European consensus guidelines for preterm infants

The recent European consensus guidelines on the management of neonatal respiratory distress syndrome in preterm infants reviewed the same evidence that was available to the ACOG Committee. In contrast to the ACOG Committee Opinion, the European guidelines made a formal recommendation: “If possible delay clamping of the umbilical cord for at least 60 s with the baby held below the mother to promote placentofetal transfusion.” The guidelines noted that a large multicenter trial is underway to determine whether this practice genuinely improves short- and long-term outcome. However, the guidelines did not mention the current lack of evidence as to whether DCC improves or worsens survival or neurosensory disability. Despite these major gaps in the evidence, the advice to delay clamping of the cord in preterm infants was graded A, which suggests the highest level of evidence to support the recommendation.

Potential mechanisms, benefits and risks

Enhancing placental transfusion by DCC might benefit the very preterm infant by increasing neonatal blood volume, thereby potentially improving perfusion and reducing organ injury. DCC may also allow more time for spontaneous breathing to begin before the umbilical cord is clamped, achieving a smoother transition of the cardiopulmonary and cerebral circulation and reducing the risk of invasive and potentially injurious resuscitation. DCC may also increase iron stores, reduce childhood anaemia, and increase the transfer of stem cells, which may have anti-inflammatory, neurotrophic and neuroprotective effects. However, DCC may increase the incidence and severity of jaundice and hypothermia and its long-term effects are unknown. Also, if DCC delays urgently needed resuscitation, it may cause net long-term harm.

Potential mechanisms, benefits and risks

Enhancing placental transfusion by DCC might benefit the very preterm infant by increasing neonatal blood volume, thereby potentially improving perfusion and reducing organ injury. DCC may also allow more time for spontaneous breathing to begin before the umbilical cord is clamped, achieving a smoother transition of the cardiopulmonary and cerebral circulation and reducing the risk of invasive and potentially injurious resuscitation. DCC may also increase iron stores, reduce childhood anaemia, and increase the transfer of stem cells, which may have anti-inflammatory, neurotrophic and neuroprotective effects. However, DCC may increase the incidence and severity of jaundice and hypothermia and its long-term effects are unknown. Also, if DCC delays urgently needed resuscitation, it may cause net long-term harm.

How have others interpreted current evidence?

Authors of systematic reviews and consensus statements have drawn varying conclusions from the available evidence. Importantly, few have noted that conclusions may need to change in the light of results from ongoing randomized controlled trials (RCTs), which could enroll >10 times as many very preterm infants as those on which current advice is based.

Trials in infants at <37 weeks’ gestation

The most recent Cochrane Review synthesized evidence from 15 RCTs in 738 infants who were born at <37 weeks’ gestation, an average of only 49 infants per trial, or about 25 infants per study arm in each trial. The number born at <30 weeks’ gestation could not be ascertained. Also, several studies were at risk of bias, with missing data for several outcomes. The trials compared early cord clamping, in <20 seconds, with strategies to enhance placental transfusion. These were DCCs for 30-120 seconds or, in 1 RCT, cord milking. The 4 primary outcomes were death, severe (grade 3 or 4) intraventricular hemorrhage (IVH), periventricular leukomalacia, and neurodevelopment in early childhood. Increased placental transfusion appeared to protect against the secondary outcome of IVH (all grades). Among 534 infants, the risk ratio (RR) was 0.59 (95% confidence interval [CI], 0.41–0.85; P = .0048). However, the clinical significance of this was unclear because there were too few data about the primary outcomes of severe (grades 3 or 4) IVH (n = 305; RR, 0.68; 95% CI, 0.23–1.96; P = .20) and neurodevelopment at age 2-3 years (n = 0). There were no differences in development in 58 children 7 months after discharge from hospital. The authors concluded that “there were insufficient data for reliable conclusions about the comparative effects on any of the primary outcomes for this review.”

DCC also improved other short-term outcomes, including necrotizing enterocolitis, transfusions for anemia, use of inotropes, late onset sepsis, and increased peak bilirubin. However, the Cochrane authors concluded that “larger multicentre studies are essential and demand international collaboration …. Future studies should include more data … on long term neurodevelopmental outcome at two years of age. …”

Trials in infants at <30 weeks’ gestation

In a systematic review, Ghavam et al evaluated neurodevelopmental outcome at 18-24 months in RCTs of very low birthweight (<1000 g) preterm infants of <30 weeks’ gestation. Infants were assigned randomly either to early clamping or to enhanced placental transfusion by DCC or milking. Trial authors were contacted for additional information. In 10 eligible RCTs, 199 infants were enrolled, which was an average of 20 per trial or approximately 10 per study arm in each trial. Information on the primary outcome of neurodevelopment at 18-24 months could be obtained for just 96 infants, from just 3 of the 10 trials. No difference was found in rates of disability or death between early clamping and enhanced placental transfusion in these 3 trials.

Two RCTs followed 42 children at 18-24 months but used different developmental scales and were inconclusive. Short-term benefits in all 10 trials included improved blood pressure and hemoglobin concentration, fewer blood transfusions, late-onset sepsis, and a trend ( P = .08) to reduced IVH of all grades. The authors concluded that, for very low birthweight infants of <30 weeks’ gestation, “paucity of data on neurodevelopmental outcomes and safety concerns tempers enthusiasm for these interventions. Appropriately designed RCTs to assess short-term and long-term outcomes are needed.”

