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).

Placental pathology and long-term neurodevelopment of very preterm infants.

OBJECTIVE: The objective of the study was to compare neonatal morbidity and long-term neurodevelopmental outcome between very preterm infants with placental underperfusion and very preterm infants with histological chorioamnionitis. STUDY DESIGN: We measured the mental and motor development at age 2 and 7 years in 51 very preterm infants with placental underperfusion and 21 very preterm infants with histological chorioamnionitis. RESULTS: At 2 years, very preterm infants with placental underperfusion had poorer mental development than very preterm infants with histological chorioamnionitis (mean [SD] 90.8 [18.3] vs 104.1 [17.2], adjusted d = 1.12, P = .001). Motor development was not different between both groups (92.8 [17.2] vs 96.8 [8.7], adjusted d = 0.52, P = .12). At 7 years, large, although nonsignificant, effects were found for better mental and motor development and fewer behavioral problems in infants with histological chorioamnionitis. CONCLUSION: Placental pathology contributes to variance in mental development at 2 years and should be taken into account when evaluating neurodevelopmental outcome of very preterm infants.

Antiplatelet Agents and the Prevention of Spontaneous Preterm Birth: A Systematic Review and Meta-analysis.

OBJECTIVE: Spontaneous preterm birth is an important cause of neonatal mortality and morbidity. An increasing body of evidence suggests that uteroplacental ischemia plays an important role in the etiology of spontaneous preterm birth. We aimed to study whether antiplatelet agents reduce the risk of spontaneous preterm birth. DATA SOURCES: We included data from an individual participant data meta-analysis of studies that had evaluated the effect of antiplatelet agents to reduce preeclampsia (Perinatal Antiplatelet Review of International Studies Individual Participant Data). METHODS OF STUDY SELECTION: The meta-analysis included 31 studies that randomized women to low-dose aspirin-dipyridamole or placebo-no treatment as a primary preventive strategy for preeclampsia. For the current study we analyzed data from 17 trials (28,797 women) that supplied data on type of delivery (spontaneous compared with indicated birth). TABULATION, INTEGRATION, AND RESULTS: Primary endpoints were spontaneous preterm birth at less than 37 weeks, less than 34 weeks, and less than 28 weeks of gestation. We analyzed outcomes for each trial separately using χ statistics and combined in an individual participant data meta-analysis using a binary logistic regression model. Women assigned to antiplatelet treatment compared with placebo or no treatment had a lower risk of spontaneous preterm birth at less than 37 weeks (relative risk [RR] 0.93, 95% confidence interval [CI] 0.86-0.996) and less than 34 weeks of gestation (RR 0.86, 95% CI 0.76-0.99). The RR of having a spontaneous preterm birth at less than 37 weeks of gestation was 0.83 (95% CI 0.73-0.95) for women who have had a previous pregnancy and 0.98 (95% CI 0.89-1.09) for women in their first pregnancy. The treatment effect was stable in all other prespecified subgroups. CONCLUSION: Antiplatelet agents reduce spontaneous preterm birth in pregnant women at risk for preeclampsia.

Placental histology in spontaneous and indicated preterm birth: A case control study.

INTRODUCTION: Placental pathology is an important contributor in preterm birth, both spontaneous and indicated. The aim of this study was to describe and compare placental histological features of spontaneous preterm birth versus indicated preterm birth. METHODS: A case control study was performed at the University Medical Center Utrecht. Women with spontaneous or indicated preterm birth (17-37 weeks of gestation) delivered in 2009 were included. Women with a pregnancy complicated by congenital and/or chromosomal abnormalities were excluded. Placentas were systematically examined by an expert pathologist blinded for pregnancy outcome, except for gestational age. Placental histological abnormalities were classified into infectious inflammatory lesions and maternal vascular malperfusion lesions and compared between spontaneous and indicated preterm birth. Analysis was stratified for immature (17-23+6 weeks), extremely (24-27+6 weeks), very (28-31+6 weeks) and moderate/late (32-36+6 weeks) preterm birth. RESULTS: We included 233 women, 121 women with spontaneous preterm birth and 112 women with indicated preterm birth. Among women with spontaneous extremely preterm birth, higher rates of severe chorioamnionitis were found (56.0% vs. 0%). Furthermore, a shift from infectious-inflammatory lesions to maternal vascular malperfusion lesions was seen after 28 weeks; in women with spontaneous very and moderate/late preterm birth, maternal vascular malperfusion lesions were the main finding (46.8% and 47.7% respectively). In women with indicated preterm birth, maternal vascular malperfusion lesions were most often contributing through all gestational age categories. CONCLUSION: Maternal vascular malperfusion lesions are most frequent in both spontaneous and indicated very and moderate/late preterm birth. In spontaneous extreme preterm birth chorioamnionitis is the main finding.

