Tocolysis compared with no tocolysis in women with threatened preterm birth and ruptured membranes: A propensity score analysis.

INTRODUCTION: In women with preterm ruptured membranes and contractions, the administration of tocolysis is controversial. This study compares tocolysis with no tocolysis in women with threatened preterm birth and ruptured membranes. OBJECTIVE: To compare tocolysis with no tocolysis in women with threatened preterm birth and ruptured membranes. STUDY DESIGN: Data from the APOSTEL III RCT was combined with data from the National Maternity Hospital, Dublin. In the APOSTEL III trial, women with threatened preterm birth were randomized to atosiban or nifedipine. Patient data from Ireland were obtained from a cohort of women with threatened preterm birth with ruptured membranes. The Irish women received no tocolytic treatment. Only women with ruptured membranes and contractions were selected. We studied women with singleton or twin pregnancies and a gestational age between 25+0 and 33+6 weeks. Propensity score matching was performed to create comparable groups. Primary outcome was a composite adverse neonatal outcome. Secondary outcomes were individual components of the primary outcome, as well as neonatal intensive care unit (NICU) admission, gestational age at delivery, prolongation of pregnancy and mode of delivery. RESULTS: 153 women from the Apostel III trial were compared with 51 eligible women of the Irish cohort. We could match 46 women who received tocolysis and 46 women who received no tocolysis. All women had ruptured membranes. Maternal age, BMI, parity and gestational age at study entry were comparable between the groups after matching. There were no statistically significant differences in neonatal composite outcome (9.6 % in the tocolysis group versus 18 % in the control group, OR 0.46, 95 % CI 0.13-1.63). We found a lower incidence of NICU admission in the tocolysis group (63 %) than in the control group (94 %; OR 0.11, 95 % CI 0.03-0.41), which could be explained by differences in national admission policies. There were no statistically significant differences between tocolysis and no tocolysis in any of the other outcomes including sepsis, gestational age at delivery and time to delivery. CONCLUSION: In this propensity score analysis of women with threatened preterm birth and ruptured membranes, tocolytic therapy did not alter composite adverse neonatal outcome or time to delivery.

Effects of tocolysis with nifedipine or atosiban on child outcome: follow-up of the APOSTEL III trial.

OBJECTIVE: To compare the long-term effects of tocolysis with nifedipine or atosiban on child outcome at age 2.5-5.5 years. DESIGN: The APOSTEL III trial was a multicentre randomised controlled trial that compared tocolysis with nifedipine or atosiban in 503 women with threatened preterm birth. Neonatal outcomes did not differ between both treatment arms, except for a higher incidence of intubation in the atosiban group. METHODS: Parents were asked to complete four questionnaires regarding neurodevelopment, executive function, behaviour problems and general health. MAIN OUTCOME MEASURES: The main long-term outcome measure was a composite of abnormal development at the age of 2.5-5.5 years. RESULTS: Of the 426 women eligible for follow-up, 196 (46%) parents returned the questionnaires for 115 children in the nifedipine group and 110 children in the atosiban group. Abnormal development occurred in 32 children (30%) in the nifedipine group and in 38 children (38%) in the atosiban group (OR 0.74, 95% CI 0.41-1.34). The separate outcomes for neurodevelopment, executive function, behaviour, and general health showed no significant differences between the groups. Sensitivity analysis for all children of the APOSTEL III trial, including a comparison of deceased children, resulted in a higher rate of healthy survival in the nifedipine group (64 versus 54%), but there was no significant difference in the overall mortality rate (5.4 versus 2.7%). There were no significant subgroup effects. CONCLUSION: Outcomes on broad child neurodevelopment, executive function, behaviour and general health were comparable in both groups. Neither nifedipine nor atosiban can be considered as the preferred treatment for women with threatened preterm birth. TWEETABLE ABSTRACT: Nifedipine- and atosiban-exposed children had comparable long-term outcomes, including neurodevelopment, executive function and behaviour.

Follow-up ultrasound in second-trimester low-positioned anterior and posterior placentae: prospective cohort study.

