Tocolysis in the management of preterm prelabor rupture of membranes at 22-33 weeks of gestation: study protocol for a multicenter, double-blind, randomized controlled trial comparing nifedipine with placebo (TOCOPROM).

BACKGROUND: Preterm prelabor rupture of membranes (PPROM) before 34 weeks of gestation complicates 1% of pregnancies and accounts for one-third of preterm births. International guidelines recommend expectant management, along with antenatal steroids before 34 weeks and antibiotics. Up-to-date evidence about the risks and benefits of administering tocolysis after PPROM, however, is lacking. In theory, reducing uterine contractility could delay delivery and reduce the risks of prematurity and its adverse short- and long-term consequences, but it might also prolong fetal exposure to inflammation, infection, and acute obstetric complications, potentially associated with neonatal death or long-term sequelae. The primary objective of this study is to assess whether short-term (48 h) tocolysis reduces perinatal mortality/morbidity in PPROM at 22 to 33 completed weeks of gestation. METHODS: A randomized, double-blind, placebo-controlled, superiority trial will be performed in 29 French maternity units. Women with PPROM between 220/7 and 336/7 weeks of gestation, a singleton pregnancy, and no condition contraindicating expectant management will be randomized to receive a 48-hour oral treatment by either nifedipine or placebo (1:1 ratio). The primary outcome will be the occurrence of perinatal mortality/morbidity, a composite outcome including fetal death, neonatal death, or severe neonatal morbidity before discharge. If we assume an alpha-risk of 0.05 and beta-risk of 0.20 (i.e., a statistical power of 80%), 702 women (351 per arm) are required to show a reduction of the primary endpoint from 35% (placebo group) to 25% (nifedipine group). We plan to increase the required number of subjects by 20%, to replace any patients who leave the study early. The total number of subjects required is thus 850. Data will be analyzed by the intention-to-treat principle. DISCUSSION: This trial will inform practices and policies worldwide. Optimized prenatal management to improve the prognosis of infants born preterm could benefit about 50,000 women in the European Union and 40,000 in the United States each year. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03976063 (registration date June 5, 2019).

Peripartum cardiomyopathy and acute heart failure associated with prolonged tocolytic therapy in pregnancy: A case report.

RATIONALE: Peripartum cardiomyopathy (PPCM) is a rare and sometimes fatal systolic heart failure that affects women during late pregnancy or the early postpartum period. Heart failure symptoms can mimic the physiological changes of normal pregnancy, and the diagnosis is based on echocardiography. PATIENT CONCERNS: A 38-year-old multiparous woman with a history of cervical incompetence underwent cervical cerclage and received tocolysis for 100 days. DIAGNOSES: She delivered vaginally at 37 weeks of gestation but developed postpartum decompensated acute heart failure with low left ventricular ejection fraction (LVEF: 34%) and was diagnosed with PPCM. INTERVENTIONS: She received standard therapy for acute heart failure. OUTCOMES: The patient's pulmonary edema cleared, and she was fully ambulatory 6 days after admission. A follow-up echocardiogram 3 months later demonstrated recovery of LVEF to 66%. LESSONS: Prolonged tocolysis may contribute to cardiomyopathy and should be used with caution. PPCM management requires standard treatments for acute heart failure with modifications for fetal safety.

Maintaining and repeating tocolysis: A reflection on evidence.

It is inherent to human logic that both doctors and patients want to suppress uterine contractions when a woman presents in threatened preterm labor. Tocolysis is widely applied in women with threatened preterm labor with a variety of drugs. According to literature, tocolysis is indicated to enable transfer to a tertiary center as well as to ensure the administration of corticosteroids for fetal maturation. There is international discrepancy in the content and the implementation of guidelines on preterm labor. Tocolysis is often maintained or repeated. Nevertheless, the benefit of prolonging pregnancy has not yet been proven, and it is not impossible that prolongation of the pregnancy in a potential hostile environment could harm the fetus. Here we reflect on the use of tocolysis, focusing on maintenance and repeated tocolysis, and compare international guidelines and practices to available evidence. Finally, we propose strategies to improve the evaluation and use of tocolytics, with potential implications for future research.

