Does peripartum infection increase the incidence of cerebral palsy in extremely low birthweight infants?

Costantine, Maged M.; How, Helen Y.; Coppage, Kristin; Maxwell, Rose A.; Sibai, Baha M.

doi:10.1016/j.ajog.2007.01.009

« Previous Next »American Journal of Obstetrics & Gynecology
Volume 196, Issue 5 , Pages e6-e8, May 2007

Does peripartum infection increase the incidence of cerebral palsy in extremely low birthweight infants?

University of Cincinnati, Cincinnati, OH.

Received 1 August 2006; received in revised form 12 December 2006; accepted 5 January 2007.

Objectives

This study was undertaken to determine the perinatal predictors of cerebral palsy in extremely low birthweight infants (<1000 g).

Study Design

A case control study of infants with birthweight of less than 1000 g (19 with cerebral palsy and 38 controls) who survived beyond 18-22 months of corrected age was performed. Outcome variables included maternal demographics, obstetric complications, and neonatal outcome (gestational age at delivery, birthweight, Apgar scores, intrauterine growth restriction, respiratory distress syndrome, intraventricular hemorrhage, and neonatal sepsis). Data analysis consisted of t tests, χ², and analysis of variance when appropriate.

Results

There were no significant differences between cerebral palsy and control groups with regard to mode of delivery, Apgar scores, preeclampsia, antenatal vaginal bleeding, or the use of magnesium sulfate. However, male gender (odds ratio 3.70; 95% CI 1.05-12.5), primigravid status (odds ratio 5.52; 95% CI 1.67-18.3), early neonatal sepsis (odds ratio 12.9; 95% CI 2.94-57.2) and chorioamnionitis, both clinical and histologic (odds ratio 3.71; 95% CI 1.16-11.9) were significantly associated with the development of cerebral palsy. The strong association between cerebral palsy and chorioamnionitis, as well as early neonatal sepsis, remain significant after adjustment for primigravid status and male gender.

Conclusion

In extremely low birthweight infants, cerebral palsy was strongly associated with chorioamnionitis, early neonatal sepsis, male gender, and primigravid status.

Key words: cerebral palsy, chorioamnionitis, extremely low birthweight

For the past 20 years the survival rate of extremely low birthweight (ELBW) infants (500-1000 g) has improved because of advances in obstetric and neonatal care. Preterm birth is considered as one of the most important risk factor for cerebral palsy (CP). The risk of CP is inversely proportional to gestational age (GA) and is 60 times higher at less than 28 weeks’ of gestation than at term.¹ Recent studies have proposed infection (subclinical and clinical) as a possible mechanism in the development of CP. It is believed that fetal cytokinemia that develops after the onset of maternal and fetal infection produces an inflammatory response that leads to neonatal brain injury predisposing the fetus to CP. Umbilical cord cytokine levels were also found to be associated with cerebral periventricular leukomalacia (cPVL) .²

In a meta-analysis by Wu et al,³ clinical chorioamnionitis was associated with both CP and cPVL in preterm infants. Indeed, an estimated 60-100% of infants with cPVL will have CP develop.⁴ Preeclampsia has been shown to be protective against CP in preterm infants.⁵ Exposure to magnesium sulfate (MgSO₄) alone was also found to be protective⁶ of CP in subgroup of infants born to women who were not preeclamptic.

The objective of this study was to investigate the peripartum factors that are related to the development of CP in ELBW infants.

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Materials and Methods

Institutional Review Board approval was obtained from the University of Cincinnati Hospital (TUH) and the Cincinnati Children’s Hospital Medical Center (CCHMC). The study population was drawn from a cohort of ELBW infants born at the TUH between January 1993 and December 2002. All infants were monitored at the CP clinic at the CCHMC where the diagnosis of CP was made at 18-22 months from the infant corrected age. Infants with major congenital abnormalities were excluded. A total of 230 ELBW infants born during this period were identified. Of these, 19 infants developed CP. A matched control group of 38 neonates without CP was selected. The matching was on a 2:1 basis. All control subjects were identified within a year of birth of the subject and matched by race, delivery mode, and GA.

