Evaluation of low-dose aspirin in the prevention of recurrent spontaneous preterm labour (the APRIL study): A multicentre, randomised, double-blinded, placebo-controlled trial.

BACKGROUND: Preterm birth is the leading cause of neonatal morbidity and mortality. The recurrence rate of spontaneous preterm birth is high, and additional preventive measures are required. Our objective was to assess the effectiveness of low-dose aspirin compared to placebo in the prevention of preterm birth in women with a previous spontaneous preterm birth. METHODS AND FINDINGS: We performed a parallel multicentre, randomised, double-blinded, placebo-controlled trial (the APRIL study). The study was performed in 8 tertiary and 26 secondary care hospitals in the Netherlands. We included women with a singleton pregnancy and a history of spontaneous preterm birth of a singleton between 22 and 37 weeks. Participants were randomly assigned to aspirin 80 mg daily or placebo initiated between 8 and 16 weeks of gestation and continued until 36 weeks or delivery. Randomisation was computer generated, with allocation concealment by using sequentially numbered medication containers. Participants, their healthcare providers, and researchers were blinded for treatment allocation. The primary outcome was preterm birth <37 weeks of gestation. Secondary outcomes included a composite of poor neonatal outcome (bronchopulmonary dysplasia, periventricular leukomalacia > grade 1, intraventricular hemorrhage > grade 2, necrotising enterocolitis > stage 1, retinopathy of prematurity, culture proven sepsis, or perinatal death). Analyses were performed by intention to treat. From May 31, 2016 to June 13, 2019, 406 women were randomised to aspirin (n = 204) or placebo (n = 202). A total of 387 women (81.1% of white ethnic origin, mean age 32.5 ± SD 3.8) were included in the final analysis: 194 women were allocated to aspirin and 193 to placebo. Preterm birth <37 weeks occurred in 41 (21.2%) women in the aspirin group and 49 (25.4%) in the placebo group (relative risk (RR) 0.83, 95% confidence interval (CI) 0.58 to 1.20, p = 0.32). In women with ≥80% medication adherence, preterm birth occurred in 24 (19.2%) versus 30 (24.8%) women (RR 0.77, 95% CI 0.48 to 1.25, p = 0.29). The rate of the composite of poor neonatal outcome was 4.6% (n = 9) versus 2.6% (n = 5) (RR 1.79, 95% CI 0.61 to 5.25, p = 0.29). Among all randomised women, serious adverse events occurred in 11 out of 204 (5.4%) women allocated to aspirin and 11 out of 202 (5.4%) women allocated to placebo. None of these serious adverse events was considered to be associated with treatment allocation. The main study limitation is the underpowered sample size due to the lower than expected preterm birth rates. CONCLUSIONS: In this study, we observed that low-dose aspirin did not significantly reduce the preterm birth rate in women with a previous spontaneous preterm birth. However, a modest reduction of preterm birth with aspirin cannot be ruled out. Further research is required to determine a possible beneficial effect of low-dose aspirin for women with a previous spontaneous preterm birth. TRIAL REGISTRATION: Dutch Trial Register (NL5553, NTR5675) https://www.trialregister.nl/trial/5553.

Intrahepatic cholestasis of pregnancy: maternal and fetal outcomes associated with elevated bile acid levels.

OBJECTIVE: The primary aim of this study was to investigate the correlation between pregnancy outcome and bile acid (BA) levels in pregnancies that were affected by intrahepatic cholestasis of pregnancy (ICP). In addition, correlations between maternal and fetal BA levels were explored. STUDY DESIGN: We conducted a retrospective study that included women with pruritus and BA levels ≥10 µmol/L between January 2005 and August 2012 in 3 large hospitals in the Netherlands. The study group was divided in mild (10-39 µmol/L), moderate (40-99 µmol/L), and severe (≥100 µmol/L) ICP. Main outcome measures were spontaneous preterm birth, meconium-stained amniotic fluid, asphyxia, and perinatal death. Univariate and multivariate logistic regression analysis was used to study associations between BA levels and adverse outcome. RESULTS: A total of 215 women were included. Gestational age at diagnosis and gestational age at delivery were significantly lower in the severe, as compared with the mild, ICP group (P < .001). Spontaneous preterm birth (19.0%), meconium-stained fluid (47.6%), and perinatal death (9.5%) occurred significantly more often in cases with severe ICP. Higher BA levels were associated significantly with spontaneous preterm birth (adjusted odds ratio [aOR], 1.15; 95% confidence interval [CI], 1.03-1.28), meconium-stained amniotic fluid (aOR, 1.15; 95% CI, 1.06-1.25), and perinatal death (aOR, 1.26; 95% CI, 1.01-1.57). Maternal BA levels at diagnosis and at delivery were correlated positively with umbilical cord blood BA levels (P = .006 and .012, respectively). CONCLUSION: Severe ICP is associated with adverse pregnancy outcome. Levels of BA correlate between mother and fetus.