Tocolysis after preterm premature rupture of membranes and neonatal outcome: a propensity-score analysis.

BACKGROUND: There are conflicting results regarding tocolysis in cases of preterm premature rupture of membranes. Delaying delivery may reduce neonatal morbidity because of prematurity and allow for prenatal corticosteroids and, if necessary, in utero transfer. However, that may increase the risks of maternofetal infection and its adverse consequences. OBJECTIVE: The objective of the study was to investigate whether tocolytic therapy in cases of preterm premature rupture of membranes is associated with improved neonatal or obstetric outcomes. STUDY DESIGN: Etude Epidémiologique sur les Petits Ages Gestationnels 2 is a French national prospective, population-based cohort study of preterm births that occurred in 546 maternity units in 2011. Inclusion criteria in this analysis were women with preterm premature rupture of membranes at 24-32 weeks' gestation and singleton gestations. Outcomes were survival to discharge without severe morbidity, latency prolonged by ≥48 hours and histological chorioamnionitis. Uterine contractions at admission, individual and obstetric characteristics, and neonatal outcomes were compared by tocolytic treatment or not. Propensity scores and inverse probability of treatment weighting for each woman were used to minimize indication bias in estimating the association of tocolytic therapy with outcomes. RESULTS: The study population consisted of 803 women; 596 (73.4%) received tocolysis. Women with and without tocolysis did not differ in neonatal survival without severe morbidity (86.7% vs 83.9%, P = .39), latency prolonged by ≥48 hours (75.1% vs 77.4%, P = .59), or histological chorioamnionitis (50.0% vs 47.6%, P = .73). After applying propensity scores and assigning inverse probability of treatment weighting, tocolysis was not associated with improved survival without severe morbidity as compared with no tocolysis (odds ratio, 1.01 [95% confidence interval, 0.94-1.09], latency prolonged by ≥48 hours (1.03 [95% confidence interval, 0.95-1.11]), or histological chorioamnionitis (1.03 [95% confidence interval, 0.92-1.17]). There was no association between the initial tocolytic drug used (oxytocin receptor antagonists or calcium-channel blockers vs no tocolysis) and the 3 outcomes. Sensitivity analyses of women with preterm premature rupture of membranes at 26-31 weeks' gestation, women who delivered at least 12 hours after rupture of membranes, women with direct admission after the rupture of membranes and the presence or absence of contractions gave similar results. CONCLUSION: Tocolysis in cases of preterm premature rupture of membranes is not associated with improved obstetric or neonatal outcomes; its clinical benefit remains unproven.

Tocolysis for inhibiting preterm birth in extremely preterm birth, multiple gestations and in growth-restricted fetuses: a systematic review and meta-analysis.

This systematic review was to identify available evidence on the effectiveness of tocolysis in inhibiting preterm delivery for women with threatened extremely preterm birth, multiple gestations, and growth-restricted babies, and their infants' outcomes. A comprehensive search using MEDLINE, Embase, the Cochrane Library, CINAHL, POPLINE and the WHO Global Health Library databases was conducted on 14 February 2014. For selection criteria, randomized controlled trials and non-randomized studies that compared tocolysis treatment to placebo or no treatment were considered. Selection of eligible studies, critical appraisal of the included studies, data collection, meta-analyses, and assessment of evidence quality were performed in accordance with the Cochrane Collaboration's guidance and validated assessment criteria. The search identified seven studies for extremely preterm birth, in which three were randomized controlled trials (RCTs) and four were non-randomized studies (non-RCTs). There were no eligible studies identified for women with multiple pregnancy and growth-restricted fetuses. Meta-analyses indicated no significant difference was found for the relative effectiveness of tocolytics versus placebo for prolonging pregnancy in women with extremely preterm birth (RR 1.04, 95% CI 0.83 to 1.31) or reducing the rate of perinatal deaths (RR 2.22, 95% CI 0.26 to 19.24). In summary, there is no evidence to draw conclusions on the effectiveness of tocolytic therapy for women with threatened extremely preterm birth, multiple gestations, and growth-restricted babies.

