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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

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.

AbstractObjectiveTo 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.DesignOpen label, multicentre, randomised, controlled trial.Setting20 hospitals and five obstetric ultrasound practices in the Netherlands.ParticipantsWomen 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.Interventions1:1 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 measuresPrimary 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.ResultsFrom 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)).ConclusionsIn 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 registrationInternational Clinical Trial Registry Platform (ICTRP, EUCTR2013-002884-24-NL)

In absence of direct comparisons, consensus on the preferred preventive treatment for multiple pregnancies with a short cervix is lacking. Therefore, we compared the effectiveness of a cervical pessary and vaginal progesterone in the prevention of adverse perinatal outcomes and preterm birth (PTB) in women with a multiple pregnancy, no prior spontaneous PTB (sPTB) before 34 weeks' gestation, and an asymptomatic mid-trimester shortened cervix below 38 mm. This open-label, superiority, multi-centre randomised controlled trial was conducted in 20 hospitals in the Netherlands. Women with a healthy multiple pregnancy and an asymptomatic cervical length (CL) below 38 mm between 16 and 22 weeks' gestation were eligible, with a target sample size of 332. Following an interim analysis, the study was halted for futility. A total of 276 multiples, including seven triplet pregnancies, were randomised 1:1 to receive either an Arabin cervical pessary (N = 138) or vaginal progesterone 200 mg daily (N = 138) until 36 weeks' gestation or earlier if indicated. The primary outcome was a composite adverse perinatal outcome, with secondary outcomes including rates of (s)PTB before 24, 28, 32, 34, and 37 weeks. Predefined subgroup analyses were conducted based on CL, parity, chorionicity, and number of foetuses. Among 531 neonates (pessary N = 269, progesterone N = 262), the composite adverse perinatal outcome occurred in 19.7% of neonates in the pessary group versus 13.7% in the progesterone group (crude RR 1.43; 95% CI [0.85,2.4], p = 0.18). The rates of (s)PTB were not significantly different between groups. In the subgroup with a CL of ≤25 mm, no significant difference in the composite perinatal outcome was found (41.1% versus 34.7%, RR 1.18; 95% CI [0.60,2.33], interaction p = 0.63). However, among nulliparous women, the composite outcome was more frequent in the pessary group compared to progesterone (30.0% versus 15.9%, RR 1.88; 95% CI [1.03,3.43], interaction p = 0.93). The study's main limitations include the inability to blind interventions, potentially introducing bias, and low self-reported medication compliance in the progesterone group, which may have led to overestimated adherence and underestimated progesterone's preventive potential in the per-protocol analysis. In women with multiple pregnancies and a midtrimester short cervix below 38 mm, we found no superiority of a cervical pessary compared to vaginal progesterone the prevention of perinatal complications. While progesterone may have a modest effect, future studies should focus on other interventions in multiple pregnancies such as a cerclage, both ultrasound- and physical examination-indicated. This trial was registered at the International Clinical Trial Registry Platform (ICTRP, EUCTR2013-002884-24-NL, https://trialsearch.who.int/Trial2.aspx?TrialID=EUCTR2013-002884-24-NL).

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.

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 × 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.

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.

Tocolytics are recommended in international guidelines as treatment for threatened preterm birth. Atosiban, an oxytocin receptor antagonist, is a registered tocolytic drug specifically indicated for the treatment of threatened preterm birth. Although tocolytics have been shown to delay birth, benefits on neonatal outcomes have not been demonstrated. In the APOSTEL 8 trial we aimed to assess superiority of tocolysis with atosiban compared with placebo in threatened preterm birth from 30 weeks and 0 days (30+0 weeks) to 33+6 weeks of gestation in improving neonatal morbidity and mortality. This was an international, multicentre, randomised, double-blind, superiority trial conducted in 26 hospitals in the Netherlands, England, and Ireland. After written informed consent, women aged 18 years or older with a singleton or twin pregnancy with threatened preterm birth from 30+0 to 33+6 weeks of gestation were randomly assigned (stratified by centre, 1:1 ratio) to intravenous atosiban or placebo. The primary outcome was a composite of perinatal mortality (stillbirth and death until 28 days postpartum) and six severe neonatal morbidities. Analysis was by intention-to-treat. Treatment effect was estimated as relative risk (RR) with 95% CI. This trial was prospectively registered at EudraCT (2017-001007-72) and the Netherlands Trial Registry (NL-OMON54673), and is complete. Between Dec 4, 2017, and July 24, 2023, a total of 755 participants were randomly assigned, of whom 752 were included in the intention-to-treat analysis (atosiban n=375, placebo n=377). The primary outcome occurred in 37 (8%) of 449 infants in the atosiban group and 40 (9%) of 435 in the placebo group (RR 0·90 [95% CI 0·58–1·40]). There were three (0·7%) and four (0·9%) infants who died, respectively (RR 0·73 [0·16–3·23]); all deaths were deemed unlikely to be related to the study drug. Maternal adverse events did not differ between groups, and there were no maternal deaths. We did not demonstrate superiority of atosiban over placebo in improving neonatal outcomes as treatment for threatened preterm birth from 30+0 to 33+6 weeks of gestation. As the primary goal of tocolysis should be improvement of neonatal outcomes, our outcomes question the standardised use of atosiban as treatment for threatened preterm birth from 30+0 to 33+6 weeks of gestation. Our findings should reduce practice variation across countries and will contribute to evidence-based treatment for patients with threatened preterm birth. ZonMw.

Early plasma transfusion for women with severe postpartum hemorrhage (PPH) is recommended to prevent coagulopathy. However, there is no comparative, quantitative evidence on the association of early plasma transfusion with maternal outcomes. To compare the incidence of adverse maternal outcomes among women who received plasma during the first 60 minutes of persistent PPH vs women who did not receive plasma for similarly severe persistent PPH. This multicenter cohort study used a consecutive sample of women with persistent PPH, defined as PPH refractory to first-line measures to control bleeding, between January 1, 2011, and January 1, 2013. Time-dependent propensity score matching was used to select women who received plasma during the first 60 minutes of persistent PPH and match each of them with a woman who had shown the same severity and received the same treatment of PPH but who had not received plasma at the moment of matching. Transfusions were not guided by coagulation tests. Statistical analysis was performed from June 2018 to June 2019. Transfusion of plasma during the first 60 minutes of persistent PPH vs no or later plasma transfusion. Incidence of adverse maternal outcomes, defined as a composite of death, hysterectomy, or arterial embolization. This study included 1216 women (mean [SD] age, 31.6 [5.0] years) with persistent PPH, of whom 932 (76.6%) delivered vaginally and 780 (64.1%) had PPH caused by uterine atony. Seven women (0.6%) died because of PPH, 62 women (5.1%) had a hysterectomy, and 159 women (13.1%) had arterial embolizations. Among women who received plasma during the first 60 minutes of persistent PPH, 114 women could be matched with a comparable woman who had not received plasma at the moment of matching. The incidence of adverse maternal outcomes was similar between the women, with adverse outcomes recorded in 24 women (21.2%) who received early plasma transfusion and 23 women (19.9%) who did not receive early plasma transfusion (odds ratio, 1.09; 95% CI, 0.57-2.09). Results of sensitivity analyses were comparable to the primary results. In this cohort study, initiation of plasma transfusion during the first 60 minutes of persistent PPH was not associated with adverse maternal outcomes compared with no or later plasma transfusion, independent of severity of PPH.

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.