Neonatal Glycemia and Neurodevelopmental Outcomes at 2 Years McKinlay, Christopher J D; Alsweiler, Jane M; Ansell, Judith M ...
New England journal of medicine/The New England journal of medicine,
2015-Oct-15, Volume:
373, Issue:
16
Journal Article
Peer reviewed
Open access
Neonatal hypoglycemia is common and can cause neurologic impairment, but evidence supporting thresholds for intervention is limited.
We performed a prospective cohort study involving 528 neonates ...with a gestational age of at least 35 weeks who were considered to be at risk for hypoglycemia; all were treated to maintain a blood glucose concentration of at least 47 mg per deciliter (2.6 mmol per liter). We intermittently measured blood glucose for up to 7 days. We continuously monitored interstitial glucose concentrations, which were masked to clinical staff. Assessment at 2 years included Bayley Scales of Infant Development III and tests of executive and visual function.
Of 614 children, 528 were eligible, and 404 (77% of eligible children) were assessed; 216 children (53%) had neonatal hypoglycemia (blood glucose concentration, <47 mg per deciliter). Hypoglycemia, when treated to maintain a blood glucose concentration of at least 47 mg per deciliter, was not associated with an increased risk of the primary outcomes of neurosensory impairment (risk ratio, 0.95; 95% confidence interval CI, 0.75 to 1.20; P=0.67) and processing difficulty, defined as an executive-function score or motion coherence threshold that was more than 1.5 SD from the mean (risk ratio, 0.92; 95% CI, 0.56 to 1.51; P=0.74). Risks were not increased among children with unrecognized hypoglycemia (a low interstitial glucose concentration only). The lowest blood glucose concentration, number of hypoglycemic episodes and events, and negative interstitial increment (area above the interstitial glucose concentration curve and below 47 mg per deciliter) also did not predict the outcome.
In this cohort, neonatal hypoglycemia was not associated with an adverse neurologic outcome when treatment was provided to maintain a blood glucose concentration of at least 47 mg per deciliter. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others.).
Hypoglycemia is common during neonatal transition and may cause permanent neurological impairment, but optimal intervention thresholds are unknown.
To test the hypothesis that neurodevelopment at 4.5 ...years is related to the severity and frequency of neonatal hypoglycemia.
The Children With Hypoglycemia and Their Later Development (CHYLD) Study is a prospective cohort investigation of moderate to late preterm and term infants born at risk of hypoglycemia. Clinicians were masked to neonatal interstitial glucose concentrations; outcome assessors were masked to neonatal glycemic status. The setting was a regional perinatal center in Hamilton, New Zealand. The study was conducted from December 2006 to November 2010. The dates of the follow-up were September 2011 to June 2015. Participants were 614 neonates born from 32 weeks' gestation with at least 1 risk factor for hypoglycemia, including diabetic mother, preterm, small, large, or acute illness. Blood and masked interstitial glucose concentrations were measured for up to 7 days after birth. Infants with hypoglycemia (whole-blood glucose concentration <47 mg/dL) were treated to maintain blood glucose concentration of at least 47 mg/dL.
Neonatal hypoglycemic episode, defined as at least 1 consecutive blood glucose concentration less than 47 mg/dL, a severe episode (<36 mg/dL), or recurrent (≥3 episodes). An interstitial episode was defined as an interstitial glucose concentration less than 47 mg/dL for at least 10 minutes.
Cognitive function, executive function, visual function, and motor function were assessed at 4.5 years. The primary outcome was neurosensory impairment, defined as poor performance in one or more domains.
In total, 477 of 604 eligible children (79.0%) were assessed. Their mean (SD) age at the time of assessment was 4.5 (0.1) years, and 228 (47.8%) were female. Those exposed to neonatal hypoglycemia (280 58.7%) did not have increased risk of neurosensory impairment (risk difference RD, 0.01; 95% CI, -0.07 to 0.10 and risk ratio RR, 0.96; 95% CI, 0.77 to 1.21). However, hypoglycemia was associated with increased risk of low executive function (RD, 0.05; 95% CI, 0.01 to 0.10 and RR, 2.32; 95% CI, 1.17 to 4.59) and visual motor function (RD, 0.03; 95% CI, 0.01 to 0.06 and RR, 3.67; 95% CI, 1.15 to 11.69), with highest risk in children exposed to severe, recurrent, or clinically undetected (interstitial episodes only) hypoglycemia.
