No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Maintenance tocolysis with nifedipine in threatened preterm labour: 2-year follow up of the offspring in the APOSTEL II trial
Abstract
To evaluate long-term effects of maintenance tocolysis with nifedipine on neurodevelopmental outcome of the infant.
Follow up of infants of women who participated in a multicentre randomised controlled trial on maintenance tocolysis with nifedipine versus placebo.
Two years after the APOSTEL II trial on maintenance tocolysis with nifedipine versus placebo, we asked participants to complete the Ages and Stages Questionnaire.
Infant development was measured in five domains. Developmental delay was defined as a score of ≤1 SD in one or more developmental domains. We performed exploratory subgroup analysis in women with preterm prolonged rupture of the membranes, and in women with a cervical length <10 mm at study entry.
Of the 276 women eligible for follow up, 135 (52.5%) returned the questionnaire, encompassing data of 170 infants. At 2 years of age, infants of women with nifedipine maintenance tocolysis compared with placebo had a higher overall incidence of fine motor problems (22.2 versus 7.6%, OR 3.43, 95% CI 1.29-9.14, P = 0.01), and a lower incidence of poor problem-solving (21.1 versus 29.1%, OR 0.27, 95% CI 0.08-0.95, P = 0.04).
This follow-up study revealed no clear benefit of nifedipine maintenance tocolysis at 2 years of age. As short-term adverse perinatal outcome was not reduced in the original APOSTEL II trial, we conclude that maintenance tocolysis does not appear to be beneficial at this time.
No clear benefit of nifedipine maintenance tocolysis in preterm labour on 2-year infant outcome.
© 2015 Royal College of Obstetricians and Gynaecologists.
... Long-term effects of nifedipine have only been investigated in three smaller studies. [4][5][6] Only one retrospective cohort study on the longterm effects of atosiban has been published, but this study was limited to autism spectrum disorders in children exposed to nifedipine alone or to nifedipine and atosiban in combination. 7 The APOSTEL III study was a multicentre randomised trial that compared neonatal outcomes of tocolysis with nifedipine or atosiban in threatened preterm birth.8,9 ...
... The previous APOSTEL II follow-up study compared the long-term outcomes of maintenance treatment with nifedipine versus placebo, using the ASQ-3 questionnaire. 6 Overall, nifedipine-exposed children scored more poorly on the fine-motor scale, but did better on the problem-solving scale. Two other studies compared the long-term outcome of children exposed to ritodrine and nifedipine. ...
Objective:
Compare the long-term effects of tocolysis with nifedipine or atosiban on child outcome at age 2.5-5.5 years.
Design:
The APOSTEL III trial was a multicentre RCT that compared tocolysis with nifedipine or atosiban in 503 women with threatened preterm birth. Neonatal outcomes did not differ between both treatment arms, except for a higher incidence of intubation in the atosiban group.
Methods:
Parents were asked to complete four questionnaires regarding neurodevelopment, executive function, behaviour problems, and general health.
Main outcome measures:
Main long-term outcome measure was a composite of abnormal development at the age of 2.5-5.5 years.
Results:
Of the 426 women eligible for follow up, 196 (46%) parents returned the questionnaires of 115 children in the nifedipine and 110 children in the atosiban group. Abnormal development occurred in 32 children (30%) in the nifedipine group and 38 children (38%) in the atosiban group (OR 0.74, 95% CI 0.41-1.34). The separate outcomes for neurodevelopment, executive function, behaviour, and general health showed no significant differences between the groups. Sensitivity analysis including all children of the APOSTEL III trial including a comparison of deceased children resulted in a higher rate of healthy survival in the nifedipine group (64% versus 54%), but no significant difference in overall mortality (5.4% versus 2.7%). There were no significant subgroup effects.
Conclusion:
Outcomes on broad child neurodevelopment, executive function, behaviour and general health were comparable in both groups. Neither nifedipine nor atosiban can be considered as the preferred treatment for women with threatened preterm birth.
... Long-term effects of nifedipine have only been investigated in three smaller studies. [4][5][6] Only one retrospective cohort study on the longterm effects of atosiban has been published, but this study was limited to autism spectrum disorders in children exposed to nifedipine alone or to nifedipine and atosiban in combination. 7 The APOSTEL III study was a multicentre randomised trial that compared neonatal outcomes of tocolysis with nifedipine or atosiban in threatened preterm birth.8,9 ...
... The previous APOSTEL II follow-up study compared the long-term outcomes of maintenance treatment with nifedipine versus placebo, using the ASQ-3 questionnaire. 6 Overall, nifedipine-exposed children scored more poorly on the fine-motor scale, but did better on the problem-solving scale. Two other studies compared the long-term outcome of children exposed to ritodrine and nifedipine. ...
... 19 At 2 years of age, we found a higher rate of fine motor problems in the nifedipine group (n=78) (22.2% vs 7.6%), but lower rate of poor problem-solving (21.2% vs 29.1%) compared with the placebo group (n=66). 20 We concluded that there was insufficient evidence to support use of nifedipine for maintenance tocolysis. Second, the APOSTEL III trial compared tocolysis with nifedipine versus atosiban in threatened preterm birth between 25 and 34 weeks of gestation. ...
Introduction
Currently, the majority of women worldwide with threatened preterm birth are treated with tocolytics. Although tocolytics can effectively delay birth for 48 hours, no tocolytic drug has convincingly been shown to improve neonatal outcomes and effects on long-term child development are unknown. The aim of this follow-up study of a placebo controlled randomised trial is to investigate the long-term effects of atosiban administration in case of threatened preterm birth on child’s neurodevelopment and behaviour development, overall health and mortality.
Methods and analysis
This protocol concerns a follow-up study of the multicentre randomised double-blind placebo controlled APOSTEL 8 trial (NL61439.018.17, EudraCT-number 2017-001007-72). In this trial, women with threatened preterm birth (between 30 and 34 weeks of gestation) defined as uterine contractions with (1) a cervical length of <15 mm or (2) a cervical length of 15–30 mm and a positive fibronectin test or (3) in centres where cervical length measurement is not part of the local protocol: a positive fibronectin test or Actim-Partus test or (4) ruptured membranes, are randomised to atosiban or placebo for 48 hours. The primary outcome is a composite of perinatal mortality and severe neonatal morbidity. Children born to mothers who participated in the APOSTEL 8 study (n=760) will be eligible for follow-up at 4 years of corrected age and assessed using four parent-reported questionnaires. Primary outcomes are neurodevelopment and behaviour problems. Secondary outcomes are on child growth and general health. All outcomes will be compared between the atosiban and placebo group with OR and corresponding 95% CI. Analyses will be performed using the intention-to-treat approach.
Ethics and dissemination
The Medical Research Ethics Committee from Amsterdam UMC confirmed that de Medical Research Involving Human Subjects Act (Dutch WMO-law) did not apply to our study (W21_386 # 21.431). Results will be published in a peer-reviewed journal and shared with stakeholders and participants. This protocol is published before analysis of the results.
... Исследование van Vliet E. et al. (2016) также не показало эффективности пролонгированного токолиза нифедипином [28]. Как тест на фибронектин (p=0,87), так и длина шейки матки (p=0,18) не повлияли на пролонгированный токолиз, который был неэффективен во всей рандомизированной группе [29]. ...
... The second manuscript by van Vliet et al. 3 reports the long-term effects of exposure to maintenance tocolysis with nifedipine in threatened preterm labour and neurodevelopmental outcome in children at 2 years. At 2 years of age, infants of women with nifedipine maintenance tocolysis compared with placebo had a higher overall incidence of fine motor problems (22.2 versus 7.6%; P = 0.01), and a lower incidence of poor problem-solving (21.1 versus 29.1%; P = 0.04). ...
What is known and objective:
Premature birth affects more than 15 million infants, as well as mothers and families around the world. With the relaxation of the two-child policy, the problem of premature birth has become relatively prominent in China. According to statistics, China had a birth population of 15.23 million in 2018, with a considerably large number of premature births. This study aims to evaluate the efficacy and safety of tocolysis in the treatment of preterm delivery, provide clinical evidence for medical staff and promote the self-management of patients with premature births.
Methods:
Four English databases (PubMed, Embase, Cochrane Library and Web of Science) were retrieved by computer, the retrieval time was from the establishment of each database to November 2021, and the randomized controlled trials for the treatment of preterm delivery were screened according to the pre-set natriuretic exclusion criteria. After literature screening, data selection and risk of bias evaluation were independently conducted by two researchers. R 4.1.1 and Stata 17.0 software were used for statistical analysis.
