Vaginal delivery of the second twin in unengaged cephalic presentation.

In accordance with women's preferences guidelines, referring to population-based and randomized trials, which recommends counseling women with vertex-first twins to attempt a vaginal delivery. Yet, the rising rates of twin caesareans are associated with the decline in skills of senior and junior obstetricians. Although noncephalic second twins have been in the focus of interest, prompt delivery of cephalic second twins can be trickier when the head does not engage. We illustrate how to avoid complications during instrumental delivery or internal podalic version and breech extraction of the second twin encouraging to start when membranes are still intact.

Maternal Sildenafil vs Placebo in Pregnant Women With Severe Early-Onset Fetal Growth Restriction: A Randomized Clinical Trial.

Importance: Severe early onset fetal growth restriction caused by placental dysfunction leads to high rates of perinatal mortality and neonatal morbidity. The phosphodiesterase 5 inhibitor, sildenafil, inhibits cyclic guanosine monophosphate hydrolysis, thereby activating the effects of nitric oxide, and might improve uteroplacental function and subsequent perinatal outcomes. Objective: To determine whether sildenafil reduces perinatal mortality or major morbidity. Design, Setting, and Participants: This placebo-controlled randomized clinical trial was conducted at 10 tertiary referral centers and 1 general hospital in the Netherlands from January 20, 2015, to July 16, 2018. Participants included pregnant women between 20 and 30 weeks of gestation with severe fetal growth restriction, defined as fetal abdominal circumference below the third percentile or estimated fetal weight below the fifth percentile combined with Dopplers measurements outside reference ranges or a maternal hypertensive disorder. The trial was stopped early owing to safety concerns on July 19, 2018, whereas benefit on the primary outcome was unlikely. Data were analyzed from January 20, 2015, to January 18, 2019. The prespecified primary analysis was an intention-to-treat analysis including all randomized participants. Interventions: Participants were randomized to sildenafil, 25 mg, 3 times a day vs placebo. Main Outcomes and Measures: The primary outcome was a composite of perinatal mortality or major neonatal morbidity until hospital discharge. Results: Out of 360 planned participants, a total of 216 pregnant women were included, with 108 women randomized to sildenafil (median gestational age at randomization, 24 weeks 5 days [interquartile range, 23 weeks 3 days to 25 weeks 5 days]; mean [SD] estimated fetal weight, 458 [160] g) and 108 women randomized to placebo (median gestational age, 25 weeks 0 days [interquartile range, 22 weeks 5 days to 26 weeks 3 days]; mean [SD] estimated fetal weight, 464 [186] g). In July 2018, the trial was halted owing to concerns that sildenafil may cause neonatal pulmonary hypertension, whereas benefit on the primary outcome was unlikely. The primary outcome, perinatal mortality or major neonatal morbidity, occurred in the offspring of 65 participants (60.2%) allocated to sildenafil vs 58 participants (54.2%) allocated to placebo (relative risk, 1.11; 95% CI, 0.88-1.40; P = .38). Pulmonary hypertension, a predefined outcome important for monitoring safety, occurred in 16 neonates (18.8%) in the sildenafil group vs 4 neonates (5.1%) in the placebo group (relative risk, 3.67; 95% CI, 1.28-10.51; P = .008). Conclusions and Relevance: These findings suggest that antenatal maternal sildenafil administration for severe early onset fetal growth restriction did not reduce the risk of perinatal mortality or major neonatal morbidity. The results suggest that sildenafil may increase the risk of neonatal pulmonary hypertension. Trial Registration: ClinicalTrials.gov Identifier: NCT02277132.

Development of Nationwide Recommendations to Support Prenatal Counseling in Extreme Prematurity.