Obstetric factors studied were as follows: preeclampsia, antenatal vaginal bleeding, antenatal use of steroids for fetal lung maturity, premature rupture of membranes (PROM) diagnosed by positive fern and/or nitrazine test. Chorioamnionitis (CHORIO) was defined as intrapartum fever of 100.4°F or higher, abdominal tenderness, maternal or fetal tachycardia without any other obvious cause, or the presence of polymorphoneucleocyte invasion of the placental membranes. The use of MgSO₄ for either tocolysis in preterm labor or prophylaxis in preeclampsia was noted.

Neonatal factors studied were as follows: gender, intrauterine growth restriction (IUGR), respiratory distress syndrome (RDS), intraventricular hemorrhage (IVH), and early neonatal sepsis defined as the presence of clinical signs of septicemia within 72 hours of life with or without positive blood culture. The neonates were treated with 10-14 days of intravenous antibiotics.

Data analysis consisted of t tests for continuous variables and χ² tests for categorical variables. When appropriate, analysis of variance (ANOVA) and Cochran and Mantel-Haenszel tests were used to control for preexisting group differences.

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Results

There were no statistically significant differences with regard to maternal demographics (race, MgS0₄, and steroid use), except for higher rate of primigravid status among mothers of infants with CP. Only early neonatal sepsis and male gender were significantly more frequent in children who later developed CP (Table 1).

TABLE 1. Neonatal outcomes (%)

	CP (n = 19)	No CP (n = 38)	OR	95% CI
GA at delivery (wks)	25⁺⁴±1.4	25⁺⁵±1.8
Birthweight (g)	727.1±107	807.9±138
Apgar score = <3 at 1 min	63	58	0.88	0.28-2.75
Apgar score = <7 at 5 min	89	79	0.22	0.03-1.92
Male gender	79	47	3.70	1.05-12.5
IUGR	5	8	0.65	0.06-6.69
Early neonatal sepsis	53	8	12.9	2.94-57.2
RDS	79	79	1.00	0.26-3.86
IVH	26	18	1.58	0.43-5.86

Table 2 shows the antepartum and intrapartum obstetric complications. The rate of CHORIO, both clinical and histologic, and PROM greater than 48 hours was significantly different in pregnancies with CP. In the CP group: 11 patients had CHORIO, of these 4 had clinical CHORIO only, 4 had histologic CHORIO only, 3 had both clinical and histologic CHORIO; and 2 with funisitis. In the CP group, only 14 placenta were sent to pathology for evaluation. In the control group: 8 patients had CHORIO, of these 4 had clinical CHORIO only, 4 had both clinical and histologic CHORIO; 4 with funisitis; and none had histologic CHORIO only. In the control group only 20 placenta were sent to pathology for evaluation.

TABLE 2. Obstetric complications (%)

	CP (n = 19)	No CP (n = 38)	OR	95% CI
C/S	53	53	1.00	0.33-3.01
Preeclampsia	21	16	1.42	0.35-5.80
Antenatal bleeding	42	39	1.12	0.36-3.42
Abruption	26	21	1.34	0.37-4.84
CHORIO	58	21	3.71	1.16-11.9
PROM	47	66	0.25	0.15-1.4
<24 h	11	52	0.12	0.01-1.07
24-48 h	11	12	0.92	0.08-10.1
>48 h	78	36	6.22	1.06-36.6

C/S, cesarean section.

The indications for delivery in the CP group were nonreassuring fetal status (7), spontaneous preterm labor (8), preeclampsia/HELLP (3), and IUGR (1), whereas in the control group, indications were nonreassuring fetal status (8), spontaneous preterm labor (17), preeclampsia/HELLP (3), vaginal bleeding (4), IUGR (3), and others (3). There were no differences between the 2 groups with regard to these indications.