Results and discussion:
A total of 44 RCTs were included, including 6939 patients. The results of network meta-analysis reveal that in terms of effectiveness, indomethacin was the most effective intervention measure, followed by nifedipine, and the difference was statistically significant; regarding safety, nifedipine was the safest intervention measure, followed by indomethacin, and the difference was statistically significant; and in respect of adverse reactions, ritodrine had the highest probability, and the difference was statistically significant.
What is new and conclusion:
Nifedipine may be better for delayed delivery and less likely to produce adverse pregnancy outcomes, followed by indomethacin. Limited by the number and quality of recipient studies, the aforementioned conclusions need to be verified through more high-quality studies. At the same time, the focus should be on patients with twin pregnancy and patients with clinical manifestations of extreme preterm delivery.
Preterm birth, defined as delivery <37 weeks’ gestation, is a major public health issue worldwide. An estimated 15 million babies are born preterm every year [1]. Preterm birth and the associated complications are now the leading cause of mortality in children under the age of 5 worldwide, accounting for 1 million deaths per year [2]. In the US, 11–12% of deliveries occur preterm, and worldwide, this figure is increasing. Babies born at ‘term’ – conventionally designated as 37–42 weeks’ gestation – have consistently better morbidity and mortality outcomes than those born before 37 weeks. In the short term, organ immaturity predisposes the preterm neonate to complications such as intraventricular hemorrhage and periventricular leukomalacia, necrotizing enterocolitis, and respiratory distress syndrome. Immaturity of the immune system increases the risk of neonatal sepsis, meningitis, and pneumonia. In the longer term, preterm babies have an increased prevalence of neurodevelopmental delay and chronic lung disease, and later in life, higher rates of adult-onset disease, from diabetes to hypertension and obesity [3]. Whilst extremely preterm (<28 weeks) and very preterm (28–32 weeks) neonates are at the highest risk of complications, studies have demonstrated that even late preterm birth (34 – 36 + 6 weeks) confers an increased risk of morbidity and mortality [4]. These effects appear to be pervasive, and as such premature infants have been shown to have lower educational attainment and employment than those born at term [5, 6].
Globally, preterm birth rates are rising and have a significant impact on neonatal morbidity and mortality. Preterm birth remains difficult to prevent and a number of strategies for preterm birth prevention (progesterone, cervical pessaries, cervical cerclage, tocolytics, and antibiotics) have been identified. While some of these show more promise, there is a paucity of evidence regarding the long-term effects of these strategies on childhood outcomes. Strategies used to improve the health of babies if born preterm, such as antenatal magnesium sulfate for fetal neuroprotection and antenatal corticosteroids for fetal lung maturation, show evidence of short-term benefit but lack large-scale follow-up data of long-term childhood outcomes. Future research on preterm birth interventions should include long-term follow-up of the children, ideally with similar outcome measures to allow for future meta-analyses.
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.
Objectives:
To propose guidelines for clinical practice for tocolysis in preterm labor without premature preterm rupture of the membranes (PPROM).
Materials and methods:
Bibliographic searches were performed in the Medline and Cochrane databases and gynecologist and obstetricians' international society guidelines. It is important to note that most studies included women in preterm labour with and without PPROM.
Results:
Compared with placebo, tocolytics are not associated with a reduction in neonatal mortality or morbidity (LE2). Compared with betamimetics, nifedipine is associated with a reduction in necrotizing enterocolitis, intraventricular hemorrhage and respiratory distress syndrome (LE2). There is no difference between nifedipine and atosiban regarding neonatal prognosis, except a modest reduction in NICU transfer with nifedipine (LE2). Betamimetics, atosiban and nifedipine are equivalent to prolong pregnancy for more than 48hours (LE2). Compared with betamimetics, nifedipine reduces delivery before 34 WG and is associated with a longer pregnancy (LE2). Atosiban and nifedipine are equivalent to prolong the pregnancy over 7 days (LE2), but in women with spontaneous preterm labour without PPROM, nifedipine reduces deliveries before 37 WG and pregnancy prolongation is longer, without improving neonatal prognosis (LE2). Maternal severe adverse effects may occur with all tocolytics (LE4). Betamimetics cardiovascular adverse effects are frequents (LE2) and may be serious (maternal death) (LE4). Nifedipine and atosiban reduce maternal adverse effect compared with placebo (LE2). Cardiovascular adverse effects are moderately increased with nifedipine compared with atosiban (LE2), without increasing treatment discontinuation (LE2). Regarding their benefits on pregnancy prolongation and good maternal tolerance, atosiban and nifedipine can be used for tocolysis in spontaneous preterm labour without PPROM (Grade B), for singleton and multiple pregnancies (Professional Consensus). Advantageously, nifedipine is orally taken and is inexpensive (Professional Consensus). Nicardipine should not be used for tocolysis (Professional Consensus) and betamimetics should not be prescribed anymore for tocolysis (Grade C). All tocolytic treatment should be prescribed for up to 48hours (Grade B). In case of initial tocolysis failure, another treatment may be proposed with the other class of tocolytic (Professional Consensus). Different class of tocolytics should not be combined (Grade C). Scientific data are lacking to propose guidelines regarding a rescue tocolysis, after a first previous successful tocolysis with complete antenatal corticosteroid therapy (Professional Consensus). There is no scientific evidence to propose a tocolysis in women with advanced dilatation (GradeC), nor prescribe a tocolysis after 34 WG (Professional Consensus). There is no evidence to define a gestational age lower limit for tocolysis (Professional Consensus).
Conclusion:
Nifedpine and atosiban can be used for tocolysis (Grade B), including for multiple pregnancies (Professional Consensus). Maintenance tocolysis is useless (Grade C) and potentially harmful (Grade C). Betamimetics should not be used for tocolysis (Professional Consensus).
Objective:
Preterm birth is the most common cause of neonatal morbidity and mortality. Around one third of preterm deliveries starts with preterm prelabor rupture of membranes (PPROM). The aim of this trial was to study the effect of prolonged tocolysis with nifedipine versus placebo in women with PPROM on perinatal outcome and prolongation of pregnancy.
Study design:
The Apostel IV was a nationwide multicenter randomized placebo controlled trial. We included women with PPROM without contractions between 24(+0) and 33(+6) weeks of gestation. Participants were randomly allocated to daily 80mg nifedipine or placebo, until the start of labor, with a maximum of 18 days. The primary outcome measure was a composite of poor neonatal outcome, including perinatal death, bronchopulmonary dysplasia, periventricular leukomalacia>grade 1, intraventricular hemorrhage>grade 2, necrotizing enterocolitis>stage 1 and culture proven sepsis. Secondary outcomes were gestational age at delivery and prolongation of pregnancy. Analysis was by intention to treat. To detect a reduction of poor neonatal outcome from 30% to 10%, 120 women needed to be randomized.
Trial registry:
NTR 3363.
Results:
Between October 2012 and December 2014 we randomized 25 women to nifedipine and 25 women to placebo. Due to slow recruitment the study was stopped prematurely. The median gestational age at randomization was 29.9 weeks (IQR 27.7-31.3) in the nifedipine group and 27.0 weeks (IQR 24.7-29.9) in the placebo group. Other baseline characteristics were comparable. The adverse perinatal outcome occurred in 9 neonates (33.3%) in the nifedipine group and 9 neonates (32.1%) in the placebo group (RR 1.04, 95% CI 0.49-2.2). Two perinatal deaths occurred, both in the nifedipine group. Bronchopulmonary dysplasia was seen less frequently in the nifedipine group (0% versus 17.9%; p=0.03). Prolongation of pregnancy did not differ between the nifedipine and placebo group (median 11 versus 8 days, HR 1.02; 95% CI 0.58-1.79).
Conclusion:
This randomized trial did not show a beneficial effect of prolonged tocolysis on neonatal outcomes or prolongation of pregnancy in women with PPROM without contractions. However, since results are based on a small sample size, a difference in effectiveness cannot be excluded.
Blocking the transient receptor potential vanilloid 4 (TRPV4) channel may be a viable new therapeutic approach to preterm labor (Ying et al., this issue).