Evaluation of strategies regarding management of imminent preterm delivery before 32 weeks of gestation: a regional cohort study among 1375 women in the Netherlands.

OBJECTIVE: To evaluate the management of imminent preterm delivery with respect to prescription of antenatal corticosteroids (ACS) and referral to a tertiary center. STUDY DESIGN: A retrospective cohort study existing of 1 perinatal center and 9 referring hospitals. All women who received their first dose of ACS in 1 of the 10 hospitals between 24+0 and 32+0 weeks of gestation and/or delivered before 32 weeks of gestation from 2005 until 2010. Patients were identified using the electronic database of hospital pharmacies. Main outcome measures were time interval from administration to delivery for different indications and number of women who were not referred in time to a tertiary center. RESULTS: In total, 1375 women received ACS. Main indications were suspected preterm labor (44.7%), preterm prelabor rupture of membranes (15.9%), maternal indication (12.8%), fetal indication (9.2%) and vaginal blood loss (8.4%). Overall, 467 (34.0%) women delivered ≤7 days after ACS administration; 8.7% of women with vaginal blood loss and 54.5% of women with maternal indication. Among the 931 women who received ACS in the secondary hospitals, 452 (48.5%) women were referred to a tertiary hospital and 89 (6.5%) women delivered in a secondary hospital with a gestational age of less than 32 weeks. CONCLUSION: One-third of all women receiving ACS delivered within 7 days and half of the women who received ACS in a secondary hospital were referred to a tertiary center. There seems to be room for improvement regarding the timing of ACS administration and subsequently referral to a tertiary center.

Substandard care in delivery-related asphyxia among term infants: prospective cohort study.

OBJECTIVE: To assess substandard care factors in the case of delivery-related asphyxia. DESIGN: Prospective cohort study. SETTING: Catchment area of the Neonatal Intensive Care Unit (NICU) of the University Medical Center Utrecht; a region in the middle of the Netherlands covering 13% of the Dutch population. POPULATION: Term infants, without congenital malformations, who died intrapartum or were admitted to the Neonatal Intensive Care Unit due to asphyxia. METHODS: During a two-year period, cases were prospectively collected and audited by an expert panel. MAIN OUTCOME MEASURES: Substandard care factors. RESULTS: 37 735 term infants without congenital malformations were born. There were 19 intrapartum deaths, and 89 NICU admissions of which 12 neonates died. In 63 (58%) cases a substandard care factor was identified that was possibly (n= 47, 43%) or probably (n= 16, 15%) related to perinatal death or NICU admission. In primary care, substandard care factors were mainly the low frequency of examination during labor and delay in referral to secondary care. In secondary care, misinterpretation of cardiotocography and failure to respond adequately to clinical signs of fetal distress were the most common substandard care factors. CONCLUSIONS: Substandard care is present in a substantial number of cases with delivery-related asphyxia resulting in perinatal death or NICU admission. Improving the organization of obstetric care in the Netherlands as well as training of obstetric caregivers might reduce adverse outcomes.

Substandard care in antepartum term stillbirths: prospective cohort study.

OBJECTIVE: To assess substandard care factors in antepartum stillbirths at term. Design. Prospective cohort study. SETTING: A region in the middle of the Netherlands covering 13% of the Dutch population. POPULATION: Antepartum stillbirths (≥ 37 weeks) without congenital malformations. METHODS: During a two-year period, all antepartum term stillbirths were prospectively collected and audited by an expert panel. MAIN OUTCOME MEASURES: Substandard care factors. RESULTS: During the study period, 37 735 normally formed infants were delivered ≥ 37 weeks of gestation. There were 60 antepartum stillbirths (1.59 per 1,000, 95%CI 1.19-1.99). Most stillbirths occurred during apparently uncomplicated pregnancies. Twenty-one infants (35%) were small-for-gestational age but growth restriction was only suspected in 10 (47.6%) of these cases. Substandard care factors were identified in 21 (35%) cases. A relation between these factors and fetal demise was possible in nine (15%) and probable in seven (12%) of these cases. Inadequate management and recognition of suspected growth restriction (n=9) or hypertension (n=6) were the most common substandard care factors. Ten (16.7%) women felt none or decreased fetal movements for 24 hours or more before they consulted a doctor or midwife. CONCLUSION: Twenty-seven percent of all stillbirths were possibly or probably avoidable. Special attention to the recognition and adequate management of suspected growth restriction and hypertension as well as guidelines about patient information and management of decreased fetal movements might result in a reduction of stillbirths in the Netherlands.