[Peripartum cardiomyopathy]. / Cardiomyopathie du péripartum.

The peripartum cardiomyopathy is a rare form of dilated cardiomyopathy resulting from alteration of angiogenesis toward the end of pregnancy. The diagnosis is based on the association of clinical heart failure and systolic dysfunction assessed by echocardiography or magnetic resonance imaging. Diagnoses to rule out are myocardial infarction, amniotic liquid embolism, myocarditis, inherited cardiomyopathy, and history of treatment by anthracycline. Risk factors are advance maternal age (>30), multiparity, twin pregnancy, African origin, obesity, preeclampsia, gestational hypertension, and prolonged tocolytic therapy. Treatment of acute phase is identical to usual treatment of acute systolic heart failure. After delivery, VKA treatment should be discussed in case of systolic function <25% because of higher risk of thrombus. A specific treatment by bromocriptine can be initiated on a case-by-case basis. Complete recovery of systolic function is observed in 50% of cases. The mortality risk is low. Subsequent pregnancy should be discouraged, especially if systolic function did not recover.

Pharmacokinetics of nifedipine slow-release during sustained tocolysis.

OBJECTIVE: The pharmacokinetics of nifedipine as a tocolytic agent has not been studied in great detail in pregnant women and has instead focused on immediate release tablets and gastrointestinal therapeutic system (GITS) tablets. The aim of this study was to determine nifedipine slow-release half-life and distribution volume in pregnant women and to compare these with pharmacokinetic parameters of nifedipine in non-pregnant subjects described in the literature. MATERIALS: This is a study parallel to a trial studying women with threatened preterm labor between 26 + 0 and 32 + 2 weeks after initial tocolysis and a completed course of corticosteroids, who were randomly allocated to maintenance nifedipine (slow-release tablets 20 mg 4 times daily) or placebo. Exclusion criteria for the pharmacokinetic study were contra-indications for nifedipine, impaired liver function, and concomitant intake of inhibitors or inducers of the cytochrome P450 3A4 isoenzyme. Blood samples for measuring nifedipine plasma concentrations were drawn at t = 0, t = 12 hours, t = 24 hours, t = 48 hours, t = 72 hours, t = 7 days, and t = 9 days. METHODS: Pharmacokinetic parameters were estimated using iterative two-stage Bayesian population pharmacokinetic analysis by MWPharm© software. The study was designed to establish a correlation between body weight and nifedipine plasma level. RESULTS: The pharmacokinetic parameters of nifedipine slow-release tablets were determined from the data of 8 pregnant women. Nifedipine slow-release had a half-life of 2 - 5 hours, a mean distribution volume of 6.2 ± 1.9 L/kg (calculated while using a fixed biological availability of 0.45 taken from the literature due to lack of intravenous data in this population) compared to a half-life of 6 - 11 hours, and a distribution volume of 1.2 - 1.3 L/kg described in non-pregnant subjects in the literature. None of the women delivered during study medication. Study medication was continued for the duration of the pharmacokinetic study (9 days) in all women. A correlation between nifedipine plasma levels and maternal body weight was not demonstrated. This may have been caused by lack of power. CONCLUSION: Pregnant subjects in this study, using nifedipine slow-release tablets, showed a larger volume of distribution and a shorter elimination half-life than for non-pregnant subjects as published in the literature.

[Tocolysis with nifedipin; its use in current practice].

