Cervical pessary versus vaginal progesterone in women with a singleton pregnancy, a short cervix, and no history of spontaneous preterm birth at less than 34 weeks' gestation: open label, multicentre, randomised, controlled trial.

OBJECTIVE: To compare the effectiveness of cervical pessary and vaginal progesterone in the prevention of adverse perinatal outcomes and preterm birth in pregnant women of singletons with no prior spontaneous preterm birth at less than 34 weeks' gestation and who have a short cervix of 35 mm or less. DESIGN: Open label, multicentre, randomised, controlled trial. SETTING: 20 hospitals and five obstetric ultrasound practices in the Netherlands. PARTICIPANTS: Women with a healthy singleton pregnancy and an asymptomatic short cervix of 35 mm or less between 18 and 22 weeks' gestation were eligible. Exclusion criteria were prior spontaneous preterm birth at less than 34 weeks, a cerclage in situ, maternal age of younger than 18 years, major congenital abnormalities, prior participation in this trial, vaginal blood loss, contractions, cervical length of less than 2 mm or cervical dilatation of 3 cm or more. Sample size was set at 628 participants. INTERVENTIONS: 1:1 randomisation to an Arabin cervical pessary or vaginal progesterone 200 mg daily up to 36 weeks' of gestation or earlier in case of ruptured membranes, signs of infection, or preterm labour besides routine obstetric care. MAIN OUTCOME MEASURES: Primary outcome was a composite adverse perinatal outcome. Secondary outcomes were rates of (spontaneous) preterm birth at less than 28, 32, 34, and 37 weeks. A predefined subgroup analysis was planned for cervical length of 25 mm or less. RESULTS: From 1 July 2014 to 31 March 2022, 635 participants were randomly assigned to pessary (n=315) or to progesterone (n=320). 612 were included in the intention to treat analysis. The composite adverse perinatal outcome occurred in 19 (6%) of 303 participants with a pessary versus 17 (6%) of 309 in the progesterone group (crude relative risk 1.1 (95% confidence interval (CI) 0.60 to 2.2)). The rates of spontaneous preterm birth were not significantly different between groups. In the subgroup of cervical length of 25 mm or less, spontaneous preterm birth at less than 28 weeks occurred more often after pessary than after progesterone (10/62 (16%) v 3/69 (4%), relative risk 3.7 (95% CI 1.1 to 12.9)) and adverse perinatal outcomes seemed more frequent in the pessary group (15/62 (24%) v 8/69 (12%), relative risk 2.1 (0.95 to 4.6)). CONCLUSIONS: In women with a singleton pregnancy with no prior spontaneous preterm birth at less than 34 weeks' gestation and with a midtrimester short cervix of 35 mm or less, pessary is not better than vaginal progesterone. In the subgroup of a cervical length of 25 mm or less, a pessary seemed less effective in preventing adverse outcomes. Overall, for women with single baby pregnancies, a short cervix, and no prior spontaneous preterm birth less than 34 weeks' gestation, superiority of a cervical pessary compared with vaginal progesterone to prevent preterm birth and consecutive adverse outcomes could not be proven. TRIAL REGISTRATION: International Clinical Trial Registry Platform (ICTRP, EUCTR2013-002884-24-NL).

SUGAR-DIP trial: oral medication strategy versus insulin for diabetes in pregnancy, study protocol for a multicentre, open-label, non-inferiority, randomised controlled trial.