Antenatal allopurinol for reduction of birth asphyxia induced brain damage (ALLO-Trial); a randomized double blind placebo controlled multicenter study.

BACKGROUND: Hypoxic-ischaemic encephalopathy is associated with development of cerebral palsy and cognitive disability later in life and is therefore one of the fundamental problems in perinatal medicine. The xanthine-oxidase inhibitor allopurinol reduces the formation of free radicals, thereby limiting the amount of hypoxia-reperfusion damage. In case of suspected intra-uterine hypoxia, both animal and human studies suggest that maternal administration of allopurinol immediately prior to delivery reduces hypoxic-ischaemic encephalopathy. METHODS/DESIGN: The proposed trial is a randomized double blind placebo controlled multicenter study in pregnant women at term in whom the foetus is suspected of intra-uterine hypoxia.Allopurinol 500 mg IV or placebo will be administered antenatally to the pregnant woman when foetal hypoxia is suspected. Foetal distress is being diagnosed by the clinician as an abnormal or non-reassuring foetal heart rate trace, preferably accompanied by either significant ST-wave abnormalities (as detected by the STAN-monitor) or an abnormal foetal blood scalp sampling (pH < 7.20).Primary outcome measures are the amount of S100B (a marker for brain tissue damage) and the severity of oxidative stress (measured by isoprostane, neuroprostane, non protein bound iron and hypoxanthine), both measured in umbilical cord blood. Secondary outcome measures are neonatal mortality, serious composite neonatal morbidity and long-term neurological outcome. Furthermore pharmacokinetics and pharmacodynamics will be investigated.We expect an inclusion of 220 patients (110 per group) to be feasible in an inclusion period of two years. Given a suspected mean value of S100B of 1.05 ug/L (SD 0.37 ug/L) in the placebo group this trial has a power of 90% (alpha 0.05) to detect a mean value of S100B of 0.89 ug/L (SD 0.37 ug/L) in the 'allopurinol-treated' group (z-test2-sided). Analysis will be by intention to treat and it allows for one interim analysis. DISCUSSION: In this trial we aim to answer the question whether antenatal allopurinol administration reduces hypoxic-ischaemic encephalopathy in neonates exposed to foetal hypoxia. TRIAL REGISTRATION NUMBER: Clinical Trials, protocol registration system: NCT00189007.

Maternal allopurinol administration during suspected fetal hypoxia: a novel neuroprotective intervention? A multicentre randomised placebo controlled trial.

OBJECTIVE: To determine whether maternal allopurinol treatment during suspected fetal hypoxia would reduce the release of biomarkers associated with neonatal brain damage. DESIGN: A randomised double-blind placebo controlled multicentre trial. PATIENTS: We studied women in labour at term with clinical indices of fetal hypoxia, prompting immediate delivery. SETTING: Delivery rooms of 11 Dutch hospitals. INTERVENTION: When immediate delivery was foreseen based on suspected fetal hypoxia, women were allocated to receive allopurinol 500 mg intravenous (ALLO) or placebo intravenous (CONT). MAIN OUTCOME MEASURES: Primary endpoint was the difference in cord S100ß, a tissue-specific biomarker for brain damage. RESULTS: 222 women were randomised to receive allopurinol (ALLO, n=111) or placebo (CONT, n=111). Cord S100ß was not significantly different between the two groups: 44.5 pg/mL (IQR 20.2-71.4) in the ALLO group versus 54.9 pg/mL (IQR 26.8-94.7) in the CONT group (difference in median -7.69 (95% CI -24.9 to 9.52)). Post hoc subgroup analysis showed a potential treatment effect of allopurinol on the proportion of infants with a cord S100ß value above the 75th percentile in girls (ALLO n=5 (12%) vs CONT n=10 (31%); risk ratio (RR) 0.37 (95% CI 0.14 to 0.99)) but not in boys (ALLO n=18 (32%) vs CONT n=15 (25%); RR 1.4 (95% CI 0.84 to 2.3)). Also, cord neuroketal levels were significantly lower in girls treated with allopurinol as compared with placebo treated girls: 18.0 pg/mL (95% CI 12.1 to 26.9) in the ALLO group versus 32.2 pg/mL (95% CI 22.7 to 45.7) in the CONT group (geometric mean difference -16.4 (95% CI -24.6 to -1.64)). CONCLUSIONS: Maternal treatment with allopurinol during fetal hypoxia did not significantly lower neuronal damage markers in cord blood. Post hoc analysis revealed a potential beneficial treatment effect in girls. TRIAL REGISTRATION NUMBER: NCT00189007, Dutch Trial Register NTR1383.