Table 3 shows that early neonatal sepsis, CHORIO, both clinical and histologic, and PROM more than 48 hours remained significantly different between the CP and control group after adjustment for primigravid status. However, only CHORIO and early neonatal sepsis remained significantly different between the CP and control group after adjustment for infant gender.

TABLE 3. Factors significant for CP after adjustment for gender and primigravid status

	Adjusted to primigravid status		Adjusted to male gender
	OR	95% CI	OR	95% CI
Early neonatal sepsis	13.8	2.51-75.8	18.4	3.12-108
CHORIO	2.80	1.69-4.54	3.66	1.09-12.2
PROM <24 h	0.15	0.02-0.96	0.16	0.02-1.21
PROM >48 h	4.57	1.06-19.8	5.31	0.87-32.3

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Comment

Principal findings of the study

In this retrospective case control study, we found that the rate of development of CP in ELBW infants was 8.3%. CHORIO, both clinical and histologic, and early neonatal sepsis were significant risk factors for the development of CP in ELBW infants with odds ratios (ORs) ranging from 2.8-3.7 for CHORIO and 13.8-18.4 for early neonatal sepsis. This significant relationship remained even after adjustment for primigravid status and infant gender.

Despite the claim that preeclampsia is protective against CP in preterm infants,⁵ we cannot explain why preeclampsia was not found to be protective in our study. In fact, a recent publication by Thorngren-Jerneck and Herbst,⁷ reported that preeclampsia is associated with increased risk of CP (OR 1.5, 95% CI 1.3-2.4).

Clinical implication of the study

It is possible that conservative management in women with PROM especially at GA of 28 weeks or less consistent with a birthweight of 1000 g or less, may potentially cause more harm to the fetus because of the development of clinical or subclinical infections leading to the development of CP. However, our study was retrospective; this question can only be addressed in a randomized trial, because induction of labor might result in more neonatal deaths related to extreme prematurity.

Strength and weakness of the study

The major strength of this study is the large database from which we drew the study population, which allowed us to match for several variables that could have potentially influenced our results. Another strength of this study is that all these infants were monitored in the same CP clinic.

One limitation of our study is its retrospective nature and inclusion of infants who survived to at least 18 months of age. It is possible that some infants who were destined to have CP develop died before 18 months; this may have influenced our results.

A second limitation of our study is the small sample size of infants who had CP develop. And as a result we were unable to stratify the CP infants according to their birthweight or GA at delivery.

Future areas of investigation

Future studies with larger sample sizes are needed to evaluate the risk factors leading to development of CP. A large multicenter randomized trial will be required to further investigate the benefit of conservative management in women with early preterm PROM at GA of 28 weeks or less or birthweight of 1000 g or less, who remain undelivered 48 hours after receiving steroids.

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References

Jacobsson B, Hagberg G, Hagberg B, Lansfor L, Niklasson A, Hagberg H. Cerebral palsy in preterm infants: a population-based case-control study of antenatal and intrapartal risk factors. Acta Paediatr. 2002;91:946–951

Yoon BH, Romero R, Jun JK, et al. Amniotic fluid inflammatory cytokines, neonatal brain white matter lesions and cerebral palsy. Am J Obstet Gynecol. 1997;177:19–26

Wu YW, Colford JM. Chorioamnionitis as a risk factor for cerebral palsy: a meta-analysis. JAMA. 2000;284:1417–1424

Leviton A, Paneth N. White matter damage in preterm newborns—an epidemiologic perspective. Early Hum Dev. 1990;24:1–22

Murphy DJ, Sellers S, MacKenzie IZ, Yudkin PL, Johnson AM. Case-control study of antenatal and intrapartum risk factors for cerebral palsy in very preterm singleton babies. Lancet. 1995;346:1449–1454

Nelson KB, Grether JK. Can magnesium sulfate reduce the risk of cerebral palsy in very low birthweight infants?. Pediatrics. 1995;95:263–269
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