INTRODUCTION: In women with gestational diabetes mellitus (GDM) requiring pharmacotherapy, insulin was the established first-line treatment. More recently, oral glucose lowering drugs (OGLDs) have gained popularity as a patient-friendly, less expensive and safe alternative. Monotherapy with metformin or glibenclamide (glyburide) is incorporated in several international guidelines. In women who do not reach sufficient glucose control with OGLD monotherapy, usually insulin is added, either with or without continuation of OGLDs. No reliable data from clinical trials, however, are available on the effectiveness of a treatment strategy using all three agents, metformin, glibenclamide and insulin, in a stepwise approach, compared with insulin-only therapy for improving pregnancy outcomes. In this trial, we aim to assess the clinical effectiveness, cost-effectiveness and patient experience of a stepwise combined OGLD treatment protocol, compared with conventional insulin-based therapy for GDM. METHODS: The SUGAR-DIP trial is an open-label, multicentre randomised controlled non-inferiority trial. Participants are women with GDM who do not reach target glycaemic control with modification of diet, between 16 and 34 weeks of gestation. Participants will be randomised to either treatment with OGLDs, starting with metformin and supplemented as needed with glibenclamide, or randomised to treatment with insulin. In women who do not reach target glycaemic control with combined metformin and glibenclamide, glibenclamide will be substituted with insulin, while continuing metformin. The primary outcome will be the incidence of large-for-gestational-age infants (birth weight >90th percentile). Secondary outcome measures are maternal diabetes-related endpoints, obstetric complications, neonatal complications and cost-effectiveness analysis. Outcomes will be analysed according to the intention-to-treat principle. ETHICS AND DISSEMINATION: The study protocol was approved by the Ethics Committee of the Utrecht University Medical Centre. Approval by the boards of management for all participating hospitals will be obtained. Trial results will be submitted for publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NTR6134; Pre-results.

Women's Experiences with and Preference for Induction of Labor with Oral Misoprostol or Foley Catheter at Term.

Objective We assessed experience and preferences among term women undergoing induction of labor with oral misoprostol or Foley catheter. Study Design In 18 of the 29 participating hospitals in the PROBAAT-II trial, women were asked to complete a questionnaire within 24 hours after delivery. We adapted a validated questionnaire about expectancy and experience of labor and asked women whether they would prefer the same method again in a future pregnancy. Results The questionnaire was completed by 502 (72%) of 695 eligible women; 273 (54%) had been randomly allocated to oral misoprostol and 229 (46%) to Foley catheter. Experience of the duration of labor, pain during labor, general satisfaction with labor, and feelings of control and fear related to their expectation were comparable between both the groups. In the oral misoprostol group, 6% of the women would prefer the other method if induction is necessary in future pregnancy, versus 12% in the Foley catheter group (risk ratio: 0.70; 95% confidence interval: 0.55-0.90; p = 0.02). Conclusion Women's experiences of labor after induction with oral misoprostol or Foley catheter are comparable. However, women in the Foley catheter group prefer more often to choose a different method for future inductions.

Low-Dose versus Standard-Dose Intravenous Immunoglobulin to Prevent Fetal Intracranial Hemorrhage in Fetal and Neonatal Alloimmune Thrombocytopenia: A Randomized Trial.

OBJECTIVE: Pregnancies at risk of fetal and neonatal alloimmune thrombocytopenia (FNAIT) are commonly treated using weekly intravenous immunoglobulin (IVIG) at 1 g/kg maternal weight. IVIG is an expensive multidonor human blood product with dose-related side effects. Our aim was to evaluate the effectiveness of IVIG at a lower dose, i.e., 0.5 g/kg. METHODS: This was a randomized controlled multicenter trial conducted in Sweden, the Netherlands and Australia. Pregnant women with human platelet antigen alloantibodies and an affected previous child without intracranial hemorrhage (ICH) were enrolled. The participants were randomized to IVIG at 0.5 or 1 g/kg per week. The analyses were per intention to treat. The primary outcome was fetal or neonatal ICH. Secondary outcomes were platelet count at birth, maternal and neonatal IgG levels, neonatal treatment and bleeding other than ICH. RESULTS: A total of 23 women were randomized into two groups (low dose: n = 12; standard dose: n = 11). The trial was stopped early due to poor recruitment. No ICH occurred. The median newborn platelet count was 81 × 10(9)/l (range 8-269) in the 0.5 g/kg group versus 110 × 10(9)/l (range 11-279) in the 1 g/kg group (p = 0.644). CONCLUSION: The risk of adverse outcomes in FNAIT pregnancies treated with IVIG at 0.5 g/kg is very low, similar to that using 1 g/kg, although our uncompleted trial lacked the power to conclusively prove the noninferiority of using the low dose.

Haemolytic anaemia after nitrofurantoin treatment in a pregnant woman with G6PD deficiency.