Spiral artery remodeling and maternal cardiovascular risk: the spiral artery remodeling (SPAR) study.

BACKGROUND: Women with a history of placental bed disorders, including preeclampsia and intrauterine growth restriction have an increased long-term risk of cardiovascular disease (CVD). Further, similarities exist between atherosclerosis and abnormalities observed in placental bed spiral arteries in pregnancies affected by preeclampsia and intrauterine growth restriction, such as acute atherosis and defective remodeling. This suggests a common pathophysiological pathway underlying both disorders. OBJECTIVES: The aim of this study was to investigate vascular and inflammatory lesions in the placental bed of women with preeclampsia and normal pregnancy using a systematic approach to characterize lesions of the placental bed, and relate spiral artery pathology to postpartum CVD risk assessment. METHODS: Placental bed punch biopsies were performed following caesarean section and systematically studied to assess vascular pathology, arterial remodeling, and the presence of CD3, CD56, and CD68 cells. In addition, levels of modifiable CVD risk factors were assessed immediately postpartum. RESULTS: We found fewer spiral arteries with complete remodeling in women with preeclampsia than in the control group (21 vs. 68%; P = 0.008). Further, women with preeclampsia showed less presence of CD3 cells in both the decidua and the myometrium. Preliminary findings of CVD risk factor assessment postpartum suggest a correlation between acute atherosis and higher triglyceride and low-density lipoprotein cholesterol levels. CONCLUSION: Systematic study of vascular pathology in uterine spiral artery biopsy samples in relation to CVD risk factors provides valuable insight into the link between cardiovascular health and placental bed disorders.

Nifedipine versus placebo in the treatment of preterm prelabor rupture of membranes: a randomized controlled trial: Assessment of perinatal outcome by use of tocolysis in early labor-APOSTEL IV trial.

OBJECTIVE: Preterm birth is the most common cause of neonatal morbidity and mortality. Around one third of preterm deliveries starts with preterm prelabor rupture of membranes (PPROM). The aim of this trial was to study the effect of prolonged tocolysis with nifedipine versus placebo in women with PPROM on perinatal outcome and prolongation of pregnancy. STUDY DESIGN: The Apostel IV was a nationwide multicenter randomized placebo controlled trial. We included women with PPROM without contractions between 24(+0) and 33(+6) weeks of gestation. Participants were randomly allocated to daily 80mg nifedipine or placebo, until the start of labor, with a maximum of 18 days. The primary outcome measure was a composite of poor neonatal outcome, including perinatal death, bronchopulmonary dysplasia, periventricular leukomalacia>grade 1, intraventricular hemorrhage>grade 2, necrotizing enterocolitis>stage 1 and culture proven sepsis. Secondary outcomes were gestational age at delivery and prolongation of pregnancy. Analysis was by intention to treat. To detect a reduction of poor neonatal outcome from 30% to 10%, 120 women needed to be randomized. TRIAL REGISTRY: NTR 3363. RESULTS: Between October 2012 and December 2014 we randomized 25 women to nifedipine and 25 women to placebo. Due to slow recruitment the study was stopped prematurely. The median gestational age at randomization was 29.9 weeks (IQR 27.7-31.3) in the nifedipine group and 27.0 weeks (IQR 24.7-29.9) in the placebo group. Other baseline characteristics were comparable. The adverse perinatal outcome occurred in 9 neonates (33.3%) in the nifedipine group and 9 neonates (32.1%) in the placebo group (RR 1.04, 95% CI 0.49-2.2). Two perinatal deaths occurred, both in the nifedipine group. Bronchopulmonary dysplasia was seen less frequently in the nifedipine group (0% versus 17.9%; p=0.03). Prolongation of pregnancy did not differ between the nifedipine and placebo group (median 11 versus 8 days, HR 1.02; 95% CI 0.58-1.79). CONCLUSION: This randomized trial did not show a beneficial effect of prolonged tocolysis on neonatal outcomes or prolongation of pregnancy in women with PPROM without contractions. However, since results are based on a small sample size, a difference in effectiveness cannot be excluded.

[Increased risk of type II diabetes mellitus and cardiovascular disease after gestational diabetes mellitus: a systematic review]. / Verhoogd risico op diabetes mellitus type 2 en hart- en vaatziekten na diabetes gravidarum: een systematische review.