Cerebellar injury is increasingly recognized as an important complication of very preterm birth. However, the neurodevelopmental consequences of early life cerebellar injury in prematurely born infants have not been well elucidated. We performed a literature search of studies published between 1997 and 2014 describing neurodevelopmental outcomes of preterm infants following direct cerebellar injury or indirect cerebellar injury/underdevelopment. Available data suggests that both direct and indirect mechanisms of cerebellar injury appear to stunt cerebellar growth and adversely affect neurodevelopment. This review also provides important insights into the highly integrated cerebral-cerebellar structural and functional correlates. Finally, this review highlights that early life impairment of cerebellar growth extends far beyond motor impairments and plays a critical, previously underrecognized role in the long-term cognitive, behavioral, and social deficits associated with brain injury among premature infants. These data point to a developmental form of the cerebellar cognitive affective syndrome previously described in adults. Longitudinal prospective studies using serial advanced magnetic resonance imaging techniques are needed to better delineate the full extent of the role of prematurity-related cerebellar injury and topography in the genesis of cognitive, social-behavioral dysfunction.
This second paper in the Born Too Soon supplement presents a review of the epidemiology of preterm birth, and its burden globally, including priorities for action to improve the data. Worldwide an estimated 11.1% of all livebirths in 2010 were born preterm (14.9 million babies born before 37 weeks of gestation), with preterm birth rates increasing in most countries with reliable trend data. Direct complications of preterm birth account for one million deaths each year, and preterm birth is a risk factor in over 50% of all neonatal deaths. In addition, preterm birth can result in a range of long-term complications in survivors, with the frequency and severity of adverse outcomes rising with decreasing gestational age and decreasing quality of care. The economic costs of preterm birth are large in terms of immediate neonatal intensive care, ongoing long-term complex health needs, as well as lost economic productivity. Preterm birth is a syndrome with a variety of causes and underlying factors usually divided into spontaneous and provider-initiated preterm births. Consistent recording of all pregnancy outcomes, including stillbirths, and standard application of preterm definitions is important in all settings to advance both the understanding and the monitoring of trends. Context specific innovative solutions to prevent preterm birth and hence reduce preterm birth rates all around the world are urgently needed. Strengthened data systems are required to adequately track trends in preterm birth rates and program effectiveness. These efforts must be coupled with action now to implement improved antenatal, obstetric and newborn care to increase survival and reduce disability amongst those born too soon.
Importance
Perinatal infections are commonly present in preterm and very low-birth-weight (VLWB) infants and might contribute to adverse neurodevelopmental outcome.
Objective
To summarize studies evaluating the effect of perinatal infections on neurodevelopmental outcome in very preterm/VLBW infants.
Evidence Review
On December 12, 2011, we searched Medline, PsycINFO, Embase, and Web of Knowledge for studies on infections and neurodevelopmental outcome. All titles and abstracts were assessed for eligibility by 2 independent reviewers. We also screened the reference lists of identified articles to search for additional eligible studies. Preselected criteria justified inclusion in this meta-analysis: (1) the study included infants born very preterm (≤32 weeks) and/or with VLBW (≤1500 g); (2) the study compared infants with and without perinatal infection; (3) there was follow-up using the Bayley Scales of Infant Development 2nd edition; and (4) results were published in an English-language peer-reviewed journal. The quality of each included study was assessed using the Newcastle-Ottawa Scale.
Findings
This meta-analysis includes 18 studies encompassing data on 13.755 very preterm/VLBW infants. Very preterm/VLBW infants with perinatal infections had poorer mental (d = −0.25; P < .001) and motor (d = −0.37; P < .001) development compared with very preterm/VLBW infants without infections. Mental development was most impaired by necrotizing enterocolitis (d = −0.40; P < .001) and meningitis (d = −0.37; P < .001). Motor development was most impaired by necrotizing enterocolitis (d = −0.66; P < .001). Chorioamnionitis did not affect mental (d = −0.05; P = .37) or motor (d = 0.19; P = .08) development.
Conclusions and Relevance
Postnatal infections have detrimental effects on mental and motor development in very preterm/VLBW infants.
In threatened preterm labor, maintenance tocolysis with nifedipine, after an initial course of tocolysis and corticosteroids for 48 hours, may improve perinatal outcome.
To determine whether maintenance tocolysis with nifedipine will reduce adverse perinatal outcomes due to premature birth.
APOSTEL-II (Assessment of Perinatal Outcome with Sustained Tocolysis in Early Labor) is a double-blind, placebo-controlled trial performed in 11 perinatal units including all tertiary centers in The Netherlands. From June 2008 to February 2010, women with threatened preterm labor between 26 weeks (plus 0 days) and 32 weeks (plus 2 days) gestation, who had not delivered after 48 hours of tocolysis and a completed course of corticosteroids, were enrolled. Surviving infants were followed up until 6 months after birth (ended August 2010).
Randomization assigned 406 women to maintenance tocolysis with nifedipine orally (80 mg/d; n = 201) or placebo (n = 205) for 12 days. Assigned treatment was masked from investigators, participants, clinicians, and research nurses.
Primary outcome was a composite of adverse perinatal outcomes (perinatal death, chronic lung disease, neonatal sepsis, intraventricular hemorrhage >grade 2, periventricular leukomalacia >grade 1, or necrotizing enterocolitis). Analyses were completed on an intention-to-treat basis.
Mean (SD) gestational age at randomization was 29.2 (1.7) weeks for both groups. Adverse perinatal outcome was not significantly different between groups: 11.9% (24/201; 95% CI, 7.5%-16.4%) for nifedipine vs 13.7% (28/205; 95% CI, 9.0%-18.4%) for placebo (relative risk, 0.87; 95% CI, 0.53-1.45).
In patients with threatened preterm labor, nifedipine-maintained tocolysis did not result in a statistically significant reduction in adverse perinatal outcomes when compared with placebo. Although the lower than anticipated rate of adverse perinatal outcomes in the control group indicates that a benefit of nifedipine cannot completely be excluded, its use for maintenance tocolysis does not appear beneficial at this time.
trialregister.nl Identifier: NTR1336.
Although preterm infants born at 29 to 36 gestational weeks (GW) are at risk for developmental delay, they do not always benefit from systematic follow-up. Primary care physicians are then responsible for their developmental surveillance and need effective screening tests. This study aimed to determine whether the Ages and Stages Questionnaires (ASQ) at 12 and 24 months' corrected age (CA) identify developmental delay in preterm infants.
With a cross-sectional design involving 2 observations at 12 and 24 months' CA, 124 and 112 preterm infants were assessed. Infants were born between May 2004 and April 2006 at 29 to 36 GW. The ASQ and the Bayley Scales of Infant Development were used. Concurrent validity was calculated by using κ coefficient, sensitivity, and specificity.
At 12 months' CA, the ASQ did not perform well in identifying infants with mental delay (κ = 0.08-0.19; sensitivity = 0.20-0.60; specificity = 0.68-0.88). Agreement (κ = 0.28-0.44) and specificity (0.90-0.97) were better for the psychomotor scale, but the sensitivity remained insufficient (0.25-0.52). At 24 months, the ASQ had good sensitivity (0.75-0.92) and specificity (0.55-0.78) for detecting mental delays (κ = 0.45). Results remained unsatisfactory for detecting motor delays (sensitivity = 0.31-0.50; specificity = 0.73-0.92).
Preterm infants with developmental delays at 12 months' CA are not adequately identified with the ASQ. At 24 months' CA, the ASQ identifies mental delays but not psychomotor delays. Additional measures should be used to increase yield of detecting at-risk preterm infants.
Our goals were to (1) validate the parental Ages and Stages Questionnaires (ASQ) as a screening tool for psychomotor development among a cohort of ex-premature infants reaching 2 years, and (2) analyse the influence of parental socio-economic status and maternal education on the efficacy of the questionnaire. A regional population of 703 very preterm infants (<35 weeks gestational age) born between 2003 and 2006 were evaluated at 2 years by their parents who completed the ASQ, by a pediatric clinical examination, and by the revised Brunet Lezine psychometric test with establishment of a DQ score. Detailed information regarding parental socio-economic status was available for 419 infants. At 2 years corrected age, 630 infants (89.6%) had an optimal neuromotor examination. Overall ASQ scores for predicting a DQ score ≤85 produced an area under the receiver operator curve value of 0.85 (95% Confidence Interval:0.82-0.87). An ASQ cut-off score of ≤220 had optimal discriminatory power for identifying a DQ score ≤85 with a sensitivity of 0.85 (95%CI:0.75-0.91), a specificity of 0.72 (95%CI:0.69-0.75), a positive likelihood ratio of 3, and a negative likelihood ratio of 0.21. The median value for ASQ was not significantly associated with socio-economic level or maternal education. ASQ is an easy and reliable tool regardless of the socio-economic status of the family to predict normal neurologic outcome in ex-premature infants at 2 years of age. ASQ may be beneficial with a low-cost impact to some follow-up programs, and helps to establish a genuine sense of parental involvement.