Neonatal hypoglycemia was not associated with increased risk of combined neurosensory impairment at 4.5 years but was associated with a dose-dependent increased risk of poor executive function and visual motor function, even if not detected clinically, and may thus influence later learning. Randomized trials are needed to determine optimal screening and intervention thresholds based on assessment of neurodevelopment at least to school age.
Background
It has been unclear whether repeat dose(s) of prenatal corticosteroids are beneficial.
Objectives
To assess the effectiveness and safety of repeat dose(s) of prenatal corticosteroids.
...Search methods
We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (20 January 2015), searched reference lists of retrieved studies and contacted authors for further data.
Selection criteria
Randomised controlled trials of women who had already received a single course of corticosteroids seven or more days previously and considered still at risk of preterm birth.
Data collection and analysis
We assessed trial quality and extracted data independently.
Main results
We included 10 trials (a total of 4733 women and 5700 babies) with low to moderate risk of bias. Treatment of women who remain at risk of preterm birth seven or more days after an initial course of prenatal corticosteroids with repeat dose(s), compared with no repeat corticosteroid treatment, reduced the risk of their infants experiencing the primary outcomes respiratory distress syndrome (risk ratio (RR) 0.83, 95% confidence interval (CI) 0.75 to 0.91, eight trials, 3206 infants, number needed to treat to benefit (NNTB) 17, 95% CI 11 to 32) and serious infant outcome (RR 0.84, 95% CI 0.75 to 0.94, seven trials, 5094 infants, NNTB 30, 95% CI 19 to 79).
Treatment with repeat dose(s) of corticosteroid was associated with a reduction in mean birthweight (mean difference (MD) ‐75.79 g, 95% CI ‐117.63 to ‐33.96, nine trials, 5626 infants). However, outcomes that adjusted birthweight for gestational age (birthweight Z scores, birthweight multiples of the median and small‐for‐gestational age) did not differ between treatment groups.
At early childhood follow‐up, no statistically significant differences were seen for infants exposed to repeat prenatal corticosteroids compared with unexposed infants for the primary outcomes (total deaths; survival free of any disability or major disability; disability; or serious outcome) or in the secondary outcome growth assessments. In women, for the two primary outcomes, there was no increase in infectious morbidity of chorioamnionitis or puerperal sepsis, and the likelihood of a caesarean birth was unchanged.
Authors' conclusions
The short‐term benefits for babies of less respiratory distress and fewer serious health problems in the first few weeks after birth support the use of repeat dose(s) of prenatal corticosteroids for women still at risk of preterm birth seven days or more after an initial course. These benefits were associated with a small reduction in size at birth. The current available evidence reassuringly shows no significant harm in early childhood, although no benefit.
Further research is needed on the long‐term benefits and risks for the woman and baby. Individual patient data meta‐analysis may clarify how to maximise benefit and minimise harm.
Background
Magnesium sulphate has been used in some settings as a tocolytic agent to inhibit uterine activity in women in preterm labour with the aim of preventing preterm birth.
Objectives
To assess ...the effects of magnesium sulphate therapy given to women in threatened preterm labour with the aim of preventing preterm birth and its sequelae.
Search methods
We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (last searched 31 January 2014).
Selection criteria
Randomised controlled trials of magnesium sulphate as the only tocolytic, administered by any route, compared with either placebo, no treatment or alternative tocolytic therapy (not magnesium sulphate) to women considered to be in preterm labour.
Data collection and analysis
At least two review authors assessed trial eligibility and risk of bias and undertook data extraction independently.