OBJECTIVES: To develop a nationwide, evidence-based framework to support prenatal counseling in extreme prematurity, focusing on organization, decision-making, content, and style aspects. METHODS: A nationwide multicenter RAND-modified Delphi method study was performed between November 2016 and December 2017 in the Netherlands. Firstly, recommendations were extracted from literature and previous studies. Secondly, an expert panel (n = 21) with experienced parents, obstetricians, and neonatologists rated the recommendations on importance for inclusion in the framework. Thirdly, ratings were discussed in a consensus meeting. The final set of recommendations was approved and transformed into a framework. RESULTS: A total of 101 recommendations on organization, decision-making, content, and style were included in the framework, including tools to support personalization. The most important recommendations regarding organization were to have both parents involved in the counseling with both the neonatologist and obstetrician. The shared decision-making model was recommended for deciding between active support and comfort care. Main recommendations regarding content of conversation were explanation of treatment options, information on survival, risk of permanent consequences, impossibility to predict an individual course, possibility for multiple future decision moments, and a discussion on parental values and standards. It was considered important to avoid jargon, check understanding, and provide a summary. The expert panel, patient organization, and national professional associations (gynecology and pediatrics) approved the framework. CONCLUSIONS: A nationwide, evidence-based framework for prenatal counseling in extreme prematurity was developed. It contains recommendations and tools for personalization in the domains of organization, decision-making, content, and style of prenatal counseling.

Balloon catheter for induction of labor in women with one previous cesarean and an unfavorable cervix.

INTRODUCTION: When women with a previous cesarean section and an unfavorable cervix have an indication for delivery, the choice is to induce labor or to perform a cesarean section. This study aims to assess the effectiveness and safety of a balloon catheter as a method of induction of labor in women with one previous cesarean section and an unfavorable cervix compared with an elective repeat cesarean section. MATERIAL AND METHODS: We performed a prospective cohort study in 51 hospitals in the Netherlands on term women with one previous cesarean section, a live singleton fetus in cephalic position, an unfavorable cervix and an indication for delivery. We recorded obstetric, maternal and neonatal characteristics. We compared the outcome of women who were induced with a balloon catheter with the outcome of women who delivered by elective repeat cesarean section. Main outcomes were maternal and neonatal morbidity. Mode of delivery was a secondary outcome for women who were induced. Adjusted odds ratios (aOR) were calculated using logistic regression, adjusted for potential confounders. RESULTS: Analysis was performed on 993 women who were induced and 321 women who had a repeat cesarean section (August 2011 until September 2012). Among the women who were induced, 560 (56.4%) delivered vaginally and 11 (1.1%) sustained a uterine rupture. Composite adverse maternal outcome (uterine rupture, severe postpartum hemorrhage or postpartum infection) occurred in 73 (7.4%) in the balloon and 14 (4.5%) women in the repeat cesarean section group (aOR 1.58, 95% confidence interval [CI] 0.85-2.96). Composite adverse neonatal outcome (Apgar score <7 at 5 minutes or umbilical pH <7.10) occurred in 57 (5.7%) and 10 (3.2%) neonates, respectively (aOR 1.40, 95% CI 0.87-3.48). Women who were induced had a shorter postpartum admission time (2.0 vs 3.0 days (P < 0.0001)). CONCLUSIONS: In women with a previous cesarean section and a need for delivery, induction of labor with a balloon catheter does not result in a significant increase in adverse maternal and neonatal outcomes as compared with planned cesarean section.

Subsequent pregnancy outcome after mid-trimester termination of pregnancy for preeclampsia.

BACKGROUND: In this study we determined the outcome of subsequent pregnancies after termination of pregnancy for preeclampsia, with the purpose of presenting data useful for counselling these women on future pregnancies. STUDY DESIGN: The cohort consisted of 131 women with a history of termination of pregnancy for preeclampsia. RESULTS: Data of 79 pregnancies were available for analysis, including 13 women with chronic hypertension and 16 women with thrombophilia. There were seven miscarriages (8.8%) and 72 ongoing pregnancies. Low-dose aspirin was prescribed for 64 women (89%). The mean gestational age at delivery was 356/7 ± 4 weeks with a mean birth weight of 2571 ± 938 g. Overall recurrence rate for preeclampsia was 29% at a mean gestational age of 32 weeks. Thirty-eight women had an uncomplicated pregnancy (53%). The women with chronic hypertension had the highest recurrence rate of 38%. Neonatal mortality was 4%. CONCLUSION: The course of subsequent pregnancies after mid-trimester termination for preeclampsia is uncomplicated in 53% with a recurrence rate for preeclampsia of 29%. The mean gestational age at delivery was 11 weeks later and birth weight 2000 g higher than in the index pregnancy.

