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The optimal mode of delivery for very low birth weight (VLBW) infants is controversial. In our previous population-based study,1 we showed that cesarean delivery did not enhance the survival of vertex-presenting VLBW neonates. However, we did not address outcomes other than mortality, especially neurologic outcomes, which might have influenced long-term outcome.
Germinal matrix–intraventricular hemorrhage is the most common form of intracranial hemorrhage in preterm infants. It occurs in 15–25% of infants delivered at less than 32 weeks of gestation.2 The incidence decreases with advancing gestational age and is influenced by certain perinatal risk factors. Ninety percent occur in the first 3 days after birth and rarely beyond the first week of life. Grades 3 and 4 intraventricular hemorrhage, hereby defined as severe intraventricular hemorrhage, is associated with increased neurodevelopmental morbidity later in life.3 Intraventricular hemorrhage was previously shown to be associated with both spontaneous preterm delivery and younger gestational age at delivery.4
The cause of intraventricular hemorrhage is multifactorial, but the stress of labor was considered as one of the contributing factors.5 This has led to the idea that cesarean delivery might reduce the risk for these neurologic complications. However, the data found in the literature are conflicting. Some claim that cesarean delivery decreases the risk of intraventricular hemorrhage,5–10 whereas others could not show any association between cesarean delivery and decreased risk for intraventricular hemorrhage.2,11–19 The aim of this population-based observational study was to investigate the independent association between mode of delivery and severe intraventricular hemorrhage in singleton vertex-presenting VLBW liveborn infants.
MATERIALS AND METHODS
Our study was based on analysis of data collected prospectively by the Israel National VLBW Infant Database, which includes perinatal and neonatal data on all newborns with birth weight 1,500 g or less born in Israel from 1995 to 2004. All 28 neonatal departments in Israel are included in data collection, which comprises the Israel National VLBW Infant Database (see the Appendix online at www.greenjournal.org/cgi/content/full/112/1/21/DC1.). Data are prospectively collected on a prestructured form and include maternal demographic information, pregnancy history, antenatal care, details of the delivery, the infant’s status at delivery, diagnoses, procedures and complications during hospital stay, and outcome at discharge. All liveborn infants in Israel receive a unique identification number at birth. Patient information received by the database coordinator is checked for missing items and logic errors, corrected, completed, and then entered into a computerized database. Patient information is crosschecked with the national birth registry, and data from any missing infants are requested from the birth hospital. The database included 99% of all liveborn VLBW infants in Israel. Hospital of birth and patient identification remain confidential by consensus agreement of all participating centers. Data are collected on all infants until discharge home or death. This study was approved by the human research committee of the Sheba Medical Center, Tel Hashomer, Israel.
Data are collected by the neonatologists in each perinatal center. All departments use operating manual and standard definitions, which were defined by the scientific committee before data collection and have remained unaltered since. Gestational age (in completed weeks) was determined by the best obstetric estimate of gestational age based on last menstrual period, obstetric history and examination, prenatal ultrasonography, and postnatal physical examination. Small for gestational age (SGA) was defined as birth weight more than 2 standard deviations below the mean weight for gestational age, according to the intrauterine growth charts of Usher and Mclean.20 Antenatal steroid treatment was defined as “partial” if delivery occurred less than 24 hours after the first dose or more than 1 week after the last dose, and “complete” if delivery occurred more than 24 hours and less than 7 days after a complete course of treatment. Premature rupture of membranes (PROM) was defined as membrane rupture more than 6 hours before the onset of regular spontaneous uterine contractions. Diagnosis of amnionitis was based on high maternal temperature (more than 37.8°C orally or more than 38°C rectally), recorded twice more than 1 hour apart, during the rupture of membranes or during the first 6 hours after delivery, provided no other cause for the fever was found. Preterm labor was considered in the presence of uterine contractions occurring before 35 weeks of gestation together with cervical effacement and dilatation. Maternal hypertensive disorder was defined as either chronic hypertension (persistent elevation of blood pressure before 20 weeks of gestation or before pregnancy) or pregnancy-induced hypertension if blood pressure above 145/95 mm Hg was first recorded after 20 weeks of gestation. Mortality was defined as death occurring before discharge from hospital.