Preterm labour is the main cause of perinatal morbidity and mortality in the Western world. At present, there is evidence that tocolysis for 48 hours is useful in women with threatened preterm labour at least before 32 weeks. This allows transfer of the patient to a perinatal centre, and maximizes the effect of corticosteroids for improved neonatal survival. It is questionable whether treatment with tocolytics should be maintained after 48 hours.
The APOSTEL II trial is a multicentre placebo-controlled study. Pregnant women admitted for threatened preterm labour who have been treated with 48 hours corticosteroids and tocolysis will be eligible to participate in the trial between 26+0 and 32+2 weeks gestational age. They will be randomly allocated to nifedipine (intervention) or placebo (control) for twelve days or until delivery, whatever comes first.Primary outcome is a composite of perinatal death, and severe neonatal morbidity up to evaluation at 6 months after birth. Secondary outcomes are gestational age at delivery, number of days in neonatal intensive care and total days of the first 6 months out of hospital. In addition a cost-effectiveness analysis will be performed. Analysis will be by intention to treat. The power calculation is based on an expected 11% difference in adverse neonatal outcome. This implies that 406 women have to be randomised (two sided test, beta 0.2 at alpha 0.05).
This trial will provide evidence as to whether maintenance tocolysis reduces severe perinatal morbidity and mortality in women with threatened preterm labour before 32 weeks.
Clinical trial registration: http://www.trialregister.nl, NTR 1336, date of registration: June 3rd 2008.
To evaluate Doppler velocimetry (resistance index (RI) and peak systolic velocity (PSV)) in the maternal-fetal circulation before and 5 and 24 h after tocolysis with oral nifedipine.
This was a prospective, observational, analytic cohort study performed in 47 pregnant women undergoing nifedipine tocolysis, each subject acting as her own control. Doppler assessment of uterine, umbilical and fetal middle cerebral (MCA) arteries was performed before and 5 and 24 h after an initial 20-mg sublingual dose, which was repeated twice at 20-min intervals if contractions failed to diminish. The maintenance dose consisted of 20 mg orally every 6 h for 24 h up to a total of 100-120 mg nifedipine. We analyzed whether there was a time effect and compared values at the different time-points.
The MCA-RI had decreased significantly after 24 h of tocolysis (0 h = 0.85; 5 h = 0.85; 24 h = 0.81; P = 0.001), with no differences in uterine or umbilical arteries or in the MCA to umbilical artery ratio. The MCA-PSV had reduced significantly after 5 h (0 h = 41.5 cm/s; 5 h = 34.7 cm/s; P = 0.001), returning close to baseline levels between 5 and 24 h. The PSV increased significantly between 5 and 24 h in the right uterine artery (5 h = 55.1 cm/s; 24 h = 65.0 cm/s; P = 0.037) and in the umbilical artery (5 h = 28.4 cm/s; 24 h = 33.1 cm/s; P = 0.038).
Nifedipine tocolysis is associated with a reduction in RI in the MCA but not in the uterine or umbilical arteries, a reduction in PSV in the MCA after 5 h but returning to baseline within 24 h, and an increase in PSV between 5 and 24 h in the umbilical and right uterine arteries.
The choice of first-line tocolytic agent is a topic of worldwide debate. The oxytocin receptor antagonist atosiban and the calcium antagonist nifedipine appear to be effective in postponing delivery. However, information is lacking on their possible effects on the fetal biophysical profile.
To study the direct fetal effects of tocolysis with atosiban or nifedipine combined with a course of betamethasone.
We performed a randomised controlled study including women with preterm labour requiring tocolytic treatment. Primary outcome measures were the effects on fetal heart rate (FHR) and its variation. Secondary endpoints were the effects on fetal movement and blood flow (pulsatility index - PI) of the umbilical (UA) and medial cerebral arteries (MCA).
One-hour recordings of FHR and fetal movements were made on each of five successive days (days 0-4). Fetal blood flow velocity patterns were studied daily by Doppler ultrasound. Baseline characteristics of 31 women who had not delivered at day 0 and needed no escape tocolysis did not differ between the study groups. Multilevel analysis showed no significant effect of either tocolytic on FHR and movement parameters over the 5-day study period. The use of tocolytics also did not significantly alter the time courses of PI-values for UA (p = 0.37) and MCA (p = 0.62).
This study demonstrates for the first time the direct effects of atosiban on fetal movement, heart rate and blood flow. Tocolysis with either atosiban or nifedipine combined with betamethasone administration appears to have no direct fetal adverse effects.
Estrogen-mediated neuroprotection is observed in neurodegenerative disease and neurotrauma models; however, determining a mechanism for these effects has been difficult. We propose that estrogen may limit cell death in the nervous system tissue by inhibiting increases in intracellular free Ca(2+). Here, we present data using VSC 4.1 cell line, a ventral spinal motoneuron and neuroblastoma hybrid cell line. Treatment with 1 mM glutamate for 24 h induced apoptosis. When cells were pre-treated with 100 nM 17beta-estradiol (estrogen) for 1 h and then co-treated with glutamate, apoptotic death was significantly attenuated. Estrogen also prevented glutamate-mediated changes in resting membrane potential and membrane capacitance. Treatment with either 17 alpha-estradiol or cell impermeable estrogen did not mimic the findings seen with estrogen. Glutamate treatment significantly increased both intracellular free Ca(2+) and the activities of downstream proteases such as calpain and caspase-3. Estrogen attenuated both the increases in intracellular free Ca(2+) and protease activities. In order to determine the pathway responsible for estrogen-mediated inhibition of these increases in intracellular free Ca(2+), cells were treated with several Ca(2+) entry inhibitors, but only the L-type Ca(2+) channel blocker nifedipine demonstrated cytoprotective effects comparable to estrogen. To expand these findings, cells were treated with the L-type Ca(2+) channel agonist FPL 64176, which increased both cell death and intracellular free Ca(2+), and estrogen inhibited both effects. From these observations, we conclude that estrogen limits glutamate-induced cell death in VSC 4.1 cells through effects on L-type Ca(2+) channels, inhibiting Ca(2+) influx as well as activation of the pro-apoptotic proteases calpain and caspase-3.
Children who suffer from perinatal brain injury often deal with the dramatic consequences of this misfortune for the rest of their lives. Despite the severe clinical and socioeconomic significance, no effective clinical strategies have yet been developed to counteract this condition. As shown in recent studies, perinatal brain injury is usually brought about by cerebral ischemia, cerebral hemorrhage, or an ascending intrauterine infection. This review focuses on the pathophysiologic pathways activated by these insults and describes neuroprotective strategies that can be derived from these mechanisms. Fetal cerebral ischemia causes an acute breakdown of neuronal membrane potential followed by the release of excitatory amino acids such as glutamate and aspartate. Glutamate binds to postsynaptically located glutamate receptors that regulate calcium channels. The resulting calcium influx activates proteases, lipases, and endonucleases, which in turn destroy the cellular skeleton. A second wave of neuronal cell damage occurs during the reperfusion phase. This cell damage is thought to be caused by the postischemic release of oxygen radicals, synthesis of nitric oxide, inflammatory reactions, and an imbalance between the excitatory and inhibitory neurotransmitter systems. Furthermore, secondary neuronal cell damage may be brought about in part by induction of a cellular suicide program known as apoptosis. Recent studies have shown that inflammatory reactions not only aggravate secondary neuronal damage after cerebral ischemia, but may also injure the immature brain directly. This damage may be mediated by cardiovascular effects of endotoxins leading to cerebral hypoperfusion and by activation of apoptotic pathways in oligodendrocyte progenitors through the release of proinflammatory cytokines. Periventricular or intraventricular hemorrhage (PIVH) is a typical lesion of the immature brain. The inability of preterm fetuses to redistribute cardiac output in favor of the central organs and their lack of cerebral autoregulation may cause significant fluctuations in cerebral blood flow when oxygen is in short supply. Disruption of the thin-walled blood vessels in the germinal matrix with subsequent cerebral hemorrhage is often the inevitable result and is at times associated with cerebral hemorrhagic infarction. Knowledge of these pathophysiologic mechanisms has enabled scientists to develop new therapeutic strategies, which have been shown to be neuroprotective in animal experiments. The potential of such therapies is discussed here, particularly the promising effects of postischemic induction of cerebral hypothermia, the application of the calcium-antagonist flunarizine, and the administration of magnesium.