AIM: The aim of the study is to establish the safety and efficacy of calcium channel blocker- Nifedipin as tocolytic agents. A wide range of tocolytics have been utilized for the management of preterm labor Calcium channel blockers, namely nifedipine, gained popularity as tocolytics due to the oral route of administration, availability of immediate- and slow-release preparations, the low incidence of maternal adverse effects associated with their use, and the fact that they are inexpensive. METHODS: 88 pregnant women in preterm labor participated in a prospective longitudinal study Inclusion criteria were: gestational age between 24 and 34 weeks gestation; uterine contractions in 10-15 min interval; single pregnancy, lack of contraindications for tocolysis. In all cases the calcium antagonist Nifedipine was used in dosage 4 x 10 mg per os. The clinical response to tocolysis, gestational age at delivery and potential side effects were analyzed. RESULTS: 91 pregnant women participated in the study. Three were excluded because they refused to participate. 88 pregnancies were finally analyzed. In nine of them maternal contractions persisted despite of treatment. The other 79 pregnancies were delayed 48 hours to receive antenatal corticosteroids. From all these 79 pregancies 66 delayed 7 days. The most common adverse effects were tachycardia, hypotonia, headache, dizziness, but they escape soon after the first dose. CONCLUSION: Nifedipine is an effective oral tocolytic with few maternal side effects.

B-type natriuretic peptide measurement for early diagnosis of acute pulmonary edema during pregnancy.

Calcium-channel blockers administered to pregnant women as tocolytic agents can cause acute pulmonary edema. The first signs of this severe complication can be atypical and so delay introduction of appropriate therapy. We describe three cases in whom B-type natriuretic peptide measurements proved to be relevant in early diagnosis and monitoring of pregnant women with acute pulmonary edema. B-type natriuretic peptide measurement in this setting could contribute to timely diagnosis and improve follow-up.

[Tocolysis in preterm labour--current recommendations]. / Tokoliza w porodzie przedwczesnym--aktualne wytyczne.

Common use of tocolytic drugs in preterm labor has not been shown to reduce the rate of neonatal mortality and morbidity Currently tocolytics should be administered in the course of a 48-h administration of antepartum glucocorticoids and/or transfer of the gravida to a center with neonatal intensive care unit. Only oxytocin receptor antagonist--atosiban and short-acting beta-agonists--fenoterol are licensed to reduce preterm uterine activity Owing to its safety and efficacy atosiban should be the first-choice tocolytic, especially in women with other diseases or multiple gestations.

Amnioinfusion before 26 weeks' gestation for severe fetal growth restriction with oligohydramnios: preliminary pilot study.

AIM: The prognosis for severe fetal growth restriction (FGR) with severe oligohydramnios before 26 weeks' gestation (WG) is currently poor; furthermore, its management is controversial. We report the innovative new management of FGR, such as therapeutic amnioinfusion and tocolysis. MATERIAL AND METHODS: For FGR and severe oligohydramnios before 26 WG complicated with absent or reversed umbilical artery end-diastolic flow velocity and/or deceleration by ultrasonography, we performed transabdominal amnioinfusion with tocolysis. Cases with multiple anomalies were excluded. Survival rate and long-term prognosis were analyzed. RESULTS: Among 570 FGR cases, 18 were included in the study. Mean diagnosis and delivery were at 22.6 ± 2.0 and 28.7 ± 3.3 WG. Median birthweight was 625 g (-4.2 standard deviation). Final survival rate was 11/13 (85%). There were five fetal deaths. In seven cases, oligohydramnios improved. Growth was detected in 10/18 fetuses. Furthermore, 8/8 decelerations, 4/12 cases of reversed umbilical artery end-diastolic flow velocity, 7/14 cases of brain-sparing effect, and 6/13 venous Doppler abnormalities were improved. When we detected umbilical cord compression, 8/10 cases were rescued. Eleven infants were followed up for an average of 5 years; one case of cerebral palsy with normal development and 10 cases with intact motor functions without major neurological handicap were confirmed. CONCLUSIONS: In cases of extremely severe FGR before 26 WG with oligohydramnios and circulatory failure, amnioinfusion might be a promising, innovative tool.

Tocolysis with the ß-2-sympathomimetic hexoprenaline increases occurrence of infantile haemangioma in preterm infants.

