposure to pregnancy complications, including preeclampsia (PE), has lifelong influences on offspring’s health. We have previously reported that experimental PE, induced in mice by administration of adenoviral sFlt1 at gestational day 8.5 combined with LPS at day 10.5, results in symmetrical growth restriction in female and asymmetrical growth restriction in male offspring. Here, we characterize the molecular phenotype of the fetal brain and liver with respect to gene transcription and DNA methylation at the end of gestation.In fetal brain and liver, expression and DNA methylation of several key regulatory genes is altered by PE exposure, mostly independent of fetal sex. These alterations point toward a decreased gluconeogenesis in the liver and stimulated neurogenesis in the brain, potentially affecting long-term brain and liver function. The observed sex-specific growth restriction pattern is not reflected in the molecular data, showing that PE, rather than tissue growth, drives the molecular phenotype of PE-exposed offspring.

Gestational complications, including preeclampsia and gestational diabetes, have long-term adverse consequences for offspring’s metabolic and cardiovascular health. A low-grade systemic inflammatory response is likely mediating this. Here, we examine the consequences of LPS-induced gestational inflammation on offspring’s health in adulthood. LPS was administered to pregnant C57Bl/6J mice on gestational day 10.5. Maternal plasma metabolomics showed oxidative stress, remaining for at least 5 days after LPS administration, likely mediating the consequences for the offspring. From weaning on, all offspring was fed a control diet; from 12 to 24 weeks of age, half of the offspring received a western-style diet (WSD). The combination of LPS-exposure and WSD resulted in hyperphagia and increased body weight and body fat mass in the female offspring. This was accompanied by changes in glucose tolerance, leptin and insulin levels and gene expression in liver and adipose tissue. In the hypothalamus, expression of genes involved in food intake regulation was slightly changed. We speculate that altered food intake behaviour is a result of dysregulation of hypothalamic signalling. Our results add to understanding of how maternal inflammation can mediate long-term health consequences for the offspring. This is relevant to many gestational complications with a pro-inflammatory reaction in place.

Contains fulltext : 172417.pdf (publisher's version ) (Open Access), BACKGROUND: Intrauterine growth retardation (IUGR) is a major risk factor for perinatal mortality and morbidity. Thus, there is a compelling need to introduce sensitive measures to detect IUGR fetuses. Routine third trimester ultrasonography is increasingly used to detect IUGR. However, we lack evidence for its clinical effectiveness and cost-effectiveness and information on ethical considerations of additional third trimester ultrasonography. This nationwide stepped wedge cluster-randomized trial examines the (cost-)effectiveness of routine third trimester ultrasonography in reducing severe adverse perinatal outcome through subsequent protocolized management. METHODS: For this trial, 15,000 women with a singleton pregnancy receiving care in 60 participating primary care midwifery practices will be included at 22 weeks of gestation. In the intervention (n = 7,500) and control group (n = 7,500) fetal growth will be monitored by serial fundal height assessments. All practices will start offering the control condition (ultrasonography based on medical indication). Every three months, 20 practices will be randomized to the intervention condition, i.e. apart from ultrasonography if indicated, two routine ultrasound examinations will be performed (at 28-30 weeks and 34-36 weeks). If IUGR is suspected, both groups will receive subsequent clinical management as described in the IRIS study protocol that will be developed before the start of the trial. The primary dichotomous clinical composite outcome is 'severe adverse perinatal outcome' up to 7 days after birth, including: perinatal death; Apgar score <4 at 5 minutes after birth; impaired consciousness; need for assisted ventilation for more than 24 h; asphyxia; septicemia; meningitis; bronchopulmonary dysplasia; intraventricular hemorrhage; cystic periventricular leukomalacia; neonatal seizures or necrotizing enterocolitis. For the economic evaluation, costs will be measured from a societal perspective. Quality of life wi