OBJECTIVES: The majority of cases of placenta previa or a low-lying placenta in the second trimester will have a normal placental position in the third trimester. The aim of this study was to assess the accuracy of the distance between the placenta and the internal os of the cervix (IOD) in the second trimester for the prediction of third-trimester low-positioned placenta, and to define a cut-off value at which all cases of third-trimester low-positioned placenta are identified. METHODS: This was a prospective cohort study including women undergoing a transvaginal ultrasound examination between 18 and 24 weeks' gestation who had a low-positioned placenta, defined as an IOD of < 20 mm. Low-positioned placenta included placenta previa, defined as a placenta covering the internal os of the cervix, and a low-lying placenta, defined as a placenta lying near to (within 20 mm) but not overlying the internal os. All women were re-evaluated in the third trimester. Relative risks for a low-positioned placenta in the third trimester were calculated for women with placenta previa vs a low-lying placenta, posterior vs anterior placenta and positive vs negative history of Cesarean section. Multilevel likelihood ratios for ranges of IOD in the prediction of a low-positioned placenta in the third trimester were calculated separately for anteriorly and posteriorly located placentae. Corresponding receiver-operating-characteristics curves were constructed. RESULTS: In total, 958 women were included in the study. In the second trimester, placentae were more frequently located on the posterior side (62.0%) than on the anterior side (38.0%). In the third trimester, 48/958 (5.0%) placentae persisted as a low-positioned placenta. Women with placenta previa in the second trimester had a higher risk of a low-positioned placenta in the third trimester than did those with a low-lying placenta in the second trimester (37/181 (20.4%) vs 11/777 (1.4%); relative risk (RR), 17.9 (95% CI, 8.9-36.0)). Women with a posterior placenta had a higher risk of a low-positioned placenta in the third trimester than did those with an anterior placenta (38/594 (6.4%) vs 10/364 (2.7%); RR, 2.4 (95% CI, 1.2-4.9)), as did women with a history of Cesarean section compared with those without such a history (14/105 (13.3%) vs 34/853 (4.0%); RR, 3.7 (95% CI, 1.9-7.2)). The cut-off value of IOD in the second trimester to identify all cases of an abnormally located placenta in the third trimester was 15.5 mm for posteriorly located placentae, while for anteriorly located placentae the IOD cut-off was lower, namely -4.5 mm, representing a 4.5-mm overlap of the placental edge over the internal os of the cervix. CONCLUSIONS: With incorporation of a safety margin of 5 mm and ensuring that all women with placenta previa undergo a follow-up scan, we recommend lowering the IOD cut-off value for follow-up in cases of an anterior low-positioned placenta from 20 to 5 mm, which would decrease the number of unnecessary follow-up ultrasound examinations without missing any high-risk women. © 2019 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Influence of cut-off value on prevalence of short cervical length.

OBJECTIVE: To assess the distribution of cervical length (CL) in a large cohort of asymptomatic low-risk women with singleton pregnancy and no previous preterm birth and to explain the low prevalence of short CL ≤ 30 mm in this cohort. METHODS: This was a secondary analysis of a multicenter cohort study with an embedded randomized controlled trial (Triple P trial; NTR-2078) on the prevention of preterm birth with progesterone. In the cohort study, CL was measured in asymptomatic low-risk women with singleton pregnancy to investigate its predictive capacity to identify those at increased risk for preterm birth. A short CL was defined by a cut-off value of ≤ 30 mm, based on existing literature. Women with a short CL were subsequently included in a randomized controlled trial evaluating the effect of progesterone, compared with placebo, on preterm birth. In total, 57 centers and 20 234 women participated in the study. Normal distributions for CL were simulated based on the mean and SD of the original data. The distribution of CL was assessed for each individual center and measurements were compared between levels of care: primary (29 ultrasound centers), secondary (21 general hospitals) and tertiary (seven university medical centers) care institutions. Comparison was also performed between centers with low, intermediate and high volume of CL measurements. CL distributions before (n = 12 284 women) and after (n = 7950 women) a national symposium, at which the prevalence of short CL measurements was addressed publicly, were analyzed. RESULTS: Between November 2009 and August 2013, 20 234 women had CL measurements, of whom 367 (1.8%) had a short CL. Mean ± SD CL was 44.2 ± 7.8 mm. A 'dip' in the distribution of CL measurements between 20 and 30 mm was observed, defined by a ratio of < 50% when comparing the number of measurements in observed and simulated normal distributions. The dip was present in 89% of participating centers. All centers showed a dip in the distribution of measurements ≤ 30 mm when analyzed according to the level of care and volume of measurements. A significant difference was found when comparing the distribution before and after publicly addressing the low prevalence of short CL (1.7% vs 2.0% of measurements were ≤ 30 mm, respectively; P < 0.001). CONCLUSIONS: A cut-off value of 30 mm for CL was used to include women in a randomized clinical trial that was embedded in a cohort study. We suggest that the use of a predefined cut-off value for a short cervix influences the distribution of the CL measurements. Since the measurement is not blinded, preference of assessors for the control or intervention arms may have introduced selection bias. This might have resulted in fewer measurements around the cut-off value. Other trials using similar designs could benefit from this observation and take precautions to avoid selection bias. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Midpregnancy Cervical Length in Nulliparous Women and its Association with Postterm Delivery and Intrapartum Cesarean Delivery.

