Placental inflammation, neonatal death and cerebral palsy in preterm infants

Abstract

A report in this issue examined the relationship between severe histological chorioamnionitis and/or funisitis (HCA/F) and neonatal death (ND) before hospital discharge or cerebral palsy (CP) at 2 years in singleton infants born between 24 and 34 weeks of gestation (Huetz et al. BJOG 2016; 123:1956–63). From 2008 to 2011 in a single hospital, of the 276 newborns potentially available for CP evaluation, 22 died before discharge, 102 had no placental analyses, and 58 were unavailable/lost-to-follow-up. Hence, 196 infants were evaluable for CP evaluation at 2 years; of which 17 had CP. The authors found nonsignificant increases in ND and CP in infants whose placentas had HCA/F, which was interpreted as lack of an association between HCA/F and CP/ND. Study weaknesses, many acknowledged by the authors, included a substantial loss-to-follow-up, many placentas not evaluated, a relatively small sample size and few cases of CP. Only about one-third of those evaluated were between 24 and 28 weeks of gestation at birth.

Numerous individual studies and meta-analyses have addressed placental histological findings, especially HCA/F, and various neonatal outcomes, especially CP/ND [Wu et al. JAMA 2000;284:1417–24; Shatrov,Obstet Gynecol 2010;116:387–92). The results have been mixed, although many studies and meta-analyses have found associations between HCA/F and ND and/or CP. Potential reasons for the discrepant findings among studies include varying definitions of chorioamnionitis, funisitis and CP, and differing time periods, birthweight, gestational age, maternal characteristics and care available to the mother and infant. Many studies adjusted for a variety of risk factors, whereas some did not.

The gestational age range included in the Huetz et al. study compared with other studies may be especially important. Huetz et al. evaluated infants born between 24 and 34 weeks of gestation whereas most previous studies included infants <28 weeks of gestation. This difference may help to explain some of the differences in outcomes, because infants born at <28 weeks of gestation are more likely to have HCA, more severe HCA and/or funisitis, and are more likely to die or have CP (Kim et al. Am J Obstet Gynecol 2015;213:S29–52). For example, infants born at <28 weeks of gestation often have rates of CP ranging from 6 to 10% whereas in the Huetz et al. study, the overall CP rate was < 1% (Hoarvath et al. Eur J Obstet Gynecol Reprod Biol 2012;163:160–4).

Generally the studies showing a positive relationship between HCA/F and CP/ND had odds ratios ranging from about 1.5 to 3.0. Whether the results were statistically significant often related to the number of pregnancies evaluated, and the prevalence of HCA/F and CP/ND. Huetz et al. had only 196 infants evaluable for CP, of which 17 had CP, and 22 were NDs. The OR of 1.41 reported for CP is within the confidence intervals of statistically significant results in several meta-analyses (Soraisham, J Perinatol 2013;33:70–5). With larger numbers, this odds ratio may have become statistically significant.

Hence we believe that this study does not confirm or deny a relationship between HCA/F and CP/ND. Going forward, because of the large number of studies and the wide disparity among results, it is unlikely that additional individual or single-centre studies with small sample sizes will help to resolve the relationship between HCA/F and CP/ND. Instead, the resolution will come from a large multicentre study with standard definitions for HCA, funisitis and CP, which is conducted in infants with clearly defined gestational age limits, and with follow up of all study infants.