Which Factors Contribute to False-Positive, False-Negative, and Invalid Results in Fetal Fibronectin Testing in Women with Symptoms of Preterm Labor?

Objective We assessed the influence of external factors on false-positive, false-negative, and invalid fibronectin results in the prediction of spontaneous delivery within 7 days. Methods We studied symptomatic women between 24 and 34 weeks' gestational age. We performed uni- and multivariable logistic regression to estimate the effect of external factors (vaginal soap, digital examination, transvaginal sonography, sexual intercourse, vaginal bleeding) on the risk of false-positive, false-negative, and invalid results, using spontaneous delivery within 7 days as the outcome. Results Out of 708 women, 237 (33%) had a false-positive result; none of the factors showed a significant association. Vaginal bleeding increased the proportion of positive fetal fibronectin (fFN) results, but was significantly associated with a lower risk of false-positive test results (odds ratio [OR], 0.22; 95% confidence intervals [CI], 0.12-0.39). Ten women (1%) had a false-negative result. None of the investigated factors was significantly associated with a significantly higher risk of false-negative results. Twenty-one tests (3%) were invalid; only vaginal bleeding showed a significant association (OR, 4.5; 95% CI, 1.7-12). Conclusion The effect of external factors on the performance of qualitative fFN testing is limited, with vaginal bleeding as the only factor that reduces its validity.

Comparison of the Actim Partus test and the fetal fibronectin test in the prediction of spontaneous preterm birth in symptomatic women undergoing cervical length measurement.

OBJECTIVE: To compare the accuracy of the Actim Partus test and fetal fibronectin (fFN) test in the prediction of spontaneous preterm delivery within seven days in symptomatic women undergoing cervical length measurement. STUDY DESIGN: We performed a post-hoc analysis on frozen samples of a nationwide cohort study in all 10 perinatal centres in the Netherlands. We selected samples from women with signs of preterm labour between 24 and 34 weeks of gestational age and a cervical length below 30mm. Delivery within seven days after initial assessment was the primary endpoint. We calculated sensitivity, specificity, and positive and negative predictive values for the combination of both the Actim Partus test and fFN test with cervical length. A test was considered positive in case of a cervical length between 15 and 30mm with a positive Actim Partus or fFN test, and a cervical length below 15mm regardless the test result. RESULTS: In total, samples of 350 women were tested, of whom 69 (20%) delivered within seven days. Eighty-four women had a positive Actim Partus test and 162 women a positive fFN test, of whom 54 (64%) and 63 (39%) delivered within seven days, respectively. Ninety-seven women had a cervical length below 15mm, of whom 50 (52%) delivered within seven days. Sensitivity, specificity, positive and negative predictive values of combining cervical length with the Actim Partus test or the fFN test were 91%, 75%, 47% and 97%, and 96%, 58%, 36% and 98%, respectively. CONCLUSION: According to this post-hoc study, in combination with cervical length, the Actim Partus test could be used as an alternative for the fFN test to identify women who will not deliver within seven days after presentation. Further evidence should be collected in a prospective comparative study.

Terminating pregnancy for severe hypertension when the fetus is considered non-viable: a retrospective cohort study.