BACKGROUND: Infantile haemangioma (IH) is the most commonly observed tumour in children. Off-label pharmacological treatment of IH with the beta-blocker propranolol induces regression of IH. Based on the fact that IH are more frequently observed in premature babies than in mature babies and the evidence that beta-blocker therapy leads to regression of IH, the authors generated the hypothesis that the use of ß-2-sympathomimetics during pregnancy for inhibiting premature labour might increase occurrence of IH in preterm infants. METHODS: For group comparison t test, Mann-Whitney U test and Fisher's exact test were used. Logistic regression was carried out by the forward stepwise method with Wald statistics. RESULTS: Data of 328 preterm infants (<32 gestational weeks) or with a birth weight of less than 1500 g (<36 gestational weeks) born between January 2006 and December 2008 were analysed. A total of 15 were excluded due do death within the 1st month of life, 38 because of lost to follow-up and six due to incomplete data. Complete data of 269 preterm infants were retrospectively analysed. During the follow-up period of median 1.6 years, 50 infants developed one or more IH within their first 6 months of life. IH occurred in 40/181 patients with intrauterine exposure to the ß-2-sympathomimetic hexoprenaline and in 10/88 without exposure (OR=4.3; 95% CI 1.4 to 13.8). Furthermore, the influence of antenatal exposure to glucocorticosteroids for induction of lung development was analysed. Prenatally exposed subjects showed reduced occurrence of IH (OR=0.2; 95% CI 0.05 to 0.8). CONCLUSION: Intrauterine exposure to the ß-2-sympathomimetic hexoprenaline might increase the occurrence of IH in preterm infants.

Effect of antenatal tocolysis on neonatal outcomes.

OBJECTIVE: Detail adverse neonatal effects in pregnancies treated with indomethacin (I), magnesium sulfate (M) or nifedipine (N). METHODS: Women in acute preterm labor with cervical dilatation 1-6 cm were randomized to receive one of three first-line tocolytic drugs. RESULTS: There were 317 neonates (I = 103, M = 95, N = 119) whose mothers were treated with tocolytic therapy. There was no difference in gestational age at randomization (average 28.6 weeks' gestation) or at delivery (31.6 weeks' gestation, p = 0.551), birth weight (p = 0.871) or ventilator days (p = 0.089) between the three groups. Neonatal morbidity was not different between the three groups; respiratory distress syndrome (p = 0.086), patent ductus arteriosus (p = 0.592), sepsis (p = 0.590), necrotizing enterocolitis (p = 0.770), intraventricular hemorrhage (p = 0.669) and periventricular leukomalacia (p = 0.124). CONCLUSIONS: There were no statistically significant differences between the three tocolytics as far as composite neonatal morbidity or mortality was concerned.

[Acute pulmonary edema and pregnancy: a descriptive study of 15 cases and review of the literature]. / Œdème aigu du poumon et grossesse : étude descriptive de 15 cas et revue de la littérature.

OBJECTIVE: To describe the incidence and the etiologies of acute pulmonary edema (APE) and the diagnostic procedure used during pregnancy and immediate post-partum. MATERIALS AND METHODS: We analyzed records from a search of codes of heart failure and APE as well as from the term "pulmonary edema" in computerized obstetric records from 2002 to 2010 in a university center of level 3. We identified maternal characteristics, the term of appearance and route of delivery, the time between symptoms and diagnosis, additional tests performed, and data from echocardiography. RESULTS: Fifteen patients had an APE during pregnancy or in the immediate post-partum period during the study period (0.05%). The mean age was 28.6 years and the mean term of appearance was 31.2±3.1 weeks of amenorrhea. The diagnosis was made in 11 cases (73.3%) before delivery and in four during post-partum. The main etiology was preeclampsia (46.6%) followed by heart disease (26.7%), then tocolysis and overfilling (13.3%). In 55% of cases, we found a diagnostic wander characterized by carrying out further unnecessary tests. The echocardiography has led to a change in management in 27.3% of cases. CONCLUSION: The APE is a rare event during pregnancy and the post-partum period and its main etiology is preeclampsia. Some other etiologies are avoidable like the use of beta-agonists by intravenous route. The diagnosis is sometimes difficult, but the realization of a chest X-ray, a simple and inexpensive test, is enough to confirm it.