Continuous intrauterine compared with cyclic oral progestin administration in perimenopausal HRT.

OBJECTIVES: Two hormone replacement therapy (HRT) regimens of combined oral estradiol with either continuous intrauterine or cyclic oral progestin were compared for 2 years. METHODS: 200 perimenopausal women randomly received an intrauterine system with continuous levonorgestrel release (20 microg/24 h) combined with oral estradiol (2 mg daily), or a cyclic oral regimen of norethisterone acetate (1 mg on day 13-22) and estradiol (days 1-21; 2 mg, days 22-28; 1 mg). Efficacy on endometrial protection, vaginal bleeding patterns, blood loss and practical use were compared during 26 cycles. RESULTS: Endometrial protection was adequate in both regimens. The cyclic regimen induced a more regular bleeding pattern. The continuous local administration induced a reduction in bleeding (P=0.001) with an initial period of prolonged and frequent bleeding. 38% became amenorrhoeic. Women found both regimens acceptable. CONCLUSIONS: Continuous intrauterine Levonorgestrel administration by using an intrauterine system can well be recommended for use in combination with oestrogen replacement therapy in perimenopausal women.

Perinatal mortality and severe morbidity in low and high risk term pregnancies in the Netherlands: prospective cohort study.

OBJECTIVE: To compare incidences of perinatal mortality and severe perinatal morbidity between low risk term pregnancies supervised in primary care by a midwife and high risk pregnancies supervised in secondary care by an obstetrician. DESIGN: Prospective cohort study using aggregated data from a national perinatal register. SETTING: Catchment area of the neonatal intensive care unit (NICU) of the University Medical Center in Utrecht, a region in the centre of the Netherlands covering 13% of the Dutch population. PARTICIPANTS: Pregnant women at 37 weeks' gestation or later with a singleton or twin pregnancy without congenital malformations. MAIN OUTCOME MEASURES: Perinatal death (antepartum, intrapartum, and neonatal) or admission to a level 3 NICU. RESULTS: During the study period 37 735 normally formed infants were delivered at 37 weeks' gestation or later. Sixty antepartum stillbirths (1.59 (95% confidence interval 1.19 to 1.99) per 1000 babies delivered), 22 intrapartum stillbirths (0.58 (0.34 to 0.83) per 1000 babies delivered), and 210 NICU admissions (5.58 (4.83 to 6.33) per 1000 live births) occurred, of which 17 neonates died (0.45 (0.24 to 0.67) per 1000 live births). The overall perinatal death rate was 2.62 (2.11 to 3.14) per 1000 babies delivered and was significantly higher for nulliparous women compared with multiparous women (relative risk 1.65, 95% confidence interval 1.11 to 2.45). Infants of pregnant women at low risk whose labour started in primary care under the supervision of a midwife had a significant higher risk of delivery related perinatal death than did infants of pregnant women at high risk whose labour started in secondary care under the supervision of an obstetrician (relative risk 2.33, 1.12 to 4.83). NICU admission rates did not differ between pregnancies supervised by a midwife and those supervised by an obstetrician. Infants of women who were referred by a midwife to an obstetrician during labour had a 3.66 times higher risk of delivery related perinatal death than did infants of women who started labour supervised by an obstetrician (relative risk 3.66, 1.58 to 8.46) and a 2.5-fold higher risk of NICU admission (2.51, 1.87 to 3.37). CONCLUSIONS: Infants of pregnant women at low risk whose labour started in primary care under the supervision of a midwife in the Netherlands had a higher risk of delivery related perinatal death and the same risk of admission to the NICU compared with infants of pregnant women at high risk whose labour started in secondary care under the supervision of an obstetrician. An important limitation of the study is that aggregated data of a large birth registry database were used and adjustment for confounders and clustering was not possible. However, the findings are unexpected and the obstetric care system of the Netherlands needs further evaluation.