OBJECTIVE: To investigate frequency and practise of termination of pregnancy for early-onset hypertensive disorders where the fetus is considered to be non-viable. STUDY DESIGN: Retrospective cohort study in all Dutch tertiary perinatal care centres (n=10), between January 2000 and January 2014. All women who underwent termination of pregnancy, without fetal surveillance or intention to intervene for fetal reasons, for early-onset hypertensive disorders in pregnancy, were analyzed. Women eligible for this study were identified in the local delivery databases. Medical records were used to collect relevant data. RESULTS: Between January 2000 and January 2014, 2,456,584 women delivered in The Netherlands, of which 238,448 (9.7%) in a tertiary care centre. A total of 161 pregnancy terminations (11-12 per year) for severe early-onset preeclampsia were identified, including 6 women with a twin pregnancy. Mean gestational age at termination was 172 days (GA 244/7)±9.4 days. In 70% of cases termination was performed at or shortly after 24 weeks' gestation. 74.5% of women developed HELLP syndrome (n=96), eclampsia (n=10) or needed admission to an ICU (n=14). Birth weight was below 500g in 64% of cases. In 69% of the cases the estimated fetal weight was within a 10% margin of the actual birth weight. CONCLUSION: Termination of pregnancy for early-onset hypertensive disorders without intervention for fetal indication occurs approximately 12 times per year in The Netherlands. More data are needed to investigate contemporary best practice regarding termination of pregnancy for early-onset hypertensive indications at the limits of fetal viability. Considering the frequency of maternal complications, termination of pregnancy and not expectant management should be considered for all women presenting with severe early onset hypertensive disorders at the limits of fetal viability.

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.

Phase-rectified signal averaging method to predict perinatal outcome in infants with very preterm fetal growth restriction- a secondary analysis of TRUFFLE-trial.

BACKGROUND: Phase-rectified signal averaging, an innovative signal processing technique, can be used to investigate quasi-periodic oscillations in noisy, nonstationary signals that are obtained from fetal heart rate. Phase-rectified signal averaging is currently the best method to predict survival after myocardial infarction in adult cardiology. Application of this method to fetal medicine has established significantly better identification than with short-term variation by computerized cardiotocography of growth-restricted fetuses. OBJECTIVE: The aim of this study was to determine the longitudinal progression of phase-rectified signal averaging indices in severely growth-restricted human fetuses and the prognostic accuracy of the technique in relation to perinatal and neurologic outcome. STUDY DESIGN: Raw data from cardiotocography monitoring of 279 human fetuses were obtained from 8 centers that took part in the multicenter European "TRUFFLE" trial on optimal timing of delivery in fetal growth restriction. Average acceleration and deceleration capacities were calculated by phase-rectified signal averaging to establish progression from 5 days to 1 day before delivery and were compared with short-term variation progression. The receiver operating characteristic curves of average acceleration and deceleration capacities and short-term variation were calculated and compared between techniques for short- and intermediate-term outcome. RESULTS: Average acceleration and deceleration capacities and short-term variation showed a progressive decrease in their diagnostic indices of fetal health from the first examination 5 days before delivery to 1 day before delivery. However, this decrease was significant 3 days before delivery for average acceleration and deceleration capacities, but 2 days before delivery for short-term variation. Compared with analysis of changes in short-term variation, analysis of (delta) average acceleration and deceleration capacities better predicted values of Apgar scores <7 and antenatal death (area under the curve for prediction of antenatal death: delta average acceleration capacity, 0.62 [confidence interval, 0.19-1.0]; delta short-term variation, 0.54 [confidence interval, 0.13-0.97]; P=.006; area under the curve for prediction Apgar <7: average deceleration capacity <24 hours before delivery, 0.64 [confidence interval, 0.52-0.76]; short-term variation <24 hours before delivery, 0.53 [confidence interval, 0.40-0.65]; P=.015). Neither phase-rectified signal averaging indices nor short-term variation showed predictive power for developmental disability at 2 years of age (Bayley developmental quotient, <95 or <85). CONCLUSION: The phase-rectified signal averaging method seems to be at least as good as short-term variation to monitor progressive deterioration of severely growth-restricted fetuses. Our findings suggest that for short-term outcomes such as Apgar score, phase-rectified signal averaging indices could be an even better test than short-term variation. Overall, our findings confirm the possible value of prospective trials based on phase-rectified signal averaging indices of autonomic nervous system of severely growth-restricted fetuses.