Contains fulltext : 118346.pdf (publisher's version ) (Open Access), IMPORTANCE: In threatened preterm labor, maintenance tocolysis with nifedipine, after an initial course of tocolysis and corticosteroids for 48 hours, may improve perinatal outcome. OBJECTIVE: To determine whether maintenance tocolysis with nifedipine will reduce adverse perinatal outcomes due to premature birth. DESIGN, SETTING, AND PARTICIPANTS: APOSTEL-II (Assessment of Perinatal Outcome with Sustained Tocolysis in Early Labor) is a double-blind, placebo-controlled trial performed in 11 perinatal units including all tertiary centers in The Netherlands. From June 2008 to February 2010, women with threatened preterm labor between 26 weeks (plus 0 days) and 32 weeks (plus 2 days) gestation, who had not delivered after 48 hours of tocolysis and a completed course of corticosteroids, were enrolled. Surviving infants were followed up until 6 months after birth (ended August 2010). INTERVENTION: Randomization assigned 406 women to maintenance tocolysis with nifedipine orally (80 mg/d; n = 201) or placebo (n = 205) for 12 days. Assigned treatment was masked from investigators, participants, clinicians, and research nurses. MAIN OUTCOME MEASURES: Primary outcome was a composite of adverse perinatal outcomes (perinatal death, chronic lung disease, neonatal sepsis, intraventricular hemorrhage >grade 2, periventricular leukomalacia >grade 1, or necrotizing enterocolitis). Analyses were completed on an intention-to-treat basis. RESULTS: Mean (SD) gestational age at randomization was 29.2 (1.7) weeks for both groups. Adverse perinatal outcome was not significantly different between groups: 11.9% (24/201; 95% CI, 7.5%-16.4%) for nifedipine vs 13.7% (28/205; 95% CI, 9.0%-18.4%) for placebo (relative risk, 0.87; 95% CI, 0.53-1.45). CONCLUSIONS AND RELEVANCE: In patients with threatened preterm labor, nifedipine-maintained tocolysis did not result in a statistically significant reduction in adverse perinatal outcomes when compared with placebo. Although the lower than anticipated

Importance: In threatened preterm labor, maintenance tocolysis with nifedipine, after an initial course of tocolysis and corticosteroids for 48 hours, may improve perinatal outcome. Objective: To determine whether maintenance tocolysis with nifedipine will reduce adverse perinatal outcomes due to premature birth. Design, Setting, and Participants: APOSTEL-II (Assessment of Perinatal Outcome with Sustained Tocolysis in Early Labor) is a double-blind, placebo-controlled trial performed in 11 perinatal units including all tertiary centers in the Netherlands. From June 2008 to February 2010, women with threatened preterm labor between 26 weeks (plus 0 days) and 32 weeks (plus 2 days) gestation, who had not delivered after 48 hours of tocolysis and a completed course of corticosteroids, were enrolled. Surviving infants were followed up until 6 months after birth (ended August 2010). Intervention: Randomization assigned 406 women to maintenance tocolysis with nifedipine orally (80 mg/d; n=201) or placebo (n=205) for 12 days. Assigned treatment was masked from investigators, participants, clinicians, and research nurses. Main Outcome Measures: Primary outc

Objective: Pregnancies complicated by intrauterine growth retardation (IUGR) beyond 36 weeks of gestation are at increased risk of neonatal morbidity and mortality. Optimal treatment in IUGR at term is highly debated. Results from the multicenter DIGITAT (Disproportionate Intrauterine Growth Intervention Trial At Term) trial show that induction of labor and expectant monitoring result in equal neonatal and maternal outcomes for comparable cesarean section rates. We report the maternal health-related quality of life (HR-QoL) that was measured alongside the trial at several points in time. Methods: Both randomized and non-randomized women were asked to participate in the HR-QoL study. Women were asked to fill out written validated questionnaires, covering background characteristics, condition-specific issues and the Short Form (SF-36), European Quality of Life (EuroQoL 6D3L), Hospital Anxiety and Depression scale (HADS), and Symptom Check List (SCL-90) at baseline, 6 weeks postpartum and 6 months postpartum. We compared the difference scores of all summary measures between the two management strategies by ANOVA. A repeated measures multivariate mixed model was

Objective: To compare the effect of induction of labour with a policy of expectant monitoring for intrauterine growth restriction near term. Design: Multicentre randomised equivalence trial (the Disproportionate Intrauterine Growth Intervention Trial At Term (DIGITAT)). Setting: Eight academic and 44 non-academic hospitals in the Netherlands between November 2004 and November 2008. Participants: Pregnant women who had a singleton pregnancy beyond 36+0 weeks' ge

Contains fulltext : 80242.pdf (publisher's version ) (Open Access), BACKGROUND: Preterm labour is the main cause of perinatal morbidity and mortality in the Western world. At present, there is evidence that tocolysis for 48 hours is useful in women with threatened preterm labour at least before 32 weeks. This allows transfer of the patient to a perinatal centre, and maximizes the effect of corticosteroids for improved neonatal survival. It is questionable whether treatment with tocolytics should be maintained after 48 hours. METHODS/DESIGN: The APOSTEL II trial is a multicentre placebo-controlled study. Pregnant women admitted for threatened preterm labour who have been treated with 48 hours corticosteroids and tocolysis will be eligible to participate in the trial between 26+0 and 32+2 weeks gestational age. They will be randomly allocated to nifedipine (intervention) or placebo (control) for twelve days or until delivery, whatever comes first.Primary outcome is a composite of perinatal death, and severe neonatal morbidity up to evaluation at 6 months after birth. Secondary outcomes are gestational age at delivery, number of days in neonatal intensive care and total days of the first 6 months out of hospital. In addition a cost-effectiveness analysis will be performed. Analysis will be by intention to treat. The power calculation is based on an expected 11% difference in adverse neonatal outcome. This implies that 406 women have to be randomised (two sided test, beta 0.2 at alpha 0.05). DISCUSSION: This trial will provide evidence as to whether maintenance tocolysis reduces severe perinatal morbidity and mortality in women with threatened preterm labour before 32 weeks. TRIAL REGISTRATION: Clinical trial registration: http://www.trialregister.nl, NTR 1336, date of registration: June 3rd 2008.