Magnesium sulfate tocolysis and intraventricular hemorrhage in very preterm infants.

OBJECTIVE: To estimate the contributory effect of tocolytic magnesium sulfate (MgSO4) exposure to intraventricular hemorrhage (IVH) in preterm infants born at 23-31 wks gestation to mothers without evidence of pregnancy induced hypertension and/or preeclampsia. METHODS: Cases with IVH and controls without IVH were selected from a population-based cohort of preterm infants admitted from January 2004 through May 2008 to the Level III Neonatal Intensive Care Unit (NICU) at Robert Wood Johnson University Hospital. Cases and controls were matched primarily by exact gestational age in completed weeks and secondarily by the birth weight that was same or similar (+/-100 g). The odds of tocolytic MgSO(4) exposure among the cases and controls was tested in a regression model to control the difference in demographic and clinical factors between the IVH cases (IVH+) and controls without IVH (IVH-). RESULTS: Eighty-nine IVH cases and 89 controls were comparable for parity, mode of delivery, antenatal corticosteroid exposure, and surfactant administration. IVH cases were less likely to have preterm premature rupture of membranes and were more likely to be born with low Apgar scores and require ventilation. Among the IVH cases, 30.3% of infants were exposed to tocolytic MgSO4 as compared to 47.2% of controls (Odds Ratio adjusted 0.471, 95% Confidence Interval 0.241, 0.906). CONCLUSIONS: Among the preterm born infants with gestational age 23-31 wks and IVH, tocolytic MgSO4 exposure was less likely to be observed than in neonates with similar clinical characteristics but without IVH, thereby suggesting that antenatal exposure to MgSO(4) may have a protective effect against IVH.

Antenatal calcium channel blocker exposure and subsequent patent ductus arteriosus in extremely low-birth-weight infants.

This study aimed to assess whether tocolytic fetal exposure to antenatal calcium channel blockers (aCCB) increases the risk for hemodynamically significant patent ductus arteriosus (hsPDA) in extremely low-birth-weight (ELBW) infants. This case-control study investigated ELBW infants (<1,000 g) without cardiac defects in a level 3 neonatal intensive care unit who had survived at least 7 days. Nifedipine was the only aCCB used for this study population. The measurements included the history of aCCB exposure, selected maternal data, hsPDA diagnosis, gestational age at birth, birth weight, mode of delivery, sex, maternal race, location of birth, Apgar scores, and selected neonatal morbidities. The end point of the study was hsPDA, defined as an echocardiographically confirmed PDA with clinical symptoms. A total of 180 infants met the study criteria. The diagnosis was hsPDA for 56% of these patients, 20% of whom had aCCB exposure. Of the infants without hsPDA, 11% had aCCB exposure (p = 0.09). No statistically significant associations were found between aCCB exposure and hsPDA after adjustment for gestational age (odds ratio [OR], 1.5; 95% confidence interval [CI], 0.6-3.7) or for gestational age and cumulative aCCB exposure of 100 mg or more (OR, 2.0; 95% CI, 0.6-6.5). A history of aCCB exposure does not appear to increase hsPDA risk in ELBW infants. Studies using neonatal serum nifedipine concentrations after antenatal exposure should be performed to confirm this conclusion.

Evaluation of maternal and neonatal outcomes after maintenance tocolysis: a retrospective study.

AIM: This study aimed to compare maternal and neonatal outcomes after no tocolysis, short-term tocolysis (≤48h), and maintenance tocolysis (>48h). METHODS: This was a retrospective study, conducted from January 2007 to June 2008, of vaginal preterm deliveries admitted to the neonatal intensive care unit (NICU) between 23 and 36 weeks of gestation. Patients were placed in three groups: no tocolysis, tocolysis ≤48h, and tocolysis >48h. The following neonatal parameters were recorded: respiratory distress syndrome, grade III or IV intraventricular hemorrhage, culture-proven sepsis, necrotizing enterocolitis, and length of NICU stay. RESULTS: A total of 162 deliveries were included in the study. Sixty-nine mothers received no tocolysis, 42 received tocolysis ≤48h, and 51 received tocolysis >48h. No adverse maternal outcomes were observed in any of the groups. There were no statistically significant differences in neonatal outcomes between the three groups. The maintenance tocolysis group had a longer pregnancy duration (P<0.0001), but their infants required longer NICU stay (P=0.0020). CONCLUSION: This study showed that maintenance tocolysis prolongs the duration of pregnancy but does not improve neonatal outcomes. Infants of mothers in the maintenance tocolysis group showed an increase in the length of NICU stay. A multicenter randomized control trial should be considered to further evaluate the need for maintenance tocolysis.