Fetal fibronectin status and cervical length in women with threatened preterm labor and the effectiveness of maintenance tocolysis.

OBJECTIVE: To assess the effect of maintenance tocolysis in women who are at high or low risk for preterm delivery according to fetal fibronectin (fFN) status and cervical length (CL). STUDY DESIGN: We compared the risk of preterm delivery in fFN pos and fFN neg women and in women with a CL <15 mm and ≥15 mm, by using the Cox regression. Differences between the effectiveness of maintenance tocolysis in high- and low-risk women were assessed by using an interaction term. RESULTS: 122 fFN tests were taken, of which 50 were fFN pos. CL was measured in 236 women, of whom 52 women had a CL <15 mm. The median gestational age at delivery was lower in fFN pos women; fFN pos women had a higher hazard for preterm delivery at any point of time (HR 4.7; 95% CI 2.9 to 7.6). Comparable results were seen for CL. Neither fFN status nor CL did alter the effect of maintenance tocolysis, which was ineffective in the total randomized group, on the risk of preterm delivery (p for interaction = 0.87 for fFN and 0.18 for CL). CONCLUSION: Maintenance tocolytic therapy with nifedipine is ineffective and not dependent on fFN or CL status.

Predictive Factors for Delivery within 7 Days after Successful 48-Hour Treatment of Threatened Preterm Labor.

Objective The aim of this study was to assess which characteristics and results of vaginal examination are predictive for delivery within 7 days, in women with threatened preterm labor after initial treatment. Study Design A secondary analysis of a randomized controlled trial on maintenance nifedipine includes women who remained undelivered after threatened preterm labor for 48 hours. We developed one model for women with premature prelabor rupture of membranes (PPROM) and one without PPROM. The predictors were identified by backward selection. We assessed calibration and discrimination and used bootstrapping techniques to correct for potential overfitting. Results For women with PPROM (model 1), nulliparity, history of preterm birth, and vaginal bleeding were included in the multivariable analysis. For women without PPROM (model 2), maternal age, vaginal bleeding, cervical length, and fetal fibronectin (fFN) status were in the multivariable analysis. Discriminative capability was moderate to good (c-statistic 0.68; 95% confidence interval [CI] 0.60-0.77 for model 1 and 0.89; 95% CI, 0.84-0.93 for model 2). Conclusion PPROM and vaginal bleeding in the current pregnancy are relevant predictive factors in all women, as are maternal age, cervical length, and fFN in women without PPROM and nulliparity, history of preterm birth in women with PPROM.

Prescribing patterns of antenatal corticosteroids in women with threatened preterm labor.

OBJECTIVE: To assess the impact of cervical length (CL) measurement and fetal fibronectin testing (fFN) on the clinicians' decision to prescribe antenatal corticosteroids (ACS) to women with symptoms of preterm labor. STUDY DESIGN: This is a secondary analysis of a prospective cohort study including women with symptoms of preterm labor and intact membranes between 24 and 34 weeks' gestation. We compared the proportion prescribed and completed ACS courses, preterm delivery within seven days and median intervals from ACS to delivery in four groups: group 1 CL<10 mm, group 2 CL 10-30 mm and positive fFN, group 3 CL 10-30 mm and negative fFN, group 4 CL>30 mm. RESULTS: ACS were prescribed to 63/65 (97%) women in group 1, 176/192 (91%) in group 2, 111/172 women (65%) in group 3 and 55/242 (23%) in group 4. In group 1, 42 (65%) women delivered within seven days, compared to 34 (18%) in group 2, 6 (3%) in group 3 and 3 (1%) in group 4. Median intervals between ACS and delivery were 6 days (IQR 3-61 days), 44 days (IQR 17-69 days), 53 days (IQR 37-77 days) and 66 days (IQR 43-78 days) in group 1, 2, 3 and 4 respectively. CONCLUSION: ACS were prescribed frequently to women with a CL of 10-30 mm and a negative fFN test or a CL>30 mm. There is room for improvement in the prescription of ACS in these low risk women.