OBJECTIVE: To evaluate the association between midpregnancy cervical length and postterm delivery and cesarean delivery during labor. STUDY DESIGN: In a multicenter cohort study, cervical length was measured in low-risk singleton pregnancies between 16 and 22 weeks of gestation. From this cohort, we identified nulliparous women who delivered beyond 34 weeks and calculated cervical length quartiles. We performed logistic regression to compare the risk of postterm delivery and intrapartum cesarean delivery to cervical length quartiles, using the lowest quartile as a reference. We adjusted for induction of labor, maternal age, ethnicity, cephalic position, preexisting hypertension, and gestational age at delivery. RESULTS: We studied 5,321 nulliparous women. Women with cervical length in the 3rd and 4th quartile were more likely to deliver at 42(+0) to 42(+6) weeks (adjusted odds ratio [aOR] 2.02, 95% confidence interval [CI] 1.07-3.79 and aOR 1.97, 95% CI 1.06-3.67, respectively). The frequency of intrapartum cesarean delivery increased with cervical length quartile from 9.4% in the 1st to 14.9% in the 4th quartile (p = 0.01). This increase was only present in intrapartum cesarean delivery because of failure to progress and not because of fetal distress. CONCLUSION: The longer the cervix at midtrimester the higher the risk of both postterm delivery and intrapartum cesarean delivery.

Is cervical length associated with maternal characteristics?

OBJECTIVE: Women with a mid-trimester short cervical length (CL) are at increased risk for preterm delivery. Consequently, CL measurement is a potential screening tool to identify women at risk for preterm birth. Our objective was to assess possible associations between CL and maternal characteristics. STUDY DESIGN: A nationwide screening study was performed in which CL was measured during the standard anomaly scan among low risk women with a singleton pregnancy. Data on maternal height, pre-pregnancy weight, ethnicity, parity and gestational age at the time of the CL measurement were collected from January 2010 to December 2012. Univariable and multivariable linear regression analyses were performed to assess the relationship between CL and maternal characteristics. RESULTS: We included 5092 women. The mean CL was 44.3mm. No association was found between CL and maternal height or gestational age of the measurement. Maternal weight was associated with CL (p=0.007, adjusted R(2) 0.03). Separate analysis for BMI did not change these results. Ethnicity, known in 2702 out of 5092 women, was associated with CL (mean CL in Caucasian women 45.0mm, Asian 43.9mm, Mediterranean 43.1mm, and African 41.8mm, p=0.003), as well as parity (mean CL multiparous 45.3mm, nulliparous 43.5mm, p<0.0001). CONCLUSION: Shorter mid-trimester cervical length is associated with higher maternal weight, younger maternal age, nulliparity and non-Caucasian ethnicity, but not with maternal height.

Influence of the 20-week anomaly scan on prenatal diagnosis and management of fetal facial clefts.