Children who suffer from perinatal brain injury often deal with the dramatic consequences of this misfortune for the rest of their lives. Despite the severe clinical and socioeconomic significance, no effective clinical strategies have yet been developed to counteract this condition. As shown in recent studies, perinatal brain injury is usually brought about by cerebral ischemia, cerebral hemorrhage, or an ascending intrauterine infection. This review focuses on the pathophysiologic pathways activated by these insults and describes neuroprotective strategies that can be derived from these mechanisms. Fetal cerebral ischemia causes an acute breakdown of neuronal membrane potential followed by the release of excitatory amino acids such as glutamate and aspartate. Glutamate binds to postsynaptically located glutamate receptors that regulate calcium channels. The resulting calcium influx activates proteases, lipases, and endonucleases, which in turn destroy the cellular skeleton. A second wave of neuronal cell damage occurs during the reperfusion phase. This cell damage is thought to be caused by the postischemic release of oxygen radicals, synthesis of nitric oxide, inflammatory reactions, and an imbalance between the excitatory and inhibitory neurotransmitter systems. Furthermore, secondary neuronal cell damage may be brought about in part by induction of a cellular suicide program known as apoptosis. Recent studies have shown that inflammatory reactions not only aggravate secondary neuronal damage after cerebral ischemia, but may also injure the immature brain directly. This damage may be mediated by cardiovascular effects of endotoxins leading to cerebral hypoperfusion and by activation of apoptotic pathways in oligodendrocyte progenitors through the release of proinflammatory cytokines. Periventricular or intraventricular hemorrhage (PIVH) is a typical lesion of the immature brain. The inability of preterm fetuses to redistribute cardiac output in favor of the central organs and their lack of cerebral autoregulation may cause significant fluctuations in cerebral blood flow when oxygen is in short supply. Disruption of the thin-walled blood vessels in the germinal matrix with subsequent cerebral hemorrhage is often the inevitable result and is at times associated with cerebral hemorrhagic infarction. Knowledge of these pathophysiologic mechanisms has enabled scientists do develop new therapeutic strategies, which have been shown to be neuroprotective in animal experiments. The potential of such therapies is discussed here, particularly the promising effects of postischemic induction of cerebral hypothermia, the application of the calcium-antagonist flunarizine, and the administration of magnesium.
The ORACLE II study published in 2001 compared use of amoxicillin-clavulanate (co-amoxiclav) and/or erythromycin, with placebo in women with spontaneous preterm labor (SPL) and intact membranes who had no clinical signs of infection, to determine whether these antibiotics could prevent or eliminate perinatal infections presumed to have a causative role in SPL. Neither drug produced any improvement in neonatal mortality or morbidity. The present study, the ORACLE Children Study II (OCS II), assessed long-term outcomes for 4473 children age 7 years, born in the United Kingdom to 4221 women enrolled in the original ORACLE II trial. The mothers completed a detailed structured questionnaire to assess the health status of the children. The primary outcome was the overall level of functional impairment (mild, moderate, or severe). Results from national curriculum tests assessed the education outcome. Follow-up data was obtained for 3196 of the 4473 children (71%). Compared to mothers who had received no erythromycin, more children born to mothers who had received any erythromycin (with or without co-amoxiclav) had any functional impairment: erythromycin (658 [42.3%] of 1554 children) versus no erythromycin (574 [38.3%] of 1498); odds ratio (OR) 1.18, 95% confidence interval (CI) 1.02-1.37. In contrast, there was no difference in the proportion of children whose mothers had received co-amoxiclav (with or without erythromycin) and those whose mothers had not received co-amoxiclav. More children whose mothers had received any erythromycin presented with bowel disorders. A higher proportion of children whose mothers had received either antibiotic developed cerebral palsy compared to those born to mothers who had not received these antibiotics: erythromycin (53 [3.3%] of 1611) versus no erythromycin (27 [1.7%] of 1562), OR 1.93, 95% CI 1.21-3.09; and co-amoxiclav (50 [3.2%] of 1587) versus no co-amoxiclav (30 [1.9%] of 1586), OR 1.69, 95% CI 1.07-2.67. With these two exceptions, neither antibiotic had effects on other medical conditions, or on the number of deaths, behavior, or educational attainment. The investigators conclude that these findings support the viewpoint that antibiotics are not advisable in SPL without clinical signs of infection.
Increasing numbers of preterm neonates survive with motor and cognitive disabilities related to less destructive forms of cerebral injury that still result in reduced cerebral growth. White matter injury results in myelination disturbances related to aberrant responses to death of pre-myelinating oligodendrocytes (preOLs). PreOLs are rapidly regenerated but fail to mature to myelinating cells. Although immature projection neurons are more resistant to hypoxia-ischemia than preOLs, they display widespread disturbances in dendritic arbor maturation, which provides an explanation for impaired cerebral growth. Thus, large numbers of cells fail to fully mature during a critical window in development of neural circuitry. These recently recognized forms of cerebral gray and white matter dysmaturation suggest new therapeutic directions centered on reversal of the processes that promote dysmaturation.
In an unselected group of women with signs of preterm labour, maintenance tocolysis is not effective in the prevention of preterm birth and does not improve neonatal outcome. Among women with signs of preterm labour, those who are fetal fibronectin positive have an increased risk of preterm birth. We investigated whether maintenance tocolysis with nifedipine would delay delivery and improve neonatal outcome in women with threatened preterm labour and a positive fetal fibronectin status.
Women with a singleton pregnancy in threatened preterm labour (24(+0) to 33(+6) weeks) with a positive fetal fibronectin test were randomised to nifedipine or placebo. Study medication was continued until 36 completed weeks' gestation. The primary endpoint was prolongation of pregnancy of seven days. Secondary endpoints were gestational age at delivery and length of NICU admission.
Of the 60 participants, 29 received nifedipine and 31 placebo. Prolongation of pregnancy by >7 days occurred in 22/29 (76%) in the nifedipine group and 25/31 (81%) in the placebo group (relative risks, RR 0.94 [0.72-1.2]). Gestational age at delivery was 36.1 ± 5.1 weeks for nifedipine and 36.8 ± 3.6 weeks for placebo (P = 0.027). Length of NICU admission [median (interquartile ranges, IQR)] was 27 (24-41) days and 16 (8-37) days in nifedipine and placebo groups, respectively (P = 0.17).
In women with threatened preterm labour who are fetal fibronectin positive, maintenance tocolysis with nifedipine does not seem to prolong pregnancy, nor reduce length of NICU admission.
To evaluate the long-term influence of very preterm birth on parental mental health, family functioning, and parenting stress at age 2 and 7 years.
Participants were 183 children born very preterm (<30 weeks gestation; n = 148 families) and 69 term-born children (n = 66 families). When children were age 7 years, parents were assessed based on the Hospital Anxiety and Depression Scale, the Family Assessment Device, the Parenting Stress Index, and the Social Support Questionnaire. Similar measures were evaluated at age 2 years.
When the children were age 7 years, parents of the very preterm-born children were more likely to report moderate to severe anxiety symptoms (P = .03), higher levels of depression symptoms (P = .03), poorer family functioning (P < .05), and higher levels of parenting stress (P < .001) compared with parents of the children born at term. Group differences in parenting stress and family functioning persisted after adjustment for social risk and child neurodevelopmental disability. There was strong evidence of a relationship between family functioning and parent-related stress at age 2 and 7 years (P < .001), but little evidence that parental mental health problems at 2 years were predictive of anxiety (P = .15) or depression (P = .28) at 7 years for parents of very preterm children.
These findings demonstrate that very preterm birth has a negative influence on parent and family functioning at 7 years after birth, which for some families is consistent with their functioning at 2 years. These results have implications for the support required by parents of very preterm children.
Calcium channel blocker maintenance therapy is one of the types of tocolytic therapy that may be used after an episode of threatened preterm labour (and usually an initial dose of tocolytic therapy) in an attempt to prevent the onset of further preterm contractions.
To assess the effects of calcium channel blockers as maintenance therapy on preventing preterm birth after threatened preterm labour.
We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 May 2013) and reference lists of retrieved studies.