We present a normotensive, pregnant woman with severe haemolytic anaemia in the third trimester of pregnancy. Owing to normal platelet count diagnoses other than HELLP syndrome were considered and investigated. The patient was treated with nitrofurantoin 3 weeks before presentation and she turned out to have a deficiency of glucose-6-phosphate dehydrogenase. After treatment with blood transfusion, vitamin B12 and folic acid the patient recovered completely. Caesarean delivery was performed because of maternal hypertension and fetal distress at 33 weeks' gestation.

Non-invasive prenatal screening for trisomy 21: what women want and are willing to pay.

OBJECTIVE: To investigate the attitude among pregnant women regarding non-invasive prenatal testing (NIPT) for detecting trisomy 21 (T21) and to quantify their willingness to pay for NIPT. METHODS: A questionnaire was administered to pregnant women who received counselling for first-trimester screening (FTS) in two hospitals and nine midwife practices in the Netherlands. RESULTS: A total of 147 women completed the questionnaire, yielding a response rate of 43%. If NIPT for detecting T21 were available, 81% stated they would choose to have this test, and 57% of women who elected not to undergo FTS in their current pregnancy would perform NIPT if available. Willingness to pay for NIPT was correlated with age and income, but not education level. The price that participants were willing to pay for NIPT was similar to the current price for FTS. CONCLUSION: The pregnant women in our study had a positive attitude regarding NIPT for T21, and more than half of the women who rejected prenatal screening would receive NIPT if available. PRACTICE IMPLICATIONS: Due to the elimination of iatrogenic miscarriage, caregivers should be aware that informed decision-making can change with respect to prenatal screening with the introduction of NIPT.

Remifentanil patient controlled analgesia versus epidural analgesia in labour. A multicentre randomized controlled trial.

BACKGROUND: Pain relief during labour is a topic of major interest in the Netherlands. Epidural analgesia is considered to be the most effective method of pain relief and recommended as first choice. However its uptake by pregnant women is limited compared to other western countries, partly as a result of non-availability due to logistic problems. Remifentanil, a synthetic opioid, is very suitable for patient controlled analgesia. Recent studies show that epidural analgesia is superior to remifentanil patient controlled analgesia in terms of pain intensity score; however there was no difference in satisfaction with pain relief between both treatments. METHODS/DESIGN: The proposed study is a multicentre randomized controlled study that assesses the cost-effectiveness of remifentanil patient controlled analgesia compared to epidural analgesia. We hypothesize that remifentanil patient controlled analgesia is as effective in improving pain appreciation scores as epidural analgesia, with lower costs and easier achievement of 24 hours availability of pain relief for women in labour and efficient pain relief for those with a contraindication for epidural analgesia.Eligible women will be informed about the study and randomized before active labour has started. Women will be randomly allocated to a strategy based on epidural analgesia or on remifentanil patient controlled analgesia when they request pain relief during labour. Primary outcome is the pain appreciation score, i.e. satisfaction with pain relief.Secondary outcome parameters are costs, patient satisfaction, pain scores (pain-intensity), mode of delivery and maternal and neonatal side effects.The economic analysis will be performed from a short-term healthcare perspective. For both strategies the cost of perinatal care for mother and child, starting at the onset of labour and ending ten days after delivery, will be registered and compared. DISCUSSION: This study, considering cost effectiveness of remifentanil as first choice analgesia versus epidural analgesia, could strongly improve the care for 180.000 women, giving birth in the Netherlands yearly by giving them access to pain relief during labour, 24 hours a day. TRIAL REGISTRATION NUMBER: Dutch Trial Register NTR2551, http://www.trialregister.nl.

Identification of cases with adverse neonatal outcome monitored by cardiotocography versus ST analysis: secondary analysis of a randomized trial.