OBJECTIVE: To investigate trends in prenatal diagnosis and termination of pregnancy rates in cases of fetal cleft lip with or without cleft palate (CL ± P), before and after the introduction in The Netherlands of the 20-week anomaly scan in 2007, and to assess the accuracy of this scan for the diagnosis of facial clefts. METHODS: This was a retrospective cohort study of consecutive cases of CL ± P diagnosed in 2001-2010 in the referral region of the Academic Medical Centre. Cases diagnosed prenatally were identified from the hospital's database. These data, grouped according to the periods before and after the introduction of the routine 20-week anomaly scan, were compared with data of all cases managed by the multidisciplinary cleft team, which services the same region, to identify cases of CL ± P that were not seen prenatally. RESULTS: We identified 123 cases of CL ± P diagnosed prenatally, of which 76% (93/123) were diagnosed before 24 weeks. In one case, the CL ± P was not confirmed after birth. There were 46 cases with associated structural anomalies and 76 isolated cases. The median gestational age at diagnosis decreased by 2 weeks after 2007 (P = 0.02). The proportion of isolated clefts detected prenatally increased significantly after 2007 (P < 0.0001), whereas the proportion of associated clefts remained stable over the years (P = 0.426). The overall detection rate of CL ± P increased from 43% before 2007 to 86% after 2007 (P < 0.0001), without an increase in terminations of pregnancy. CONCLUSION: Introduction of the routine fetal anomaly scan has decreased the gestational age at diagnosis of CL ± P and has increased the proportion diagnosed prenatally, without a significant change in the number of terminations of pregnancy.

Value of adding second-trimester uterine artery Doppler to patient characteristics in identification of nulliparous women at increased risk for pre-eclampsia: an individual patient data meta-analysis.

OBJECTIVE: To investigate the value of adding second-trimester uterine artery Doppler ultrasound to patient characteristics in the identification of nulliparous women at risk for pre-eclampsia. METHODS: For this individual patient data meta-analysis, studies published between January 1995 and December 2009 were identified in MEDLINE and EMBASE. Studies were eligible in which Doppler assessment of the uterine arteries had been performed among pregnant women and in which gestational age at ultrasound, Doppler ultrasound findings and data on the occurrence of pre-eclampsia were available. We invited corresponding authors to share their original datasets. Data were included of nulliparous women who had had a second-trimester uterine artery Doppler ultrasound examination. Shared data were checked for consistency, recoded to acquire uniformity and merged into a single dataset. We constructed random intercept logistic regression models for each of the patient and Doppler characteristics in isolation and for combinations. We compared goodness of fit, discrimination and calibration. RESULTS: We analyzed eight datasets, reporting on 6708 nulliparous women, of whom 302 (4.5%) developed pre-eclampsia. Doppler findings included higher, lower and mean pulsatility index (PI) and resistance index (RI) and any or bilateral notching. Of these, the best predictors were combinations of mean PI or RI and bilateral notching, with areas under the receiver-operating characteristics curve (AUC) of 0.75 (95% confidence interval (CI), 0.56-0.95) and 0.70 (95% CI, 0.66-0.74), respectively. Addition of Doppler findings to the patient characteristics blood pressure or body mass index (BMI) significantly improved discrimination. A model with blood pressure, PI and bilateral notching had an AUC of 0.85 (95% CI, 0.67-1.00). CONCLUSIONS: The addition of Doppler characteristics of mean PI or RI and bilateral notching to patient characteristics of blood pressure or BMI improves the identification of nulliparous women at risk for pre-eclampsia.

Is short first-trimester crown-rump length associated with spontaneous preterm birth?

OBJECTIVE: To assess the association between first-trimester crown-rump length (CRL) and the risk of spontaneous preterm birth before 32 weeks' gestation. METHODS: We performed a matched case-control study of 129 women with spontaneous preterm birth at < 32 weeks' gestation (cases) and 129 women with term deliveries (controls) using data stored in the ultrasound and obstetric databases of our tertiary referral center. Cases and controls were individually matched based on maternal age, parity, history of preterm birth and medical indication for antenatal care. Fetal CRL measured between 8 + 0 and 13 + 6 weeks was expressed as multiples of the median (MoM) expected CRL, based on last menstrual period. We investigated the association between CRL-MoM and spontaneous preterm birth using logistic regression analysis. RESULTS: CRL-MoM was not associated with spontaneous preterm birth: odds ratio (OR) 1.10 (95% CI, 0.89-1.36) per 0.10 MoM increase in CRL. Timing of measurement did not influence the model (P = 0.59). This was confirmed when restricting the analysis to the 93 pairs with CRL measurements made between 10 + 0 and 13 + 6 weeks: OR for preterm birth 1.07 (95% CI, 0.83-1.37) per 0.10 MoM increase in CRL. CONCLUSION: A short CRL in the first trimester is not associated with spontaneous preterm birth before 32 weeks' gestation, thus short CRL cannot be used to identify women at increased risk of preterm birth.