Randomised controlled trials of calcium channel blockers used as maintenance therapy to prevent preterm birth after threatened preterm labour, compared with placebo or no treatment.
Two review authors independently assessed study eligibility, extracted data and assessed the risk of bias of included studies.
We included six trials that enrolled 794 women and their babies and all assessed nifedipine as calcium channel blocker maintenance therapy. The six trials were judged to be at a moderate risk of bias overall. No differences in the incidence of preterm birth (risk ratio (RR) 0.97; 95% confidence interval (CI) 0.87 to 1.09; five trials, 681 women), birth within 48 hours of treatment (RR 0.46; 95% CI 0.07 to 3.00; two trials, 128 women) or neonatal mortality (average RR 0.75; 95% CI 0.05 to 11.76; two trials, 133 infants) were seen when nifedipine maintenance therapy was compared with placebo or no treatment. No stillbirths were reported in the one trial that provided data for this outcome. No trials reported on longer-term follow-up of infants.Women receiving nifedipine maintenance therapy were significantly more likely to have their pregnancy prolonged (mean difference (MD) 5.35 days; 95% CI 0.49 to 10.21; four trials, 275 women); however, no differences between groups were shown for birth at less than 34 weeks' gestation, birth at less than 28 weeks' gestation, birth within seven days of treatment, or gestational age at birth. No significant differences were shown between the nifedipine and control groups for any of the secondary neonatal morbidities reported. Similarly, no significant differences were seen for the outcomes relating to the use of health services, except for in one trial, where infants whose mothers received nifedipine were significantly more likely to have a longer length of hospital stay as compared with infants born to mothers who received a placebo (MD 14.00 days; 95% CI 4.21 to 23.79; 60 infants).
Based on the current available evidence, maintenance treatment with a calcium channel blocker after threatened preterm labour does not prevent preterm birth or improve maternal or infant outcomes.
In 1950, the World Health Organisation (WHO) defined prematurity as a birthweight of 2500 g or less and in 1961 as a gestational age of less than 37 weeks. The time in between marks an era in which there was growing recognition of the importance of gestational age at birth and how to influence it. The latter was facilitated too by the development of tocography, which permitted some semi-objective measurement of uterine contractility. Along with it, came a growing interest in agents that could control uterine contractility beyond the earlier classical approaches of hormones and gastrointestinal spasmolytics. Hence, the early 1960s saw much research interest in agents, such as nylidrine, isoxsuprine, and orciprenaline that could suppress uterine contractility as one of their many beta-agonist properties. Subsequently, two approaches would be used to shift the balance towards uterine function over and above the influence on other bodily functions. One consisted of supplementing these drugs with agents, such as calcium antagonists and beta-receptor blockers that were hoped to suppress non-uterine actions. The other was a search for drugs in the same class with greater uterospecificity and more selective binding to uterine as opposed to other receptors. Neither of these approaches has ever fully fulfilled the hopes that were pinned on them, but they resulted in the availability of a large number of agents to suppress uterine contractility. The advent of prostaglandins as regulators of uterine contractility and the ability to suppress their biosynthesis saw another range of attempts to suppress uterine activity. They included aspirin, sodium salicylate, flufenamic acid, sulindac and indomethacin, but some were clearly based on a defective understanding of how uterine prostaglandin synthesis can be influenced. In the meantime, a flurry of other agents came and went, often more than once, testifying to the ingenuity of clinicians in trying to solve a problem that is poorly understood. Some, such as relaxin and ethanol, came and disappeared. Others, such as calcium antagonists, entered the scene as protectors against the non-uterine effects of other agents, went, and re-entered the scene in their own right. Still others, such as magnesium sulphate, came, lingered around, and became credited with effects in preterm labour that do not depend on affecting uterine contractility. Amidst this all arose the term tocolysis, coined in 1964 by Mosler from the Greek stems ‘τκζ’ and ‘λυɛιν’, to epitomise all of this ingenuity.
Objective:
The objective of this study is to examine the neurodevelopmental outcome at 30 to 42 months corrected age of preterm infants with histological chorioamnionitis (HCA).
Study design:
The study design is a retrospective cohort study with a prospective follow-up. All surviving infants with birth gestational age <29 weeks, born between 2000 and 2006, who had a neurodevelopmental assessment at 30 to 42 months corrected age were included. We compared the neurodevelopmental outcomes of infants with or without HCA.
Result:
Of the 384 infants, 197 (51%) were born to mothers with evidence of HCA. Infants with HCA were of lower gestational age (26 weeks vs 26.6 weeks) and more likely to have intraventricular hemorrhage (27.9% vs 14.4%), periventricular leukomalacia (2.5% vs 0%) and retinopathy of prematurity ≥ stage 3 (31.4% vs 22.4%). On univariate analysis, infants with HCA were more likely to have cerebral palsy (12.6% vs 6.4%, P=0.04). There was no significant difference in the incidence of cognitive delay, deafness, blindness, or total major disabilities between the two groups. After adjusting for perinatal variables, HCA was associated with increased risk of cerebral palsy (odds ratio (OR): 2.45; 95% confidence interval (CI) 1.11 to 5.40), but not for total major disabilities (OR: 1.22; 95% CI: 0.64 to 2.34). There was a trend towards increased risk of cerebral palsy with HCA with funisitis.
Conclusion:
HCA is associated with increased risk of cerebral palsy at 30 to 42 months corrected age in preterm infants.
Brain injury in premature infants is of enormous public health importance because of the large number of such infants who survive with serious neurodevelopmental disability, including major cognitive deficits and motor disability. This type of brain injury is generally thought to consist primarily of periventricular leukomalacia (PVL), a distinctive form of cerebral white matter injury. Important new work shows that PVL is frequently accompanied by neuronal/axonal disease, affecting the cerebral white matter, thalamus, basal ganglia, cerebral cortex, brain stem, and cerebellum. This constellation of PVL and neuronal/axonal disease is sufficiently distinctive to be termed "encephalopathy of prematurity". The thesis of this Review is that the encephalopathy of prematurity is a complex amalgam of primary destructive disease and secondary maturational and trophic disturbances. This Review integrates the fascinating confluence of new insights into both brain injury and brain development during the human premature period.
To estimate whether maintenance nifedipine tocolysis after arrested preterm labor prolongs pregnancy and improves neonatal outcomes.
A prospective, randomized double-blind, multicenter study was conducted. After successful tocolysis, patients were randomly assigned to receive 20 mg nifedipine or an identical-appearing placebo every 4-6 hours until 37 weeks of gestation. The primary outcome was attainment of 37 weeks of gestation. Patients were enrolled between 24 weeks and 34 weeks if they had six or fewer contractions per hour, intact membranes, and less than 4 cm cervical dilation. Exclusion criteria were placental abruption or previa, fetal anomaly incompatible with life, or maternal medical contraindication to tocolysis. Sixty-six patients were required for 80% power to detect a 50% reduction in birth before 37 weeks, with a two-tailed alpha of 0.05. Data were analyzed by intent to treat.
Seventy-one patients were randomly assigned. Two patients were excluded after randomization and one was lost to follow-up. Thirty-five patients received placebo, and 33 received nifedipine. There were no maternal demographic differences between groups; the placebo group was significantly more dilated and effaced at study entry. There was no difference in attainment of 37 weeks (39% nifedipine compared with 37% placebo, P>.91), mean delay of delivery (33.5+/-19.9 days nifedipine compared with 32.6+/-21.4 days placebo, P=.81) or delay of delivery for greater than 48 hours or 1, 2, 3, or 4 weeks. Neonatal outcomes were similar between groups.
When compared with placebo, maintenance nifedipine tocolysis did not confer a large reduction in preterm birth or improvement in neonatal outcomes.
ClinicalTrials.gov, www.clinicaltrials.gov, NCT00185952
I.
The ORACLE II trial compared the use of erythromycin and/or amoxicillin-clavulanate (co-amoxiclav) with that of placebo for women in spontaneous preterm labour and intact membranes, without overt signs of clinical infection, by use of a factorial randomised design. The aim of the present study--the ORACLE Children Study II--was to determine the long-term effects on children after exposure to antibiotics in this clinical situation.
We assessed children at age 7 years born to the 4221 women who had completed the ORACLE II study and who were eligible for follow-up with a structured parental questionnaire to assess the child's health status. Functional impairment was defined as the presence of any level of functional impairment (severe, moderate, or mild) derived from the mark III Multi-Attribute Health Status classification system. Educational outcomes were assessed with national curriculum test results for children resident in England.