Need for adequate power and follow up

Adequate sample size and power are critical in perinatal trials. Recent neonatal oxygen-targeting trials underline the need for studies to be powered to detect reliably the incidence of substantive outcomes such as death. Childhood follow-up evaluation is also critical. Many interventions in pregnancy and the newborn infant have suggested short-term benefit, but longer term evidence has been inconclusive or indicated harm. Several examples underline the need for caution.

High-dose postnatal steroids

Toward the end of last century, many babies at risk of chronic lung disease were treated with high-dose steroids soon after birth. Early trials had suggested short-term benefits (eg, less oxygen dependence and chronic lung disease), so high-dose steroids were increasingly adopted world-wide. Follow-up studies did not show improved survival, and some studies showed an increase in cerebral palsy.

Antenatal antibiotics and antenatal thyrotropin-releasing hormone

The Overview of the Role of Antibiotics in Curtailing Labour and Early delivery (ORACLE) trial of antibiotics in women who were at risk of preterm birth suggested the hypothesis, in 2226 singleton infants who were born to women with preterm rupture of membranes, that antibiotics reduced major cerebral abnormality in infants before discharge. Despite this, there was no improvement in functional impairment in 7-year-old children. Furthermore, 2 antibiotics that were given to women in preterm labor with intact membranes increased the risk of cerebral palsy by 60-90%.

Early trials of antenatal thyrotropin-releasing hormone in women who were at risk of preterm birth suggested that thyrotropin-releasing hormone reduced neonatal chronic lung disease and hospital deaths. However, 2 more RCTs, in >4 times as many women, found no benefit for neonatal chronic lung disease or hospital death but found an increased risk of motor delay at 12 months and of mental delay at 12 and 24 months.

Oxygen, severe retinopathy, and survival

Perhaps the most dramatic example of the necessity for childhood follow-up evaluation in RCTs is described by Silverman. An early RCT of liberal vs restricted oxygen therapy in preterm infants suggested that oxygen curtailment did not increase mortality rates but did reduce retinopathy with cicatricial eye disease, which is a major cause of blindness, by two thirds. Restriction of oxygen therapy to concentrations <40% rapidly became routine practice, regardless of the presence of hypoxia. Survivors in this RCT never received followed-up evaluation. Later, widespread excesses in the incidence of spastic diplegia and death were attributed to hypoxic respiratory failure because of arbitrary, inappropriate oxygen restriction. It was estimated that “every sighted infant gained may have cost some 16 deaths.”

These examples suggest that, despite promising short-term evidence of benefit, without studies that are powered to detect changes in mortality rates and without long-term data we cannot exclude the possibility that DCC may do more harm than good.

Is IVH a reliable surrogate for childhood impairment?

It is unclear whether isolated, low-grade (grades 1 and 2) IVH without white matter damage or ventricular dilation increases the risk of adverse developmental outcome in childhood. Of 3 recent cohort studies, 1 study concluded that, except when accompanied or followed by a white matter lesion, isolated IVH is associated with no more than a mild increase (and possibly no increase) in adverse developmental outcome. Another study found that, at 18-22 months, neurodevelopmental outcomes of very low gestational-age infants with isolated low-grade IVH did not differ significantly from those without IVH. A third concluded that infants with isolated grades 1 and 2 IVH had a 50% increase in moderate-severe neurosensory impairment in early childhood.

By contrast, lesions often referred to as severe (grade 3 or 4) IVH, but which are more properly described as evidence of white matter damage, clearly are associated with greater risk of neurodevelopmental impairment and psychiatric disorder. White matter damage is thus a better surrogate of important brain injury than IVH of all grades, but evaluation of outcomes in childhood provides still more reliable evidence. In the Trial of Indomethacin Prophylaxis in Preterms, indomethacin prophylaxis reduced the odds of severe (grade 3 or 4) IVH in extremely low birthweight infants by 30% compared with placebo, but there was no difference in long-term outcome.

Criteria for new standards of care

Clinical trials with surrogate endpoints do not provide an appropriate basis for long-term clinical policy in any specialty. We suggest that a new standard of perinatal care will require (1) reliable, relevant evidence of net clinical benefit, informed by (2) data on survival and childhood outcome that show no appreciable evidence of harm and (3) the perspectives of parents, professionals, and the community.

What is net clinical benefit?

For many, no other outcome in very preterm infants is as important as survival, so this usually outweighs short-term morbidity or childhood disability when considering net clinical benefit. For the most severely disabled children, some professionals, parents, and communities may consider survival worse than death. However, few trials have sufficient power to show any impact on this risk.

When there is no appreciable evidence of harm in terms of survival or childhood disability, reliable evidence of improvements in short-term morbidity would indicate net clinical benefit. The numbers of patients needed to infer “no appreciable harm” is a matter of judgment. However, the number of very preterm infants (n = 96) in whom neurodevelopment in childhood currently is reported is clearly inadequate to make such a judgment.