Main results
The 37 included trials (total of 3571 women and over 3600 babies) were generally of moderate to high risk of bias. Antenatal magnesium sulphate was compared with either placebo, no treatment, or a range of alternative tocolytic agents.
For the primary outcome of giving birth within 48 hours after trial entry, no significant differences were seen between women who received magnesium sulphate and women who did not (whether placebo/no alternative tocolytic drug, betamimetics, calcium channel blockers, cox inhibitors, prostaglandin inhibitors, or human chorionic gonadotropin) (19 trials, 1913 women). Similarly for the primary outcome of serious infant outcome, there were no significant differences between the infants exposed to magnesium sulphate and those not (whether placebo/no alternative tocolytic drug, betamimetics, calcium channel blockers, cox inhibitors, prostaglandin inhibitors, human chorionic gonadotropin or various tocolytic drugs) (18 trials; 2187 babies). No trials reported the outcome of extremely preterm birth. In the seven trials that reported serious maternal outcomes, no events were recorded.
In the group treated with magnesium sulphate compared with women receiving antenatal placebo or no alternative tocolytic drug, a borderline increased risk of total death (fetal, neonatal, infant) was seen (risk ratio (RR) 4.56, 95% confidence interval (CI) 1.00 to 20.86; two trials, 257 babies); none of the comparisons between magnesium sulphate and other classes of tocolytic drugs showed differences for this outcome (10 trials, 991 babies). The outcomes of neonatal and/or infant deaths and of fetal deaths did not show differences between magnesium sulphate and no magnesium sulphate, whether compared with placebo/no alternative tocolytic drug, or any specific class of tocolytic drug. For most of the other secondary outcomes, there were no significant differences between magnesium sulphate and the control groups for risk of preterm birth (except for a significantly lower risk with magnesium sulphate when compared with barbiturates in one trial of 65 women), gestational age at birth, interval between trial entry and birth, other neonatal morbidities, or neurodevelopmental outcomes. Duration of neonatal intensive care unit stay was significantly increased in the magnesium sulphate group compared with the calcium channel blocker group, but not when compared with cox inhibitors or prostaglandin inhibitors. No maternal deaths were reported in the four trials reporting this outcome. Significant differences between magnesium sulphate and controls were not seen for maternal adverse events severe enough to stop treatment, except for a significant benefit of magnesium sulphate compared with betamimetics in a single trial.
Authors' conclusions
Magnesium sulphate is ineffective at delaying birth or preventing preterm birth, has no apparent advantages for a range of neonatal and maternal outcomes as a tocolytic agent and its use for this indication may be associated with an increased risk of total fetal, neonatal or infant mortality (in contrast to its use in appropriate groups of women for maternal, fetal, neonatal and infant neuroprotection where beneficial effects have been demonstrated).
Encouraging awareness of fetal movements is a common strategy used to prevent stillbirths. Information provided to pregnant women about fetal movements is inconsistent perhaps due to limited ...knowledge about normal fetal movement patterns in healthy pregnancies. We aimed to describe maternally perceived fetal movement strength, frequency, and pattern in late pregnancy in women with subsequent normal outcomes.
Participants were ≥28 weeks' gestation, with a non-anomalous, singleton pregnancy who had been randomly selected from hospital booking lists and had consented to participate. Fetal movement data was gathered during pregnancy via a questionnaire administered face-to-face by research midwives. Participants remained eligible for the study if they subsequently gave birth to a live, appropriate-for-gestational-age baby at ≥37 weeks.
Participants were 274 women, with normal pregnancy outcomes. The majority (59.3%, n = 162) of women reported during antenatal interview that the strength of fetal movements had increased in the preceding two weeks. Strong fetal movements were felt by most women in the evening (72.8%, n = 195) and at night-time including bedtime (74.5%, n = 199). The perception of fetal hiccups was also reported by most women (78.8%). Women were more likely to perceive moderate or strong fetal movements when sitting quietly compared with other activities such as having a cold drink or eating.