The risk of necrotizing enterocolitis after indomethacin tocolysis.

BACKGROUND: Postnatal indomethacin is reportedly associated with an increased incidence of necrotizing enterocolitis (NEC) in preterm infants. Because indomethacin readily crosses the placenta, we hypothesized that antenatal indomethacin (AI) would increase the risk for NEC in preterm infants. OBJECTIVE: The goal of this study was to explore the association between AI and NEC in preterm infants. METHODS: Medical records of preterm infants, 23 to 32 weeks' gestational age, without major congenital anomalies, were reviewed. Maternal and neonatal data were abstracted. Association of AI within 15 days before delivery (predictor variable) and classification of NEC according to modified Bell's stage 2a or higher in the first 15 days after delivery (early NEC [primary outcome variable]) was explored by using bivariate analyses, multivariate logistic regression, and propensity score analysis. RESULTS: Of 628 eligible infants, 63 received AI and 28 developed early NEC. AI exposure was significantly associated with multiple gestation, race, antenatal corticosteroids and magnesium sulfate, lower birth weight and gestational age, umbilical arterial catheter placement, respiratory distress syndrome, postnatal vasopressors and antibiotics, patent ductus arteriosus, sepsis, NEC, intraventricular hemorrhage, and mortality. On multivariate logistic regression controlling for covariates, AI was significantly associated with early NEC (adjusted odds ratio: 7.193 [95% confidence interval: 2.514-20.575]; number needed to harm: 5). The results remained significant when analyses were repeated using AI exposure within 5 days before delivery as a predictor variable; on analyses stratified according to gestational age; and on propensity score analysis. CONCLUSIONS: AI was associated with NEC in preterm infants in the first 15 days of life in this study, as were multiple other clinical factors.

Indomethacin tocolysis and neurodevelopmental outcome.

OBJECTIVE: To compare the neurodevelopmental outcomes, at 30-42 months adjusted age, between infants exposed to antenatal indomethacin and those unexposed to antenatal indomethacin. METHODS: This was a retrospective cohort study. The study cohort consisted of all nonanomalous infants with birth weight ≤ 1250 g and/or gestational age ≤ 28 wks born between 2000 and 2003, who completed neurodevelopmental assessments between 30-42 months adjusted age. The authors compared the neurodevelopmental outcomes of infants exposed and unexposed to antenatal indomethacin. RESULTS: Of the 321 infants, 75 infants (23%) exposed to antenatal indomethacin were lower in gestational age (26.4 vs 27.8 wks). In univariate analysis, infants exposed to antenatal indomethacin had significantly increased incidence of patent ductus arteriosus (PDA) (60% vs. 39%), surgical PDA ligation (40% vs. 18%) and bronchopulmonary dysplasia (81% vs. 60%). There was no significant difference in cerebral palsy, cognitive delay, deafness, blindness and major disability between the two groups. In multivariable logistic regression analysis, antenatal indomethacin exposure was not associated with cerebral palsy (OR, 0.70; 95% CI, 0.22-2.18), cognitive delay (OR, 0.56; 95% CI, 0.28-1.12) or neurodevelopmental disability (OR, 0.50; 95% CI, 0.21-1.19). CONCLUSIONS: Neurodevelopmental outcome of preterm infants exposed to antenatal indomethacin is equivalent to those unexposed to antenatal indomethacin, despite being born earlier.