Infant wellbeing at 2 years of age in the Growth Restriction Intervention Trial (GRIT): multicentred randomised controlled trial. Methyldopa versus no drug treatment in the management of mild pre-eclampsia. Aggressive versus expectant management of severe preeclampsia at 28 to 32 weeks' gestation: a randomized controlled trial. Analgesia and sedation in preterm neonates who require ventilatory support: results from the NOPAIN trial. Neonatal Outcome and Prolonged Analgesia in Neonates.
Although delivery is widely used for preterm babies failing to thrive in utero, the effect of altering delivery timing has never been assessed in a randomised controlled trial. We aimed to compare the effect of delivering early with delaying birth for as long as possible.
                548 pregnant women were recruited by 69 hospitals in 13 European countries. Participants had fetal compromise between 24 and 36 weeks, an umbilical-artery doppler waveform recorded, and clinical uncertainty about whether immediate delivery was indicated. Before birth, 588 babies were randomly assigned to immediate delivery (n=296) or delayed delivery until the obstetrician was no longer uncertain (n=292). The main outcome was death or disability at or beyond 2 years of age. Disability was defined as a Griffiths developmental quotient of 70 or less or the presence of motor or perceptual severe disability. Analysis was by intention-to-treat. This trial has been assigned the International Standard Randomised Controlled Trial Number ISRCTN41358726.
                Primary outcomes were available on 290 (98%) immediate and 283 (97%) deferred deliveries. Overall rate of death or severe disability at 2 years was 55 (19%) of 290 immediate births, and 44 (16%) of 283 delayed births. With adjustment for gestational age and umbilical-artery doppler category, the odds ratio (95% CrI) was 1.1 (0.7-1.8). Most of the observed difference was in disability in babies younger than 31 weeks of gestation at randomisation: 14 (13%) immediate versus five (5%) delayed deliveries. No important differences in the median Griffiths developmental quotient in survivors was seen.
                The lack of difference in mortality suggests that obstetricians are delivering sick preterm babies at about the correct moment to minimise mortality. However, they could be delivering too early to minimise brain damage. These results do not lend support to the idea that obstetricians can deliver before terminal hypoxaemia to improve brain development. To evaluate the efficacy of methyldopa in the treatment of mild pre-eclampsia, to prevent its progress and to investigate its effect on the pregnancy outcomes.
                Randomised clinical trial.
                Wad Medani Hospital in the central Sudan.
                Seventy primigravidae with single, alive baby of 28-36 weeks gestational age suffering from true mild pre-eclampsia were enrolled. The patients were randomised in two groups, treatment group who received methyldopa 750-4000 mg/day (n=34) and a control group who received no treatment (n=36). All the (treatment and control) patients were drug followed as in-patients till the delivery, seen with their babies on the days 7, 42 after the delivery.
                The outcomes examined were, rise of the diastolic blood pressure to 110 mm Hg or more, occurrence of imminent eclampsia or the eclampsia, if the maturity could be achieved, occurrence of intrauterine growth retardation, abruptio placentae, mode of delivery, birth weight, placental weight, perinatal death, Apgar score and referral of the babies to the pediatrician.
                Three out of 34 (8.8%) of the treatment group had a rise in the diastolic blood pressure of 110 mm Hg, 18/36 (50%) of the control had a rise in the diastolic blood pressure of 110 mmHg (p < 0.05). Three out of thirty four (8.8%) of the treatment group developed imminent eclampsia, while 10/36 (27.8) of the control group developed imminent eclampsia (p < 0.05). The maturity was achieved in 82.3% and 88.8% of the treatment and the control, respectively (p > 0.05). There were ten (14.2%) perinatal deaths, four of them in the treatment group, while six in the control (p > 0.05). There was no difference regarding birth weight, occurrence of intrauterine growth retardation, placental weight, mode of delivery, Apgar score, referral of the babies to the paediatrician. No patient developed eclampsia or abruptio placenta; there was no maternal death in both groups.
                Methyldopa can prevent the progress of the mild pre-eclampsia to severe pre-eclampsia, without affecting the maturity, birthweight or the neonatal outcomes. Our purpose was to determine whether aggressive or expectant management of severe preeclampsia at 28 to 32 weeks is more beneficial to maternal and neonatal outcome.
                Ninety-five eligible patients were randomly assigned to either aggressive (n = 46) or expectant management (n = 49). Aggressive management patients were prepared for delivery, either by cesarean or induction, 48 hours after glucocorticoids were administered. Expectant management patients were managed with bed rest, oral antihypertensives, and intensive antenatal fetal testing.