Intraventricular hemorrhage was diagnosed by cranial ultrasonography performed before 28 days of life and graded according to the classification of Papile et al.21 The outcomes considered in this analysis were severe intraventricular hemorrhage, including Papile grades 3 and 4, and a secondary analysis of mortality and/or severe intraventricular hemorrhage. This analysis was limited to singleton vertex-presenting infants. Infants with lethal congenital malformations, delivery room deaths, and home deliveries were excluded.
To identify potential confounders influencing the relationship between mode of delivery and severe intraventricular hemorrhage, we examined the demographic, obstetric, and neonatal characteristics for univariable associations with outcome and exposure variables. Categorical variables were compared using the χ2 test. All tests were two-tailed, and P<.05 was considered statistically significant.
Next, a stepwise multivariable logistic regression analysis was performed to evaluate the effect of delivery mode on severe intraventricular hemorrhage and on the combined outcome of mortality and/or severe intraventricular hemorrhage. The following variables were included in the analysis: maternal age, ethnicity, prenatal care, infertility treatment, pregnancy and obstetric complications (including hypertensive disorders, preterm contractions, premature rupture of membranes, chorioamnionitis, antepartum hemorrhage, and steroid and tocolytic treatment), and mode of delivery. Neonatal variables included gender, gestational age, 1-minute Apgar score, and delivery room resuscitation. The variables were allowed to enter or to stay in the model at the 0.05 level of significance. The variable mode of delivery was forced into each model to determine its independent contribution to the outcome assessed. Results of the logistic regression analysis are presented as odds ratios (ORs) with the appropriate 95% confidence intervals (CI). Statistical analyses were performed using SAS 9 statistical software (SAS institute Inc., Cary, NC).
The study population consisted of 5,033 singleton vertex-presenting VLBW liveborn infants born at 24–34 weeks of gestation between 1995 and 2004. Early (less than 28 days) cranial ultrasound data were available on 4,658 (92.6%) of the neonates included in this study.
The rate of all grades of intraventricular hemorrhage was 24.6%, but only 10.4% (486 infants) had grades 3 and 4 intraventricular hemorrhage. Severe intraventricular hemorrhage was significantly associated with gestational age (Table 1), decreasing from 33.7% at 24–25 weeks to 8.5% at 28–29 weeks and 1.7% at 32–34 weeks of gestation (P<.001). The rate of severe intraventricular hemorrhage also decreased with increasing birth weight, and was significantly higher in males and in non-Jewish infants, of whom approximately 93% were of Arab ethnicity and 7% of Christian religion. The presence of premature contractions, amnionitis, and antepartum hemorrhage were associated with a higher percentage of severe intraventricular hemorrhage, whereas lower rates occurred in maternal hypertensive disorders, SGA infants, and infants who received antenatal steroids. The need for immediate resuscitation in the delivery room was significantly associated with increased risk for severe intraventricular hemorrhage.
The overall cesarean delivery rate was 54.3%. It should be noted that the rate of cesarean deliveries increased with increasing gestational age, as we have previously reported.1 Although the rate of severe intraventricular hemorrhage was 7.7% for cesarean deliveries compared with 13.6% in vaginal deliveries (P<.001), analysis stratified according to gestational age groups showed that the rates of severe intraventricular hemorrhage in vaginally or cesarean delivered infants were similar in all gestational age groups (Table 2). The combined outcome of death and/or severe intraventricular hemorrhage was also similar for vaginally and cesarean delivered infants (Table 2).