Randomized comparison of nifedipine and placebo in fibronectin-negative women with symptoms of preterm labor and a short cervix (APOSTEL-I Trial).

OBJECTIVE: To evaluate whether tocolysis with nifedipine can be omitted in women with symptoms of preterm labor, a shortened cervix, and negative fetal fibronectin test. STUDY DESIGN: A randomized noninferiority trial was performed in all Dutch perinatal centers. Women with symptoms of preterm labor between 24 and 34 weeks, intact membranes, cervical length between 10 and 30 mm, and negative fibronectin test were randomly allocated to nifedipine (80 mg/day) or placebo. The primary outcome was delivery within 7 days. Secondary outcomes were severe neonatal morbidity and mortality. We also followed all eligible nonrandomized women. RESULTS: We allocated 37 women to nifedipine and 36 women to placebo. In the nifedipine group, three women (8.1%) delivered within 7 days, compared with one woman (2.8%) in the placebo group (difference -5.3%; one-sided 95% confidence limit 4.5%). Median gestational age at delivery were respectively 37 + 0 (interquartile range [IQR] 34 + 6 to 38 + 5) and 38 + 2 (IQR 37 + 0 to 39 + 6) weeks (p = 0.008). In the nifedipine group, three pregnancies (8.1%) had a poor outcome; there were no poor outcomes in the placebo group. We observed similar trends in eligible nonrandomized women. CONCLUSION: In symptomatic women with preterm labor, a shortened cervix, and negative fibronectin test, placebo treatment is not inferior to tocolysis with nifedipine.

Novel cardiovascular biomarkers in women with a history of early preeclampsia.

OBJECTIVE: Women with a history of preeclampsia are at increased risk for future cardiovascular disease. Determination of cardiovascular biomarkers may be useful to understand the pathophysiological mechanism of cardiovascular disease development in these women. METHODS: We performed an analysis in the Preeclampsia Risk EValuation in FEMales study, a retrospective cohort consisting of 339 women with a history of early preeclampsia and 332 women after normotensive pregnancy. Women attended a follow-up visit ten years after the index pregnancy. A subset of 8 different cardiovascular biomarkers was investigated, reflecting inflammatory, metabolic, thrombotic and endothelial function markers. Associations between PE and these novel biomarkers were analyzed by linear regression analysis and adjusted for traditional cardiovascular risk factors. RESULTS: Mean age of 671 women of the PREVFEM cohort was 39 years and women were on average 10 years post index pregnancy. Women post preeclampsia had significantly higher levels of SE-selectin (adjusted difference 4.55, 99%CI 0.37; 8.74) and PAPPA (adjusted difference 19.08; 99%CI 13.18; 24.99), whereas ApoB (adjusted difference -0.23 99%CI -0.32; -0.14) was inversely associated with preeclampsia, compared to women with a previous normotensive pregnancy. Adiponectin, leptin, sICAM-1, sVCAM-1 and PAI-1 were not different between both groups. CONCLUSION: We demonstrated an independent association of preeclampsia with SE-selectin and PAPPA (markers of vascular dysfunction), which may contribute to future cardiovascular events in women post preeclampsia. However, ApoB (an apolipoprotein) was significantly lower and could point at a protective mechanism in our PE study women.

Predictive value of cervical length measurement and fibronectin testing in threatened preterm labor.