                At the time of randomization there were no differences between the two groups in mean systolic blood pressure (170 +/- 9.7 vs 172 +/- 9.4 mm Hg), diastolic blood pressure (110 +/- 5.4 vs 112 +/- 4.2 mm Hg), proteinuria (3.0 +/- 2.3 vs 3.6 +/- 2.3 gm per 24 hours), and gestational age (30.4 +/- 1.6 vs 30.7 +/- 1.5 weeks) for the aggressive and expectant management groups. The average latency period in the expectant management group was 15.4 days (range 4 to 36), and this period was not affected by the amount of proteinuria at randomization. There was no eclampsia or perinatal death in either group. The two groups had similar incidences of abruptio placentae (4.1% vs 4.3%) and similar days of postpartum hospital stay. The expectant management group had a significantly higher gestational age at delivery (32.9 +/- 1.5 vs 30.8 +/- 1.7 weeks, p < 0.0001), higher birth weight, lower incidence of admission to the neonatal intensive care unit (76% vs 100%, p = 0.002), lower mean days of hospitalization in the intensive care unit (20.2 +/- 14 vs 36.6 +/- 17.4, p < 0.0001), and lower incidence of neonatal complications.
                Expectant management, with close monitoring of mother and fetus at a perinatal center, reduces neonatal complications and neonatal stay in the newborn intensive care unit. Preterm neonates are exposed to multiple painful procedures after birth and exhibit acute physiological responses to pain. Occurrence of early intraventricular hemorrhage within 24 to 72 hours after birth suggests a role of pain and stress in the multifactorial causation of severe intraventricular hemorrhage and periventricular leukomalacia. We proposed that such neurologic outcomes in preterm neonates who require ventilatory support may be reduced by morphine analgesia or midazolam sedation compared with a placebo.
                To define the incidence of clinical outcomes in the target study population, to estimate the effect size and adverse effects associated with analgesia and sedation, and to calculate the sample size for a definitive test of this hypothesis.
                Sixty-seven preterm neonates were randomized in a pilot clinical trial from 9 centers. Neonates of 24 to 32 weeks gestation were eligible if they had been intubated and required ventilatory support for less than 8 hours and if they were enrolled within 72 hours after birth. Exclusion criteria included major congenital anomalies, severe intrapartum asphyxia, and participation in other research studies. Severity of illness was assessed by the Clinical Risk Index for Babies, and neonates were randomized to receive continuous infusions of morphine sulfate, midazolam hydrochloride, or 10% dextrose (placebo). Masked study medications were continued as long as clinically necessary, then weaned and stopped according to predefined criteria. Levels of sedation (COMFORT scores) and responses to pain (Premature Infant Pain Profile scores) were measured before, during, and 12 hours after discontinuation of drug infusion. Cranial ultrasound examinations were performed as part of routine practice, and poor neurologic outcomes were defined as neonatal death, severe intraventricular hemorrhage (grade III or IV), or periventricular leukomalacia.
                No significant differences occurred in the demographic, clinical, and socioeconomic variables related to mothers and neonates in the 3 groups or in the severity of illness at birth as measured by Clinical Risk Index for Babies scores. Two neonates in the placebo group and 1 neonate in the midazolam group died; no deaths occurred in the morphine group. Poor neurologic outcomes occurred in 24% of neonates in the placebo group, 32% in the midazolam group, and 4% in the morphine group (likelihood ratio chi2 = 7.04, P = .03). Secondary clinical outcomes and neurobehavioral outcomes at 36 weeks' postconceptional age were similar in the 3 groups. Responses elicited by endotracheal tube suction (Premature Infant Pain Profile scores) were significantly reduced during the morphine (P<.001) and midazolam (P = .002) infusions compared with the placebo group.
                This pilot trial suggests that preemptive analgesia given by continuous low-dose morphine infusion may reduce the incidence of poor neurologic outcomes in preterm neonates who require ventilatory support. Limitations in the sample size of this pilot study suggest that these results should be confirmed in a large multicenter randomized trial.
The review identified no significant differences for the primary outcomes perinatal mortality, preterm birth less than 34 weeks' gestation, and childhood neurodevelopmental handicap, although the number of studies and participants was small. While treatment with heparin appears promising with a reduction in pre-eclampsia, eclampsia, and infant birthweight less than the 10th centile for gestational age, the number of studies and participants included was small, and to date important information about serious adverse infant and long-term childhood outcomes is unavailable. Further research is required.
[Note: The 14 citations in the awaiting classification section of the review may alter the conclusions of the review once assessed.]