In the multivariable analysis (Table 3), cesarean delivery had no independent effect on the odds for severe intraventricular hemorrhage (OR 0.98, 95% CI 0.77–1.24) or for the combined outcome of death or severe intraventricular hemorrhage (OR 0.93, 95% CI 0.77–1.12). Additional risk factors for excess morbidity and mortality were delivery room resuscitation, low 1-minute Apgar score, partial or no antenatal steroid therapy, and non-Jewish ethnicity, whereas maternal hypertensive disorder and increasing gestational age had a protective effect.
The type of pregnancy complications associated with premature delivery greatly influence delivery mode and neonatal outcome. Among mothers with hypertensive disorders, 88% had cesarean deliveries. Conversely, cesarean delivery rates were lower among mothers with premature labor (28%), PROM (33%), and amnionitis (41%). We thus performed multivariable analyses of severe intraventricular hemorrhage and death or severe intraventricular hemorrhage by mode of delivery, according to four selected groups of pregnancy complications: maternal hypertensive disorders, premature labor only, PROM (with or without premature labor), and amnionitis (with or without PROM and with or without premature labor) (Table 4). These analyses showed that after adjusting for gestational age, antenatal steroid therapy, 1-minute Apgar score, and delivery room resuscitation, cesarean delivery had no advantage over vaginal delivery in decreasing the odds for severe intraventricular hemorrhage in these subgroups. The only significant finding was increased risk for severe intraventricular hemorrhage or death in the subgroup of amnionitis among those who delivered vaginally compared with those who had cesarean delivery (OR 0.54, 95% CI 0.31–0.93). However, in this group there was no effect of delivery mode on the risk of severe intraventricular hemorrhage (OR 0.71, 95% CI 0.39–1.31). We also checked the association between length of PROM and intraventricular hemorrhage risk. Premature rupture of membranes at 24 hours or more was not associated with excess intraventricular hemorrhage (9.3%) as compared with 10.4% in cases without PROM (data not shown).
A further subgroup of cesarean delivered infants in absence of these four pregnancy complications (n=858) was compared with both all vaginal deliveries (n=2,128) and with vaginal deliveries without these complications (n=173). The adjusted OR for severe intraventricular hemorrhage in this cesarean group was 0.91 (95% CI 0.65–1.27) and 0.68 (95% CI 0.37–1.28), respectively.
In this population-based study we found that the mode of delivery did not influence the odds for severe (grades 3 and 4) intraventricular hemorrhage in singleton vertex-presenting preterm VLBW infants. Although younger gestational age was strongly associated with increased risk for severe intraventricular hemorrhage, we did not furthermore show that mode of delivery influenced this association in any gestational age group (Table 2). This is in contrast to the findings of some studies claiming that cesarean delivery decreased the risk of severe intraventricular hemorrhage, especially in the younger gestational age or lower birth weight premature infants.5–10 However, many other studies could not show any significant association between cesarean delivery and decreased risk for intraventricular hemorrhage.2,11,14–16,19 A meta-analysis failed to demonstrate reduction in intraventricular hemorrhage after cesarean delivery compared with vaginal delivery.17,18
Many other perinatal factors predispose to intraventricular hemorrhage, including underlying infection and chorioamnionitits,22 whereas antenatal corticosteroids that are given for fetal lung maturation also protect against intraventricular hemorrhage.8,23,24 Pregnancy morbidities and complications may influence both the mode of delivery as well as the risk for intraventricular hemorrhage; for example, exacerbation of maternal hypertensive disorders, especially preeclampsia and eclampsia, in the absence of active labor, often results in an iatrogenic preterm delivery usually by cesarean delivery. Conversely, in women in active labor associated with spontaneous premature uterine contractions, PROM, or amnionitis, vaginal delivery may be more frequent. However, within these different subgroups of pregnancy complications, the mode of delivery did not seem to influence the odds for severe intraventricular hemorrhage (Table 4). This is in agreement with previous studies,14,15 and supports the claim that induction of labor and subsequent vaginal delivery in conditions such as preeclampsia does not increase the risk for severe intraventricular hemorrhage or mortality.25 Although the incidence of intraventricular hemorrhage was similar between vaginal and cesarean deliveries, some studies claimed that early hemorrhage (within 1 hour of birth) was more frequent after vaginal delivery, and later hemorrhage was more frequent in cesarean deliveries.26 This led to the suggestion of a possible role for the active phase of labor in the development of intraventricular hemorrhage27 and raised the possibility that although cesarean delivery before the active phase of labor did not change the overall frequency of intraventricular hemorrhage, it might decrease the progression to severe intraventricular hemorrhage.28 Although we do not have the data on how many women who had cesarean delivery were exposed to labor, the fact that no differences in the rate of severe intraventricular hemorrhage were found between cesarean and vaginal deliveries strengthens our claim that there is no association between labor and severe intraventricular hemorrhage.