OBJECTIVE: To determine the long-term risk of developing type II diabetes (T2D) and cardiovascular disease (CVD) for women with a history of gestational diabetes mellitus. DESIGN: Systematic review and meta-analysis. METHOD: Two search strategies were used in PubMed and Embase to determine the long-term risks of developing T2D and CVD after a pregnancy complicated by gestational diabetes mellitus. After critical appraisal of the papers found, 11 papers were included, involving a total of 328,423 patients. Absolute and relative risks (RRs) were calculated. RESULTS: Eight studies (n=276,829) reported on the long-term risk of T2D and 4 (n=141,048) on the long-term risk of CVD. Follow-up ranged from 3.5 to 11.5 years for T2D and from 1.2 to 74.0 years for CVD. Women with gestational diabetes had a risk of T2D varying between 9.5% and 37.0% and a risk of CVD of between 0.28% and 15.5%. Women with gestational diabetes were at increased risk of T2D (weighted RR: 13.2; 95% CI: 8.5-20.7) and CVD (weighted RR: 2.0; 95% CI: 1.1-3.7) compared to women without gestational diabetes. CONCLUSION: Women with prior gestational diabetes mellitus have a significantly increased risk of developing T2D and CVD. It is very important that gestational diabetes is recognised as a cardiovascular risk factor in daily practice. It would be desirable to screen this group of women for the presence of hyperglycaemia and other cardiovascular risk factors. Further research is required to be able to specify the long-term risk of T2D and CVD and to demonstrate whether such screening is cost-effective.

Preterm labor: current pharmacotherapy options for tocolysis.

INTRODUCTION: In the developed world, preterm birth is in quantity and in severity the most important issue in obstetric care. Adverse neonatal outcome is strongly related to gestational age at delivery. Since the pathophysiological mechanism of preterm birth is not yet completely unraveled, the development of successful preventive strategies is hampered. When preterm labor is actually threatening, current pharmacological therapies focus on inhibition of preterm contractions. This allows for transportation of the mother to a center with a neonatal intensive care unit and administration of corticosteroids to enhance fetal lung maturation. Globally, however, large practice variation exists. AREAS COVERED: The aim of this review is to provide an overview of current pharmacological therapies for preterm labor. EXPERT OPINION: For the initial tocolysis, the use of atosiban or nifedipine for 48 h is recommended based on the largest effectiveness and most favorable side effect profile. However, since data that convincingly indicate the beneficial effect of tocolytics on neonatal outcome are lacking, it might well be that tocolytics are ineffective. The role of progesterone in treatment of acute tocolysis is limited, but it might play a role in the prevention of preterm labor or as sensitizer for other tocolytic agents.

Perinatal infections and neurodevelopmental outcome in very preterm and very low-birth-weight infants: a meta-analysis.

IMPORTANCE: Perinatal infections are commonly present in preterm and very low-birth-weight (VLWB) infants and might contribute to adverse neurodevelopmental outcome. OBJECTIVE: To summarize studies evaluating the effect of perinatal infections on neurodevelopmental outcome in very preterm/VLBW infants. EVIDENCE REVIEW: On December 12, 2011, we searched Medline, PsycINFO, Embase, and Web of Knowledge for studies on infections and neurodevelopmental outcome. All titles and abstracts were assessed for eligibility by 2 independent reviewers. We also screened the reference lists of identified articles to search for additional eligible studies. Preselected criteria justified inclusion in this meta-analysis: (1) the study included infants born very preterm (≤32 weeks) and/or with VLBW (≤1500 g); (2) the study compared infants with and without perinatal infection; (3) there was follow-up using the Bayley Scales of Infant Development 2nd edition; and (4) results were published in an English-language peer-reviewed journal. The quality of each included study was assessed using the Newcastle-Ottawa Scale. FINDINGS: This meta-analysis includes 18 studies encompassing data on 13.755 very preterm/VLBW infants. Very preterm/VLBW infants with perinatal infections had poorer mental (d = -0.25; P < .001) and motor (d = -0.37; P < .001) development compared with very preterm/VLBW infants without infections. Mental development was most impaired by necrotizing enterocolitis (d = -0.40; P < .001) and meningitis (d = -0.37; P < .001). Motor development was most impaired by necrotizing enterocolitis (d = -0.66; P < .001). Chorioamnionitis did not affect mental (d = -0.05; P = .37) or motor (d = 0.19; P = .08) development. CONCLUSIONS AND RELEVANCE: Postnatal infections have detrimental effects on mental and motor development in very preterm/VLBW infants.