Accuracy of circulating placental growth factor, vascular endothelial growth factor, soluble fms-like tyrosine kinase 1 and soluble endoglin in the prediction of pre-eclampsia: a systematic review and meta-analysis.

BACKGROUND: Biomarkers have been proposed for identification of women at increased risk of developing pre-eclampsia. OBJECTIVES: To investigate the capacity of circulating placental growth factor (PlGF), vascular endothelial growth factor (VEGF), soluble fms-like tyrosine kinase-1 (sFLT1) and soluble endoglin (sENG) to predict pre-eclampsia. SEARCH STRATEGY: Medline and Embase through October 2010 and reference lists of reviews, without constraints. SELECTION CRITERIA: We included original publications on testing of PlGF, VEGF, sFLT1 and sENG in serum or plasma of pregnant women at <30 weeks of gestation and before clinical onset of pre-eclampsia. DATA COLLECTION AND ANALYSIS: Two reviewers independently identified eligible studies, extracted descriptive and test accuracy data and assessed methodological quality. Summary estimates of discriminatory performance were obtained. MAIN RESULTS: We included 34 studies. Concentrations of PlGF (27 studies) and VEGF (three studies) were lower in women who developed pre-eclampsia: standardised mean differences (SMD) -0.56 (95% CI -0.77 to -0.35) and -1.25 (95% CI -2.73 to 0.23). Concentrations of sFLT1 (19 studies) and sENG (ten studies) were higher: SMD 0.48 (95% CI 0.21-0.75) and SMD 0.54 (95% CI 0.24-0.84). The summary diagnostic odds ratios were: PlGF 9.0 (95% CI 5.6-14.5), sFLT1 6.6 (95% CI 3.1-13.7), sENG 4.2 (95% CI 2.4-7.2), which correspond to sensitivities of 32%, 26% and 18%, respectively, for a 5% false-positive rate. AUTHOR'S CONCLUSIONS: PlGF, sFLT1 and sENG showed modest but significantly different concentrations before 30 weeks of gestation in women who developed pre-eclampsia. Test accuracies of all four markers, however, are too poor for accurate prediction of pre-eclampsia in clinical practice.

Characteristics and outcome and the omphalocele circumference/abdominal circumference ratio in prenatally diagnosed fetal omphalocele.

OBJECTIVE: To evaluate the outcome of fetuses with prenatally diagnosed omphalocele and to investigate the predictive value of the omphalocele circumference/abdominal circumference (OC/AC) ratio - a measure for the relative size of the omphalocele. MATERIALS AND METHODS: This study includes all fetuses prenatally diagnosed with omphalocele at our centre between 1995 and 2007. Medical records and footage of ultrasound examinations were reviewed. Omphalocele was classified in four groups: isolated, chromosomal, syndromic, and multiple anomalies. RESULTS: Eighty-eight cases were identified: 21 (24%) were isolated and 67 had additional structural anomalies. Of the 44 fetuses (50%) with chromosomal anomalies, 2 had omphalocele as a solitary finding. Fifty-three pregnancies (60%) were terminated because of the size of the lesion or associated structural or chromosomal anomalies. Twenty-one cases resulted in a live birth, of which 17 were vaginal deliveries (81%, all uncomplicated) including 3 cases of giant omphalocele (≥5 cm). The OC/AC ratio was found predictive for herniation of the liver, respiratory insufficiency and type of surgical reconstruction. Currently, 12/88 fetuses (14%) are alive and well, including 2 infants with multiple anomalies. CONCLUSION: Identification of omphalocele should arouse suspicion of genetic abnormalities, even in cases that appear isolated. The OC/AC ratio may influence counselling regarding the postnatal course.