Contains fulltext : 79641.pdf (publisher's version ) (Open Access), BACKGROUND: At present, women with threatened preterm labor before 32 weeks of gestation are, after transfer to a perinatal center, treated with tocolytics and corticosteroids. Many of these women are treated unnecessarily. Fibronectin is an accurate predictor for the occurrence of preterm birth among women with threatened preterm labor. We will assess whether triage of these women with fibronectin testing, cervical length or their combination is cost-effective. METHODS/DESIGN: We will investigate a prospective cohort of women referred to a perinatal centre for spontaneous threatened preterm labor between 24 and 34 weeks with intact membranes. All women will be tested for fibronectin and cervical length. Women with a cervical length <10 mm and women with a cervical length between 10-30 mm in combination with a positive fibronectin test will be treated with tocolytics according to local protocol. Women with a cervical length between 10-30 mm in combination with a negative fibronectin test will be randomised between treatment with nifedipine (intervention) and placebo (control) for 48 hours. Women with a cervical length > 30 mm will be managed according to local protocol. Corticosteroids may be given to all women at the discretion of the attending physician. Primary outcome measure will be delivery within 7 days. Secondary outcome measures will be neonatal morbidity and mortality, complications of tocolytics, costs and health related quality of life. The analysis will be according to the intention to treat principle. We anticipate the probability on preterm birth within 7 days in the group of women with a negative fibronectine test to be 5%. Two groups of 110 women will be needed to assure that in case of non-inferiority the difference in the proportion of preterm deliveries < 7 days will be within a prespecified boundary of 7.5% (one sided test, beta 0.2, alpha 0.05). Data obtained from women with a positive and negative fibronectin tests in both the cohort study and

Background: Preterm labour is the main cause of perinatal morbidity and mortality in the Western world. At present, there is evidence that tocolysis for 48 hours is useful in women with threatened preterm labour at least before 32 weeks. This allows transfer of the patient to a perinatal centre, and maximizes the effect of corticosteroids for improved neonatal survival. It is questionable whether treatment with tocolytics should be maintained after 48 hours. Methods/Design: The APOSTEL II trial is a multicentre placebo-controlled study. Pregnant women admitted for threatened preterm labour who have been treated with 48 hours corticosteroids and tocolysis will be eligible to participate in the trial between 26+0and 32+2weeks gestational age. They will be randomly allocated to nifedipine (intervention) or placebo (control) for twelve days or until delivery, whatever comes first. Discussion: Primary outcome is a composite of perinatal death, and severe neonatal morbidity up to evaluation at 6 months after birth. Secondary outcomes are gestational age at delivery, number of days in neonatal intensive care and total days of the first 6 months out of hospital. In addition a cost-effectiveness analysis will be performed. Analysis will be by intention to treat. The power calculation is based on an expected 11% difference in adverse neonatal outcome. This implies that 406 women have to be randomis

Background: At present, women with threatened preterm labor before 32 weeks of gestation are, after transfer to a perinatal center, treated with tocolytics and corticosteroids. Many of these women are treated unnecessarily. Fibronectin is an accurate predictor for the occurrence of preterm birth among women with threatened preterm labor. We will assess whether triage of these women with fibronectin testing, cervical length or their combination is cost-effective. Methods/Design: We will investigate a prospective cohort of women referred to a perinatal centre for spontaneous threatened preterm labor between 24 and 34 weeks with intact membranes. All women will be tested for fibronectin and cervical length. Women with a cervical length <10 mm and women with a cervical length between 10-30 mm in combination with a positive fibronectin test will be treated with tocolytics according to local protocol. Women with a cervical length between 10-30 mm in combination with a negative fibronectin test will be randomised between treatment with nifedipine (intervention) and placebo (control) for 48 hours. Women with a cervical length > 30 mm will be managed according to local protocol. Corticosteroids may be given to all women at the discretion of the attending physician. Primary outcome measure will be delivery within 7 days. Secondary outcome measures will be neonatal morbidity and mortality, complications of tocolytics, costs and health related quality of life. The analysis will be according to the intention to treat principle. We anticipate the probability on preterm birth within 7 days in the group of women with a negative fibronectine test