Our data support informing women in the third trimester that as pregnancy advances it is normal to perceive increasingly strong movement, episodes of movements that are more vigorous than usual, fetal hiccups, and a diurnal pattern involving strong fetal movement in the evening. This information may help pregnant women to better characterise normal fetal movement and appropriately seek review when concerned about fetal movements. Care providers should be responsive to concerns about decreased fetal movements in the evening, as this is unusual.
Neonatal hypoglycemia is associated with increased risk of poor executive and visual-motor function, but implications for later learning are uncertain.
To test the hypothesis that neonatal ...hypoglycemia is associated with educational performance at age 9 to 10 years.
Prospective cohort study of moderate to late preterm and term infants born at risk of hypoglycemia. Blood and masked interstitial sensor glucose concentrations were measured for up to 7 days. Infants with hypoglycemic episodes (blood glucose concentration <47 mg/dL 2.6 mmol/L) were treated to maintain a blood glucose concentration of at least 47 mg/dL. Six hundred fourteen infants were recruited at Waikato Hospital, Hamilton, New Zealand, in 2006-2010; 480 were assessed at age 9 to 10 years in 2016-2020.
Hypoglycemia was defined as at least 1 hypoglycemic event, representing the sum of nonconcurrent hypoglycemic and interstitial episodes (sensor glucose concentration <47 mg/dL for ≥10 minutes) more than 20 minutes apart.
The primary outcome was low educational achievement, defined as performing below or well below the normative curriculum level in standardized tests of reading comprehension or mathematics. There were 47 secondary outcomes related to executive function, visual-motor function, psychosocial adaptation, and general health.
Of 587 eligible children (230 48% female), 480 (82%) were assessed at a mean age of 9.4 (SD, 0.3) years. Children who were and were not exposed to neonatal hypoglycemia did not significantly differ on rates of low educational achievement (138/304 47% vs 82/176 48%, respectively; adjusted risk difference, -2% 95% CI, -11% to 8%; adjusted relative risk, 0.95 95% CI, 0.78-1.15). Children who were exposed to neonatal hypoglycemia, compared with those not exposed, were significantly less likely to be rated by teachers as being below or well below the curriculum level for reading (68/281 24% vs 49/157 31%, respectively; adjusted risk difference, -9% 95% CI, -17% to -1%; adjusted relative risk, 0.72 95% CI, 0.53-0.99; P = .04). Groups were not significantly different for other secondary end points.
Among participants at risk of neonatal hypoglycemia who were screened and treated if needed, exposure to neonatal hypoglycemia compared with no such exposure was not significantly associated with lower educational achievement in mid-childhood.
Antenatal corticosteroids for women at risk of preterm birth reduce neonatal morbidity and mortality, but there is limited evidence regarding their effects on long-term health. This study assessed ...cardiovascular outcomes at 50 years after antenatal exposure to corticosteroids.
We assessed the adult offspring of women who participated in the first randomised, double-blind, placebo-controlled trial of antenatal betamethasone for the prevention of neonatal respiratory distress syndrome (RDS) (1969 to 1974). The first 717 mothers received 2 intramuscular injections of 12 mg betamethasone or placebo 24 h apart and the subsequent 398 received 2 injections of 24 mg betamethasone or equivalent volume of placebo. Follow-up included a health questionnaire and consent to access administrative data sources. The co-primary outcomes were the prevalence of cardiovascular risk factors (any of hypertension, hyperlipidaemia, diabetes mellitus, gestational diabetes mellitus, or prediabetes) and age at first major adverse cardiovascular event (MACE) (cardiovascular death, myocardial infarction, coronary revascularisation, stroke, admission for peripheral vascular disease, and admission for heart failure). Analyses were adjusted for gestational age at entry, sex, and clustering. Of 1,218 infants born to 1,115 mothers, we followed up 424 (46% of survivors; 212 50% female) at mean (standard deviation) age 49.3 (1.0) years. There were no differences between those exposed to betamethasone or placebo for cardiovascular risk factors (159/229 69.4% versus 131/195 67.2%; adjusted relative risk 1.02, 95% confidence interval CI 0.89, 1.18;; p = 0.735) or age at first MACE (adjusted hazard ratio 0.58, 95% CI 0.23, 1.49; p = 0.261). There were also no differences in the components of these composite outcomes or in any of the other secondary outcomes. Key limitations were follow-up rate and lack of in-person assessments.