Outcome was determined for 3196 (71%) eligible children. Overall, a greater proportion of children whose mothers had been prescribed erythromycin, with or without co-amoxiclav, had any functional impairment than did those whose mothers had received no erythromycin (658 [42.3%] of 1554 children vs 574 [38.3%] of 1498; odds ratio 1.18, 95% CI 1.02-1.37). Co-amoxiclav (with or without erythromycin) had no effect on the proportion of children with any functional impairment, compared with receipt of no co-amoxiclav (624 [40.7%] of 1523 vs 608 [40.0%] of 1520; 1.03, 0.89-1.19). No effects were seen with either antibiotic on the number of deaths, other medical conditions, behavioural patterns, or educational attainment. However, more children whose mothers had received erythromycin or co-amoxiclav developed cerebral palsy than did those born to mothers who received no erythromycin or no co-amoxiclav, respectively (erythromycin: 53 [3.3%] of 1611 vs 27 [1.7%] of 1562, 1.93, 1.21-3.09; co-amoxiclav: 50 [3.2%] of 1587 vs 30 [1.9%] of 1586, 1.69, 1.07-2.67). The number needed to harm with erythromycin was 64 (95% CI 37-209) and with co-amoxiclav 79 (42-591).
The prescription of erythromycin for women in spontaneous preterm labour with intact membranes was associated with an increase in functional impairment among their children at 7 years of age. The risk of cerebral palsy was increased by either antibiotic, although the overall risk of this condition was low.
UK Medical Research Council.
The ORACLE I trial compared the use of erythromycin and/or amoxicillin-clavulanate (co-amoxiclav) with that of placebo for women with preterm rupture of the membranes without overt signs of clinical infection, by use of a factorial randomised design. The aim of the present study--the ORACLE Children Study I--was to determine the long-term effects on children of these interventions.
We assessed children at age 7 years born to the 4148 women who had completed the ORACLE I trial and who were eligible for follow-up with a structured parental questionnaire to assess the child's health status. Functional impairment was defined as the presence of any level of functional impairment (severe, moderate, or mild) derived from the mark III Multi-Attribute Health Status classification system. Educational outcomes were assessed with national curriculum test results for children resident in England.
Outcome was determined for 3298 (75%) eligible children. There was no difference in the proportion of children with any functional impairment after prescription of erythromycin, with or without co-amoxiclav, compared with those born to mothers who received no erythromycin (594 [38.3%] of 1551 children vs 655 [40.4%] of 1620; odds ratio 0.91, 95% CI 0.79-1.05) or after prescription of co-amoxiclav, with or without erythromycin, compared with those born to mothers who received no co-amoxiclav (645 [40.6%] of 1587 vs 604 [38.1%] of 1584; 1.11, 0.96-1.28). Neither antibiotic had a significant effect on the overall level of behavioural difficulties experienced, on specific medical conditions, or on the proportions of children achieving each level in reading, writing, or mathematics at key stage one.
The prescription of antibiotics for women with preterm rupture of the membranes seems to have little effect on the health of children at 7 years of age.
UK Medical Research Council.
Nifedipine, a calcium entry blocker, has known relaxing effects on the myometrium. Thirteen women in preterm labor received nifedipine for tocolysis. Blood samples obtained serially during treatment and at the time of delivery were assayed for maternal and neonatal nifedipine concentrations. The peak concentration of nifedipine during sublingual therapy ranged from 23.4 to 197.9 ng/ml and reflected substantial interpatient variability. The mean (+/- SD) measurable trough value in patients who received 20 mg of nifedipine orally every 6 hours was 7.2 +/- 5.5 ng/ml. The maternal mean half-life of nifedipine was 81 minutes (range 49 to 137 minutes). At delivery, neonatal nifedipine levels were nondetectable in 6 of the 11 neonates available for study; in 5, values ranged from 29.5 to 1.8 ng/ml. From these results we conclude that both sublingual and oral nifedipine treatment results in variable but usually measurable maternal plasma concentrations and that placental transfer of nifedipine occurs.
To compare the efficacy of nifedipine with ritodrine in the management of preterm labor.
One hundred eighty-five singleton pregnancies with preterm labor were assigned randomly to either ritodrine intravenously (n = 90) or nifedipine orally (n = 95). The principal outcome assessed was delay of delivery.
Ritodrine was discontinued in 12 patients because of severe maternal side effects, and their results were excluded from further analysis. More women in the ritodrine group delivered within 24 hours (22 versus 11, P = .006), within 48 hours (29 versus 21, P = .03), within 1 week (45 versus 36, P = .009), and within 2 weeks (52 versus 43, P = .005) compared with those receiving nifedipine. There were significantly fewer maternal side effects in the nifedipine group. Apgar scores and umbilical artery and vein pHs were similar in both groups. The number of admissions to the neonatal intensive care unit (NICU) in the nifedipine group was significantly lower than in the ritodrine group (68.4 versus 82.1%, P = .04).
Nifedipine in comparison with ritodrine in the management of preterm labor is significantly associated with a longer postponement of deliver, fewer maternal side effects, and fewer admissions to the NICU.
Objective:
Premature infants are at increased risk of developmental disability. Early identification of problems allows intervention to ameliorate or attenuate problems. A reliable screening tool allows triage of children in this high-risk population by identifying those unlikely to need full developmental assessment. To explore the test characteristics of an established parent-completed developmental assessment questionnaire 'Ages and Stages Questionnaire' (ASQ) in follow up of an Australian population of premature infants.
Methodology:
One hundred and sixty-seven children born prematurely with corrected ages 12- to 48-months attending the Growth and Development Clinic at the Mater Children's Hospital in Brisbane, Queensland, Australia; 136 questionnaires 'ASQ' were returned completed (81%) and were compared to formal psychometric assessment (Griffith Mental Development Scales for 12- and 24-months, Bayley Mental Development Intelligence Scale for 18-months, McCarthy General Cognitive Intelligence Scale for 48-months). Developmental delay was considered to be present if any of the above psychometric assessments fell below 1.0 standard deviations (SD). The ASQ cut-off used was 2.0 SD (US data derived means and SD).
Results:
Aggregate results for all age groups comparing ASQ to psychometric assessments as 'gold standards' found the ASQ to have the following test characteristics: sensitivity (90%); specificity (77%); positive predictive value (40%); negative predictive value (98%); % over-referred (20%); % under-referred (1%); % agreement (79%). Likelihood ratio for children failing the ASQ was 3.8 and for passing the ASQ was 0.13. Twenty-one children with known disabilities were included in the study and in 14 of these, the ASQ overall score agreed with the psychometric assessment (67%).
Conclusion:
The high negative predictive value of the ASQ supports its use as a screening tool for cognitive and motor delays in the follow up of ex-premature infants. This would need to be combined with other strategies as part of a comprehensive follow up program for ex-premature infants.
In 1950, the World Health Organisation (WHO) defined prematurity as a birthweight of 2500 g or less and in 1961 as a gestational age of less than 37 weeks. The time in between marks an era in which there was growing recognition of the importance of gestational age at birth and how to influence it. The latter was facilitated too by the development of tocography, which permitted some semi-objective measurement of uterine contractility. Along with it, came a growing interest in agents that could control uterine contractility beyond the earlier classical approaches of hormones and gastrointestinal spasmolytics. Hence, the early 1960s saw much research interest in agents, such as nylidrine, isoxsuprine, and orciprenaline that could suppress uterine contractility as one of their many beta-agonist properties. Subsequently, two approaches would be used to shift the balance towards uterine function over and above the influence on other bodily functions. One consisted of supplementing these drugs with agents, such as calcium antagonists and beta-receptor blockers that were hoped to suppress non-uterine actions. The other was a search for drugs in the same class with greater uterospecificity and more selective binding to uterine as opposed to other receptors. Neither of these approaches has ever fully fulfilled the hopes that were pinned on them, but they resulted in the availability of a large number of agents to suppress uterine contractility. The advent of prostaglandins as regulators of uterine contractility and the ability to suppress their biosynthesis saw another range of attempts to suppress uterine activity. They included aspirin, sodium salicylate, flufenamic acid, sulindac and indomethacin, but some were clearly based on a defective understanding of how uterine prostaglandin synthesis can be influenced. In the meantime, a flurry of other agents came and went, often more than once, testifying to the ingenuity of clinicians in trying to solve a problem that is poorly understood. Some, such as relaxin and ethanol, came and disappeared. Others, such as calcium antagonists, entered the scene as protectors against the non-uterine effects of other agents, went, and re-entered the scene in their own right. Still others, such as magnesium sulphate, came, lingered around, and became credited with effects in preterm labour that do not depend on affecting uterine contractility. Amidst this all arose the term tocolysis, coined in 1964 by Mosler from the Greek stems 'tauomicronkappaomicronzeta' and 'lambdaupsilonepsiloniotanu', to epitomise all of this ingenuity.