OBJECTIVE: To evaluate whether correct adherence to clinical guidelines might have led to prevention of cases with adverse neonatal outcome. DESIGN: Secondary analysis of cases with adverse outcome in a multicenter randomized clinical trial. SETTING: Nine Dutch hospitals. POPULATION: Pregnant women with a term singleton fetus in cephalic position. METHODS: Data were obtained from a randomized trial that compared monitoring by STAN® (index group) with cardiotocography (control group). In both trial arms, three observers independently assessed the fetal surveillance results in all cases with adverse neonatal outcome, to determine whether an indication for intervention was present, based on current clinical guidelines. MAIN OUTCOME MEASURES: Adverse neonatal outcome cases fulfilled one or more of the following criteria: (i) metabolic acidosis in umbilical cord artery (pH < 7.05 and base deficit in extracellular fluid >12 mmol/L); (ii) umbilical cord artery pH < 7.00; (iii) perinatal death; and/or (iv) signs of moderate or severe hypoxic ischemic encephalopathy. RESULTS: We studied 5681 women, of whom 61 (1.1%) had an adverse outcome (26 index; 35 control). In these women, the number of performed operative deliveries for fetal distress was 18 (69.2%) and 16 (45.7%), respectively. Reassessment of all 61 cases showed that there was a fetal indication to intervene in 23 (88.5%) and 19 (57.6%) cases, respectively. In 13 (50.0%) vs. 11 (33.3%) cases, respectively, this indication occurred more than 20 min before the time of delivery, meaning that these adverse outcomes could possibly have been prevented. CONCLUSIONS: In our trial, more strict adherence to clinical guidelines could have led to additional identification and prevention of adverse outcome.

Prediction of neonatal metabolic acidosis in women with a singleton term pregnancy in cephalic presentation.

We sought to predict neonatal metabolic acidosis at birth using antepartum obstetric characteristics (model 1) and additional characteristics available during labor (model 2). In 5667 laboring women from a multicenter randomized trial that had a high-risk singleton pregnancy in cephalic presentation beyond 36 weeks of gestation, we predicted neonatal metabolic acidosis. Based on literature and clinical reasoning, we selected both antepartum characteristics and characteristics that became available during labor. After univariable analyses, the predictors of the multivariable models were identified by backward stepwise selection in a logistic regression analysis. Model performance was assessed by discrimination and calibration. To correct for potential overfitting, we (internally) validated the models with bootstrapping techniques. Of 5667 neonates born alive, 107 (1.9%) had metabolic acidosis. Antepartum predictors of metabolic acidosis were gestational age, nulliparity, previous cesarean delivery, and maternal diabetes. Additional intrapartum predictors were spontaneous onset of labor and meconium-stained amniotic fluid. Calibration and discrimination were acceptable for both models (c-statistic 0.64 and 0.66, respectively). In women with a high-risk singleton term pregnancy in cephalic presentation, we identified antepartum and intrapartum factors that predict neonatal metabolic acidosis at birth.

Predictive value of the baseline T-QRS ratio of the fetal electrocardiogram in intrapartum fetal monitoring: a prospective cohort study.

OBJECTIVE: To evaluate the added value of the baseline T/QRS ratio to other known risk factors in predicting adverse outcome and interventions for suspected fetal distress. DESIGN: Prospective cohort study. SETTING: Three academic and six non-academic teaching hospitals in the Netherlands. POPULATION: Laboring women with a high-risk cephalic singleton pregnancy beyond 36 weeks of gestation. METHODS: We obtained STAN(®) recordings (ST-analysis, Neoventa, Sweden) from two previous studies. Three patient groups were defined: cases with adverse outcome, cases with emergency delivery because of suspected fetal distress without adverse outcome, and a reference group of uncomplicated cases. Baseline T/QRS ratios among the adverse outcome and intervention for suspected fetal distress cases were compared to those of the uncomplicated cases. The ability of baseline T/QRS to predict adverse outcome and suspected fetal distress was determined using a multivariable logistic model. MAIN OUTCOME MEASURES: The added value of the baseline T/QRS to other known risk factors in the prediction of adverse outcome and interventions for suspected fetal distress. RESULTS: From 3462 recordings, 2459 were available for analysis. Median baseline T/QRS for uncomplicated cases, adverse outcome and interventions for suspected fetal distress were 0.12 (range 0.00-0.52), 0.12 (0.00-0.42) and 0.13 (0.00-0.39), respectively. There was no statistical difference between these groups. Multivariable analysis showed no added value of baseline T/QRS in the prediction of either adverse outcome or interventions for suspected fetal distress. CONCLUSION: Baseline T/QRS has no added value in the prediction of adverse neonatal outcome or interventions for suspected fetal distress.