There is no evidence that antenatal corticosteroids increase the prevalence of cardiovascular risk factors or incidence of cardiovascular events up to 50 years of age. Established benefits of antenatal corticosteroids are not outweighed by an increase in adult cardiovascular disease.
Background
Gestational diabetes (GDM) is glucose intolerance, first recognised in pregnancy and usually resolving after birth. GDM is associated with both short‐ and long‐term adverse effects for the ...mother and her infant. Lifestyle interventions are the primary therapeutic strategy for many women with GDM.
Objectives
To evaluate the effects of combined lifestyle interventions with or without pharmacotherapy in treating women with gestational diabetes.
Search methods
We searched the Pregnancy and Childbirth Group's Trials Register (14 May 2016), ClinicalTrials.gov, WHO International Clinical Trials Registry Platform (ICTRP) (14th May 2016) and reference lists of retrieved studies.
Selection criteria
We included only randomised controlled trials comparing a lifestyle intervention with usual care or another intervention for the treatment of pregnant women with GDM. Quasi‐randomised trials were excluded. Cross‐over trials were not eligible for inclusion. Women with pre‐existing type 1 or type 2 diabetes were excluded.
Data collection and analysis
We used standard methodological procedures expected by the Cochrane Collaboration. All selection of studies, data extraction was conducted independently by two review authors.
Main results
Fifteen trials (in 45 reports) are included in this review (4501 women, 3768 infants). None of the trials were funded by a conditional grant from a pharmaceutical company. The lifestyle interventions included a wide variety of components such as education, diet, exercise and self‐monitoring of blood glucose. The control group included usual antenatal care or diet alone. Using GRADE methodology, the quality of the evidence ranged from high to very low quality. The main reasons for downgrading evidence were inconsistency and risk of bias. We summarised the following data from the important outcomes of this review.
Lifestyle intervention versus control group
For the mother:
There was no clear evidence of a difference between lifestyle intervention and control groups for the risk of hypertensive disorders of pregnancy (pre‐eclampsia)
(average risk ratio (RR) 0.70; 95% confidence interval (CI) 0.40 to 1.22; four trials, 2796 women; I2 = 79%, Tau2 = 0.23; low‐quality evidence); caesarean section (average RR 0.90; 95% CI 0.78 to 1.05; 10 trials, 3545 women; I2 = 48%, Tau2 = 0.02; low‐quality evidence); development of type 2 diabetes
(up to a maximum of 10 years follow‐up) (RR 0.98, 95% CI 0.54 to 1.76; two trials, 486 women; I2 = 16%; low‐quality evidence); perineal trauma/tearing (RR 1.04, 95% CI 0.93 to 1.18; one trial, n = 1000 women; moderate‐quality evidence) or induction of labour (average RR 1.20, 95% CI 0.99 to 1.46; four trials, n = 2699 women; I2 = 37%; high‐quality evidence).
More women in the lifestyle intervention group had met postpartum weight goals one year after birth than in the control group (RR 1.75, 95% CI 1.05 to 2.90; 156 women; one trial, low‐quality evidence). Lifestyle interventions were associated with a decrease in the risk of postnatal depression compared with the control group (RR 0.49, 95% CI 0.31 to 0.78; one trial, n = 573 women; low‐quality evidence).
For the infant/child/adult:
Lifestyle interventions were associated with a reduction in the risk of being born large‐for‐gestational age (LGA)
(RR 0.60, 95% CI 0.50 to 0.71; six trials, 2994 infants; I2 = 4%; moderate‐quality evidence). Birthweight and the incidence of macrosomia were lower in the lifestyle intervention group.