An excess risk for severe intraventricular hemorrhage was present in the non-Jewish, predominantly Arab, infants. The reasons for this finding are not clear. However, Dollberg et al29 previously reported an excess mortality in this population. They speculated that the disparities noted suggested inadequate access to or use of effective perinatal technology, possibly associated with the rural geographic distribution of the Muslim population.
For the sake of uniformity, we limited our analysis to singleton vertex-presenting neonates, because mode of delivery and outcome in breech presentations and multiple gestation might be influenced by other factors. We also excluded VLBW infants born at more than 34 weeks because they represent a group of severe SGA infants with different morbidities than preterm VLBW infants, and furthermore, intraventricular hemorrhage occurs only rarely in this group.
Conducting an appropriately sized prospective randomized controlled study designed to answer the important clinical question whether cesarean delivery decreases the risk for severe intraventricular hemorrhage among preterm infants should still be the ultimate goal. However, it seems increasingly unlikely that such a study will be undertaken and completed in the near future. In the absence of a prospective randomized controlled study, which may not be applicable or ethical, we believe that this observational study based on a large cohort of almost all VLBW infants born in Israel provides valuable information.
During the 10-year period, 1995–2004, new technologies and treatments that included antenatal corticosteroid and surfactant use were widely used. Also, the well-structured database and the strict inclusion criteria decreased confounding variables and allow us to draw definite conclusions regarding delivery mode in very low birth weight singleton vertex-presenting infants and intraventricular hemorrhage risk.
In this study the mode of delivery did not affect the odds for severe intraventricular hemorrhage. A number of limitations, however, need to be considered. Our database cannot address the issue of the effect of mode of delivery on the rate of early (within hours of birth) compared with late intraventricular hemorrhage, especially in relation to the active phase of delivery, nor can it provide information regarding the effect of delivery on the risk of progression of the severity of the intraventricular hemorrhage.26,28 Because this was an observational study, some unknown biases and confounding variables may not be accounted for. The specific circumstances influencing the obstetric decision-making process for the individual deliveries, and factors that might have led the obstetrician to perform a caesarean section, are unknown to us. The presence of, for example, fetal distress, cord prolapse, the stage of labor at the time of admission, and other complications may influence both the management and outcome of these pregnancies. Furthermore, specific management practices in the various perinatal centers may influence both delivery mode and outcome, thus causing a clustering effect by hospital. Because hospital of birth is confidential, this potential bias cannot be excluded. This study was restricted to very low birth weight singleton vertex-presenting infants and hence would not be applicable to multiple gestations or nonvertex presentations. The cause of intraventricular hemorrhage is multifactorial and may be influenced by numerous later postnatal events, morbidities, complications, and treatments, such as respiratory distress syndrome, pneumothorax, sepsis, patent ductus arteriosus, indomethacin treatment, hypotension, and fluctuating blood pressures. Assessment of all possible associated factors was, however, beyond the scope of this study. We have chosen to limit the analysis to the effects of perinatal factors on the occurrence of intraventricular hemorrhage. Despite these limitations, our results do not support the hypothesis that cesarean delivery of singleton vertex-presenting VLBW infants reduces the odds for mortality,1 severe intraventricular hemorrhage, or combined adverse outcome of death or severe intraventricular hemorrhage.
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