Calcium channel blocker maintenance therapy is one of the types of tocolytic therapy used after an episode of threatened preterm labour (and usually an initial dose of tocolytic therapy) in an attempt to prevent the onset of further preterm contractions.
To assess the effects of calcium channel blockers as maintenance therapy on preventing preterm birth after threatened preterm labour.
We searched the Cochrane Pregnancy and Childbirth Group trials register (31 March 2004); MEDLINE (1966 to March 2004) and DARE (June 2003).
Randomised controlled trials of calcium channel blockers used as maintenance therapy to prevent preterm birth after threatened preterm labour, compared with alternative drug therapy, placebo or no treatment.
Two reviewers independently applied the selection criteria, extracted data from the included study and assessed study quality.
One trial of 74 women was included. No difference in the incidence of preterm birth was found when calcium channel blocker (nifedipine) maintenance therapy was compared with no treatment. Twenty-five women out of 37 in each group gave birth before 37 weeks (relative risk 1.00, 95% confidence interval 0.73 to 1.37). The trial did not report stillbirths and neonatal deaths prior to discharge. Neurological follow up of the infants was not addressed.
The role of maintenance therapy with calcium channel blockers for preventing preterm birth is not clear. Well designed randomised trials of sufficient size with relevant outcomes are required.
To compare the long-term psychosocial and motor effects on children exposed in utero to nifedipine or ritodrine for the management of preterm labour.
Randomised controlled trial.
Multicentre study in two university and one primary hospital in the Netherlands.
In the original trial, 185 women were randomised to either nifedipine (n = 95) or ritodrine (n = 90). Of the 185 liveborn children, 171 survived (92%), and of these 102 (61%) were followed up at age 9-12 years.
Age-specific questionnaires were administered to the parent and teacher. Additional data were obtained from medical records.
Questionnaires were used to assess the child's behavioural-emotional problems, quality of life (QoL), motor functioning, parenting distress and the child's education.
Of the 171 eligible families, 102 (61%) agreed to participate and completed the questionnaires. Response was equal in the ritodrine group (n = 54 of 83 surviving children, 65%) compared with the nifedipine group (n= 48 of 88 surviving children, 55%). After controlling for differing perinatal characteristics at birth, no significant differences between the groups were detected with respect to long-term behaviour-emotional outcome, QoL, education, motor functioning or parenting distress. Psychosocial outcome was slightly better in the nifedipine group.
The results do not support any differential postnatal effect of the tocolytic agents ritodrine or nifedipine on the child's long-term psychosocial and motor functioning. The slightly better outcome of children randomised in the nifedipine group is most likely due to more favourable perinatal outcomes in this group. These results merit further investigation in a larger group of survivors.
To assess the effect of nifedipine tocolysis on Doppler parameters of the uterine, umbilical and fetal middle cerebral arteries and atrioventricular valves in the first 48 h of therapy.
Doppler waveforms of uterine, umbilical and middle cerebral arteries and both atrioventricular valves were measured from 28 pregnant women and fetuses prior to and during nifedipine therapy for preterm labor. Maternal and fetal heart rates (FHR), maternal systolic and diastolic blood pressure, and the Doppler pulsatility index (PI) of the uterine, umbilical and middle cerebral arteries were measured. The cerebroplacental ratio (middle cerebral artery PI/umbilical artery PI) was calculated. The total time velocity integrals (TVIs) of tricuspid and mitral valves and their E- and A-wave peak velocity ratio (E/A) were measured. Friedman repeated-measures analysis of variance was used to compare the variables before and after nifedipine therapy. If significant differences were found, Wilcoxon's signed ranks test was used to analyze the difference between the two variables. A P-value of < 0.05 was considered significant.
Nifedipine maintenance was associated with a significant decline in maternal systolic and diastolic blood pressure after 24 h, while maternal heart rate and FHR were unaffected. The uterine artery PI had decreased significantly at 24 and 48 h, while the umbilical artery PI did not change significantly. The middle cerebral artery PI had decreased significantly at 24 and again at 48 h. A significant fall in the cerebroplacental Doppler ratio was maintained beyond 24 h. The mean E/A values, TVIs and TVI x FHR values at 24 and 48 h were unchanged from the baseline values.
Nifedipine maintenance tocolysis is associated with a significant decline in uterine artery and middle cerebral artery Doppler indices 24 h after the first dose. Fetal cardiac diastolic function is unaffected and the significant redistribution observed after 24 h is likely to be attributable to altered cerebral blood flow.
Outcome figures published in scientific journals are often cumbersome and difficult to understand by parents during counselling before or immediately after a very premature birth.
To provide simplified up-to-date outcome information in a table for ease of counselling.
Regional perinatal mortality rates for very premature births (23-31 weeks gestation) and incidence of significant neonatal events for those admitted to neonatal intensive care units (NICU) were obtained from the NSW Midwives Data Collection, ACT Maternal and Perinatal Data Collection and the NSW and ACT NICUS Data Collection for 2000 and 2001. Neurodevelopmental outcome was obtained for the same cohort at 2-3 years of age, corrected for prematurity. The percentage outcomes were rounded off to the closest conservative multiple of 5 for each data point in a table.
The preterm outcome table (POT) for each gestational week was constructed from a total of 2315 births. Of these, 401 (17.3%) were reported as stillborn and were predominantly of 23 to 25 weeks gestation. Of those admitted to NICU, hospital survival rates were 30, 50, 65, 75, 80, 90 and > 95% for 23, 24, 25, 26, 27, 28-29 and 30-31 weeks, respectively. Neurodevelopmental outcome was available for 470 (75%) children, of whom 15% had a moderate to severe functional disability at 2-3 years of age, corrected for prematurity. Simplified data on survival to discharge and outcome were tabulated.
POT appears simple and easy to use but also provides realistic data to assist clinicians in the counselling process.
To determine nifedipine concentrations in maternal plasma at steady state, and maternal and umbilical cord plasma at delivery, after tocolysis with nifedipine gastrointestinal therapeutic system (GITS) tablets.
Prospective clinical pharmacokinetic study.
Department of Obstetrics at the Zurich University Hospital.
Pregnant women treated for threatened preterm labour.
GITS dosage titrated to clinical response (30-150 mg/day). Nifedipine concentrations by high-performance liquid chromatography and turbo ion spray tandem mass spectrometry.
Steady-state nifedipine concentrations in maternal blood and nifedipine concentrations in maternal and corresponding umbilical cord blood at delivery.
Steady-state nifedipine concentrations (micrograms/l, mean +/- SE) were 54 +/- 6 (all doses, n = 31), 38 +/- 8 (60 mg/day, n = 13), and 92 +/- 12 (150 mg/day, n = 7) (P < 0.002). Umbilical cord and maternal concentrations both declined in a ln-linear regression with elimination half-lives of 20.4 and 17.4 hours. Linear regression showed a correlation between umbilical and maternal concentrations of 0.77 +/- 0.1 (n = 21, mean +/- SE).
Steady-state plasma nifedipine concentrations after repeated dosing with nifedipine GITS 30-150 mg/day in pregnant women with preterm labour do not exceed 100 micrograms/l; fetal levels are 77% of maternal levels.
Gynaecologists Nifedipine maintenance tocolysis: 2-year follow up 13 de Heus R The effects of the tocolytics atosiban and nifedipine on fetal movements, heart rate and blood flow
- Ejh Mulder
- Jb Derks
- Gha Visser
Royal College of Obstetricians and Gynaecologists
Nifedipine maintenance tocolysis: 2-year follow up
13 de Heus R, Mulder EJH, Derks JB, Visser GHA. The effects of the
tocolytics atosiban and nifedipine on fetal movements, heart
rate and blood flow. J Matern Fetal Neonatal Med 2009;22:485–
90.
The ASQ-3 user's Guide
- J Squires
- E Twombly
- D Bricker
- L Potter
Squires J, Twombly E, Bricker D, Potter L. The ASQ-3 user's Guide,
3rd edn. Baltimore: Brookes.