Exposure to the lifestyle intervention was associated with decreased neonatal fat mass compared with the control group (mean difference (MD) ‐37.30 g, 95% CI ‐63.97 to ‐10.63; one trial, 958 infants; low‐quality evidence). In childhood, there was no clear evidence of a difference between groups for body mass index (BMI) ≥ 85th percentile (RR 0.91, 95% CI 0.75 to 1.11; three trials, 767 children; I2 = 4%; moderate‐quality evidence).
There was no clear evidence of a difference between lifestyle intervention and control groups for the risk of perinatal death
(RR 0.09, 95% CI 0.01 to 1.70; two trials, 1988 infants; low‐quality evidence). Of 1988 infants, only five events were reported in total in the control group and there were no events in the lifestyle group. There was no clear evidence of a difference between lifestyle intervention and control groups for a composite of serious infant outcome/s (average RR 0.57, 95% CI 0.21 to 1.55; two trials, 1930 infants; I2 = 82%, Tau2 = 0.44; very low‐quality evidence) or neonatal hypoglycaemia (average RR 0.99, 95% CI 0.65 to 1.52; six trials, 3000 infants; I2 = 48%, Tau2 = 0.12; moderate‐quality evidence).
Diabetes and adiposity in adulthood and neurosensory disability in later childhoodwere not prespecified or reported as outcomes for any of the trials included in this review.
Authors' conclusions
Lifestyle interventions are the primary therapeutic strategy for women with GDM. Women receiving lifestyle interventions were less likely to have postnatal depression and were more likely to achieve postpartum weight goals. Exposure to lifestyle interventions was associated with a decreased risk of the baby being born LGA and decreased neonatal adiposity. Long‐term maternal and childhood/adulthood outcomes were poorly reported.
The value of lifestyle interventions in low‐and middle‐income countries or for different ethnicities remains unclear. The longer‐term benefits or harms of lifestyle interventions remains unclear due to limited reporting.
The contribution of individual components of lifestyle interventions could not be assessed. Ten per cent of participants also received some form of pharmacological therapy. Lifestyle interventions are useful as the primary therapeutic strategy and most commonly include healthy eating, physical activity and self‐monitoring of blood glucose concentrations.
Future research could focus on which specific interventions are most useful (as the sole intervention without pharmacological treatment), which health professionals should give them and the optimal format for providing the information. Evaluation of long‐term outcomes for the mother and her child should be a priority when planning future trials. There has been no in‐depth exploration of the costs ‘saved’ from reduction in risk of LGA/macrosomia and potential longer‐term risks for the infants.
To assess if exposure to repeat dose(s) of antenatal corticosteroids has beneficial effects on neurodevelopment and general health in mid-childhood, at 6 to 8 years' corrected age.
Women at risk for ...very preterm birth, who had received a course of corticosteroids ≥7 days previously, were randomized to intramuscular betamethasone (11.4 mg Celestone Chronodose) or saline placebo, repeated weekly if risk of very preterm birth remained. Mid-childhood assessments included neurocognitive function, behavior, growth, lung function, blood pressure, health-related quality of life, and health service utilization. The primary outcome was survival free of neurosensory disability.
Of the 1059 eligible long-term survivors, 963 (91%) were included in the primary outcome; 479 (91%) in the repeat corticosteroid group and 484 (91%) in the placebo group. The rate of survival free of neurosensory disability was similar in both groups (78.3% repeat versus 77.3% placebo; risk ratio 1.00, 95% confidence interval, 0.94-1.08). Neurodevelopment, including cognitive function, and behavior, body size, blood pressure, spirometry, and health-related quality of life were similar in both groups, as was the use of health services.
Treatment with repeat dose(s) of antenatal corticosteroids was associated with neither benefit nor harm in mid-childhood. Our finding of long-term safety supports the use of repeat dose(s) of antenatal corticosteroids, in view of the related neonatal benefits. For women at risk for preterm birth before 32 weeks' gestation, ≥7 days after an initial course of antenatal corticosteroids, clinicians could consider using a single injection of betamethasone, repeated weekly if risk remains.
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