OBJECTIVE: To estimate the performance of combining cervical length measurement with fetal fibronectin testing in predicting delivery in women with symptoms of preterm labor. METHODS: We conducted a prospective nationwide cohort study in all 10 perinatal centers in The Netherlands. Women with symptoms of preterm labor between 24 and 34 weeks of gestation with intact membranes were included. In all women, qualitative fibronectin testing (0.050-microgram/mL cutoff) and cervical length measurement were performed. Logistic regression was used to predict spontaneous preterm delivery within 7 days after testing. A risk less than 5%, corresponding to the risk for women with a cervical length of at least 25 mm, was considered as low risk. RESULTS: Between December 2009 and August 2012, 714 women were enrolled. Fibronectin results and cervical length were available for 665 women, of whom 80 (12%) delivered within 7 days. Women with a cervical length of at least 30 mm or with a cervical length between 15 and 30 mm with a negative fibronectin result were at low risk (less than 5%) of spontaneous delivery within 7 days. Fibronectin testing in case of a cervical length between 15 and 30 mm additionally classified 103 women (15% of the cohort) as low risk and 36 women (5% of the cohort) as high risk. CONCLUSION: Cervical length measurement, combined with fetal fibronectin testing in case of a cervical length between 15 and 30 mm, improves identification of women with a low risk to deliver spontaneously within 7 days. LEVEL OF EVIDENCE: II.

Prediction of preterm birth in multiple pregnancies: development of a multivariable model including cervical length measurement at 16 to 21 weeks' gestation.

OBJECTIVE: To develop a multivariable prognostic model for the risk of preterm delivery in women with multiple pregnancy that includes cervical length measurement at 16 to 21 weeks' gestation and other variables. METHODS: We used data from a previous randomized trial. We assessed the association between maternal and pregnancy characteristics including cervical length measurement at 16 to 21 weeks' gestation and time to delivery using multivariable Cox regression modelling. Performance of the final model was assessed for the outcomes of preterm and very preterm delivery using calibration and discrimination measures. RESULTS: We studied 507 women, of whom 270 (53%) delivered < 37 weeks (preterm) and 66 (13%) < 32 weeks (very preterm). Women with cervical length < 30 mm delivered more often preterm (hazard ratio 1.9; 95% CI 0.7 to 4.8). Other independently contributing predictors were previous preterm delivery, monochorionicity, smoking, educational level, and triplet pregnancy. Prediction models for preterm and very preterm delivery had a c-index of 0.68 (95% CI 0.63 to 0.72) and 0.68 (95% CI 0.62 to 0.75), respectively, and showed good calibration. CONCLUSION: In women with a multiple pregnancy, the risk of preterm delivery can be assessed with a multivariable model incorporating cervical length and other predictors.

Objectif : Élaborer un modèle pronostique multivarié (comportant la mesure de la longueur cervicale à 16 - 21 semaines de gestation et d'autres variables) pour ce qui est du risque d'accouchement préterme chez les femmes connaissant une grossesse multiple. Méthodes : Nous avons utilisé les données issues d'un essai randomisé précédent. Nous avons évalué l'association entre les caractéristiques maternelles et de grossesse (dont la mesure de la longueur cervicale à 16 - 21 semaines de gestation et le délai avant l'accouchement) au moyen du modèle de régression multivariée de Cox. Le rendement du modèle final a été évalué en fonction de critères d'évaluation traitant du moment de l'accouchement (préterme et très préterme) au moyen de mesures d'étalonnage et de discrimination. Résultats : Nous avons étudié 507 femmes, dont 270 (53 %) ont accouché < 37 semaines (préterme) et 66 (13 %) < 32 semaines (très préterme). Les femmes qui présentaient une longueur cervicale < 30 mm ont plus souvent connu un accouchement préterme (densité de l'incidence, 1,9; IC à 95 %, 0,7 - 4,8). Parmi les autres facteurs prédictifs indépendants, on trouvait les antécédents d'accouchement préterme, la monochorionicité, le tabagisme, le niveau de scolarité et la présence d'une grossesse triple. Les modèles prédictifs pour ce qui est des accouchements préterme et très préterme comptaient un indice C de 0,68 (IC à 95 %, 0,63 - 0,72) et de 0,68 (IC à 95 %, 0,62 - 0,75), respectivement, et présentaient un bon étalonnage. Conclusion : Chez les femmes qui connaissent une grossesse multiple, le risque d'accouchement préterme peut être évalué au moyen d'un modèle multivarié comportant la mesure de la longueur cervicale et d'autres facteurs prédictifs. 