Background: Around 80% of intrauterine growth restricted (IUGR) infants are born at term. They have an increase in perinatal mortality and morbidity including behavioral problems, minor developmental delay and spastic cerebral palsy. Management is controversial, in particular the decision whether to induce labour or await spontaneous delivery with strict fetal and maternal surveillance. We propose a randomised trial to compare effectiveness, costs and maternal quality of life for induction of labour versus expectant management in women with a suspected IUGR fetus at term. Methods/design: The proposed trial is a multi-centre randomised study in pregnant women who are suspected on clinical grounds of having an IUGR child at a gestational age between 36+0 and 41+0 weeks. After informed consent women will be randomly allocated to either induction of labour or expectant management with maternal and fetal monitoring. Randomisation will be web-based. The primary outcome measure will be a composite neonatal morbidity and mortality. Secondary outcomes will be severe maternal morbidity, maternal quality of life and costs. Moreover, we aim to assess neurodevelopmental and neurobehavioral outcome at two years as assessed by a postal enquiry (Child Behavioral Check List-CBCL and Ages and Stages Questionnaire-ASQ). Analysis will be by intention to treat. Quality of life analysis and a preference study will also be performed in the same study population. Health technology assessment with an economic analysis is part of this so called Digitat trial (Disproportionate Intrauterine Growth Intervention Trial At Term). The study aims to include 325 patients per arm. Discussion: This trial will provide evidence for which strategy is superior in terms of neonatal and maternal morbidity and mortality, costs and maternal quality of life aspects. This will be the first randomised trial for IUGR at term.

Contains fulltext : 65628.pdf ( ) (Open Access), BACKGROUND: Around 80% of intrauterine growth restricted (IUGR) infants are born at term. They have an increase in perinatal mortality and morbidity including behavioral problems, minor developmental delay and spastic cerebral palsy. Management is controversial, in particular the decision whether to induce labour or await spontaneous delivery with strict fetal and maternal surveillance. We propose a randomised trial to compare effectiveness, costs and maternal quality of life for induction of labour versus expectant management in women with a suspected IUGR fetus at term. METHODS/DESIGN: The proposed trial is a multi-centre randomised study in pregnant women who are suspected on clinical grounds of having an IUGR child at a gestational age between 36+0 and 41+0 weeks. After informed consent women will be randomly allocated to either induction of labour or expectant management with maternal and fetal monitoring. Randomisation will be web-based. The primary outcome measure will be a composite neonatal morbidity and mortality. Secondary outcomes will be severe maternal morbidity, maternal quality of life and costs. Moreover, we aim to assess neurodevelopmental and neurobehavioral outcome at two years as assessed by a postal enquiry (Child Behavioral Check List-CBCL and Ages and Stages Questionnaire-ASQ). Analysis will be by intention to treat. Quality of life analysis and a preference study will also be performed in the same study population. Health technology assessment with an economic analysis is part of this so called Digitat trial (Disproportionate Intrauterine Growth Intervention Trial At Term). The study aims to include 325 patients per arm. DISCUSSION: This trial will provide evidence for which strategy is superior in terms of neonatal and maternal morbidity and mortality, costs and maternal quality of life aspects. This will be the first randomised trial for IUGR at term. TRIAL REGISTRATION: Dutch Trial Register and ISRCTN-Register: ISRCTN10363217.

Item does not contain fulltext, OBJECTIVES: To describe the use of fetal MRI as an adjunct to high-resolution ultrasound in parental counselling in a family with a central nervous system (CNS) abnormality, resembling the agyria-pachyria complex, of probably autosomal recessive inheritance. METHODS: Description of the use of fetal MRI as an adjunct to high-resolution ultrasound in three consecutive pregnancies in a family with a CNS abnormality. RESULTS: Fetal MRI, by showing more detailed abnormalities of the CNS, proved to be very useful in parental counselling because of the definitive diagnosis available early in pregnancy. In the first two pregnancies, ultrasound examination revealed mild pyelectasis, megacystis and an enlarged posterior fossa with small cerebellum. MRI at 22-33 weeks confirmed these abnormalities, but also showed pachygyria. In the third pregnancy, MRI at 19 weeks showed no abnormalities, a finding of decisive importance for counselling. CONCLUSION: Fetal MRI was useful both for early diagnosis and prenatal management in this family with an agyria-pachyria complex CNS abnormality.