Cost-effectiveness of cardiotocography plus ST analysis of the fetal electrocardiogram compared with cardiotocography only.

OBJECTIVE: To assess the cost-effectiveness of addition of ST analysis of the fetal electrocardiogram (ECG; STAN) to cardiotocography (CTG) for fetal surveillance during labor compared with CTG only. DESIGN: Cost-effectiveness analysis based on a randomized clinical trial on ST analysis of the fetal ECG. SETTING: Obstetric departments of three academic and six general hospitals in The Netherlands. Population. Laboring women with a singleton high-risk pregnancy, a fetus in cephalic presentation, a gestational age >36 weeks and an indication for internal electronic fetal monitoring. METHODS: A trial-based cost-effectiveness analysis was performed from a health-care provider perspective. MAIN OUTCOME MEASURES: Primary health outcome was the incidence of metabolic acidosis measured in the umbilical artery. Direct medical costs were estimated from start of labor to childbirth. Cost-effectiveness was expressed as costs to prevent one case of metabolic acidosis. RESULTS: The incidence of metabolic acidosis was 0.7% in the ST-analysis group and 1.0% in the CTG-only group (relative risk 0.70; 95% confidence interval 0.38-1.28). Per delivery, the mean costs per patient of CTG plus ST analysis (n= 2 827) were €1,345 vs. €1,316 for CTG only (n= 2 840), with a mean difference of €29 (95% confidence interval -€9 to €77) until childbirth. The incremental costs of ST analysis to prevent one case of metabolic acidosis were €9 667. CONCLUSIONS: The additional costs of monitoring by ST analysis of the fetal ECG are very limited when compared with monitoring by CTG only and very low compared with the total costs of delivery.

Severe fetal thrombocytopenia in Rhesus D alloimmunized pregnancies.

OBJECTIVE: The objective of the study was to evaluate the incidence of fetal thrombocytopenia and association with hydrops in Rhesus D alloimmunization. STUDY DESIGN: The study was a retrospective chart review of 914 intrauterine transfusions in 314 pregnancies performed between 1988 and 2005 in a single institution. The incidence of thrombocytopenia and severity of hydrops at cordocentesis were assessed and correlated with perinatal mortality. RESULTS: Thrombocytopenia (less than 150 x 10(9)/L) was found in 241 of 914 (26%) and severe thrombocytopenia (less than 50 x 10(9)/L) in 25 of 914 (3%) cordocentesis. Twenty-three percent of severely hydropic fetuses had severe thrombocytopenia, compared with 3% and 1% of mildly hydropic and nonhydropic fetuses, respectively. Thrombocytopenia was an independent risk factor for perinatal mortality. Mortality in fetuses that were severely thrombocytopenic and severely hydropic was 67%. CONCLUSION: Thrombocytopenia is common in hydropic anemic fetuses. Severe thrombocytopenia is associated with a poor prognosis, irrespective of the presence of hydrops. The option of platelet transfusion in severely hydropic anemic fetuses needs further study.

Fetal and neonatal alloimmune thrombocytopenia.

Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is one of the major causes of both severe thrombocytopenia and intracranial haemorrhage in fetuses and term neonates. The incidence of FNAIT is estimated to be one in 1000-2000 births. FNAIT is caused by maternal immunoglobulin G alloantibodies, which cross the placenta and are directed against human platelet antigens (HPA) on fetal platelets. In Caucasian individuals, the immunodominant antigen is HPA-1a, which is responsible for approximately 85% of FNAIT cases. The most feared complication of a low platelet count in the fetus or the neonate is intracranial haemorrhage and subsequent neurological handicaps. Over the last 15 years, there has been a gradual change in antenatal treatment, from an invasive management protocol to a less invasive management protocol to a completely non-invasive approach. However, controversy still exists over the optimal antenatal management strategy.

Postnatal management of fetal and neonatal alloimmune thrombocytopenia: the role of matched platelet transfusion and IVIG.