Effect of maintenance tocolysis with nifedipine in threatened preterm labor on perinatal outcomes: a randomized controlled trial.

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 rate of adverse perinatal outcomes in the control group indicates that a benefit of nifedipine cannot completely be excluded, its use for maintenance tocolysis does not appear beneficial at this time. TRIAL REGISTRATION: trialregister.nl Identifier: NTR1336.

Electrocardiographic parameters in women ten years post-early preeclampsia.

OBJECTIVE: Women with a history of preeclampsia are at increased risk to develop cardiovascular disease (CVD) later in life, especially hypertension is common. In this study we aimed to evaluate electrocardiographic parameters as a proxy for detrimental hypertensive effects and later CVD. METHODS: The Preeclampsia Risk EValuation study in FEMales (PREVFEM) study is a prospective cohort study consisting of 339 women with a history of early onset preeclampsia (EOP) and 332 age-matched women without a history if EOP as reference. At ten years post index pregnancy a 12-lead electrocardiogram recording was made. RESULTS: There were no significant differences in ECG parameters between both groups at 3 9years of age. In our cohort of young women SBP (OR(mmHg): 1.04; 95% CI: 1.2-1.06) as well as DBP (OR(mmHg): 1.04; 95% CI: 1.01-1.07) and stage 2 hypertension (OR: 3.35; 95% CI: 1.16-9.63) were significantly associated with ECG criteria for LVH, but not for other ECG abnormalities. EOP gives no significant adjusted risk on ECG abnormalities compared to women without EOP. CONCLUSION: EOP is no significant predictor of non-specific ECG abnormalities. Routine ECG screening in young women after preeclampsia is not recommended in non-hypertensive women, but may be useful when hypertension is present.

Cardiovascular risk factors in women 10 years post early preeclampsia: the Preeclampsia Risk EValuation in FEMales study (PREVFEM).

INTRODUCTION: Preeclampsia is a complication of pregnancy and a known risk factor for cardiovascular disease (CVD) later in a women's life. The best approach for prevention of CVD in affected young women is yet unclear. We sought to investigate the prevalence of cardiovascular risk factors in women at 10 years post preeclampsia in comparison with a reference group. METHODS: Women with a history of early preeclampsia (exposed), DBP ≥ 90 mmHg with proteinuria ≥ 0.3 gram/24 h before 32 weeks of gestation, and an equal number of women after uncomplicated pregnancy (non-exposed) from the obstetric database of 1991-2007, were sent a questionnaire and invited for a cardiovascular screening programme. RESULTS: The current study included 339 exposed women and 332 non-exposed women, 10 years post index-pregnancy. Systolic and diastolic blood pressures (SBP/DBP) were 127/86 mmHg versus 119/79 mmHg in the exposed and reference group respectively (p < 0.001). Exposure to early preeclampsia was associated with a threefold increased prevalence of hypertension (adjusted odds ratio (OR) 3.59, 95%CI 2.48-5.20). BMI and waist circumference were 26.9 kg/m(2) and 86.5 cm in the exposed group and 26.2 kg/m(2) (p = 0.07) and 83 cm (p = 0.001) in the non-exposed group. We found no differences in levels of glucose, lipids and CRP. Adjusted OR for the metabolic syndrome in women post preeclampsia was 2.18 (95% CI 1.34-3.52) compared with women in the reference group. CONCLUSION: We found a high prevalence of hypertension in young women at 10 years post early preeclampsia. More research on the timing of cardiovascular screening in these high-risk women is needed.