We evaluated the effects of platelet transfusions and intravenous immunoglobulin (IVIG) in neonates with fetal and neonatal alloimmune thrombocytopenia (FNAIT) with and without antenatal treatment with IVIG. Records of neonates with FNAIT admitted between January 2000 and November 2005 were reviewed. The patients were divided into group I, treated antenatally with IVIG for known FNAIT, and group II, postnatally diagnosed with FNAIT. The primary outcome was the time interval to reach a platelet level above 100 x 10(9)/L in relation to the type of treatment. Nineteen neonates with FNAIT were identified, 13 in group I and 6 in group II. In group I, four children were born with a platelet count above 100 x 10(9)/L and never needed treatment, and four received a single matched platelet transfusion at birth with a maintained response. Five neonates received IVIG and one matched transfusion, with all but one rapidly responding. In antenatally treated cases, postnatal IVIG had no apparent effect on the platelet count. In group II, two neonates died on day 1 with severe intracranial hemorrhage. Two of the four other patients responded to a number of unmatched platelet transfusions, with one neonate rapidly responding after one matched transfusion, while another needed nine matched transfusions before a persistent adequate platelet count was reached after 9 weeks. Postnatal IVIG had no apparent effect on the platelet count in any of our cases. In neonates with FNAIT treated antenatally with IVIG, neonatal management using a single matched platelet transfusion was adequate in all cases. In neonatally diagnosed cases not treated before birth, multiple matched platelet transfusions may be required. We found no evidence to support the use of IVIG in neonates with FNAIT.

Intravenous immunoglobulins without initial and follow-up cordocentesis in alloimmune fetal and neonatal thrombocytopenia at high risk for intracranial hemorrhage.

OBJECTIVE: To report on a less invasive treatment strategy in alloimmune fetal and neonatal thrombocytopenia (FNAIT) at high risk for either in utero or neonatal intracranial hemorrhage (ICH). METHODS: In 7 pregnancies, with a history of ICH in the older sibling, weekly intravenous immunoglobulin (IVIG) therapy to the mother (1 g/kg) without initial cordocentesis was started at a median gestational age of 16 weeks. RESULTS: In 4 pregnancies cordocentesis was avoided. One predelivery cordocentesis with platelet transfusion was performed in 3 further cases. Although none of the cases had a platelet count of >50 x 10(9)/l at cordocentesis, predelivery or birth, no ICHs were observed. The neonatal periods of the infants were uncomplicated. CONCLUSION: IVIG treatment alone might be considered in patients with both severe platelet alloimmunization and an increased risk for morbidity and mortality at cordocentesis.

Bishop score and risk of cesarean delivery after induction of labor in nulliparous women.

OBJECTIVE: To quantify the risk and risk factors for cesarean delivery associated with medical and elective induction of labor in nulliparous women. METHODS: A prospective cohort study was performed in nulliparous women at term with vertex singleton gestations who had labor induced at 2 obstetrical centers. Medical and elective indications and Bishop scores were recorded before labor induction. Obstetric and neonatal data were analyzed and compared with the results in women with a spontaneous onset of labor. Data were analyzed using univariate and multivariable regression modeling. RESULTS: A total of 1,389 women were included in the study. The cesarean delivery rate was 12.0% in women with a spontaneous onset of labor (n = 765), 23.4% in women undergoing labor induction for medical reasons (n = 435) (unadjusted odds ratio [OR] 2.24; 95% confidence interval [CI] 1.64-3.06), and 23.8% in women whose labor was electively induced (n = 189) (unadjusted OR 2.29; 95% CI 1.53-3.41). However, after adjusting for the Bishop score at admission, no significant differences in cesarean delivery rates were found among the 3 groups. A Bishop score of 5 or less was a predominant risk factor for a cesarean delivery in all 3 groups (adjusted OR 2.32; 95% CI 1.66-3.25). Other variables with significantly increased risk for cesarean delivery included maternal age of 30 years or older, body mass index of 31 or higher, use of epidural analgesia during the first stage of labor, and birth weight of 3,500 g or higher. In both induction groups, more newborns required neonatal care, more mothers needed a blood transfusion, and the maternal hospital stay was longer. CONCLUSION: Compared with spontaneous onset of labor, medical and elective induction of labor in nulliparous women at term with a single fetus in cephalic presentation is associated with an increased risk of cesarean delivery, predominantly related to an unfavorable Bishop score at admission. LEVEL OF EVIDENCE: II-2.