Journal of Pregnancy and Neonatal Medicine

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Research Article - Journal of Pregnancy and Neonatal Medicine (2021) Volume 5, Issue 4

Risk factors for clinically significant intra-ventricular hemorrhage in pregnancies complicated by preterm premature rupture of membranes

Giamberardino W1, Winn VD2 and Armstrong J1,3*

1Department of Obstetrics and Gynecology, University of Colorado Anschutz Medical Campus, USA

2Department of Obstetrics and Gynecology, Stanford University School of Medicine, USA

3Department of Pediatrics, University of Colorado Anschutz Medical Campus, USA

Corresponding Author:
Jennifer Armstrong
Department of Obstetrics and Gynecology
University of Colorado Anschutz Medical Campus
E-mail: [email protected]

Accepted date: 29th October, 2021

Citation: Giamberardino W, Winn VD, Armstrong J. Risk Factors for Clinically Significant Intra-Ventricular Hemorrhage in Pregnancies Complicated by Preterm Premature Rupture of Membranes. J Preg Neonatal Med 2021; 5(4).

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Objectives: Preterm birth is a major cause of adverse perinatal outcomes, including intraventricular hemorrhage (IVH). IVH has been shown to contribute to lasting neurological disability, however the role of maternal characteristics and potentially modifiable risk factors that contribute to these outcomes have not been well defined. We sought to determine predictors of IVH in pregnancies complicated by early preterm premature rupture of membranes (PPROM).

Study design: We performed a retrospective cohort study of all singleton pregnancies with early PPROM <32 weeks GA and delivery >22 weeks GA at University of Colorado Hospital (UCH) from 1/1/2007-12/31/2011. Clinically significant IVH (Grade III or IV) was the primary outcome of this study. To determine independent predictors of IVH we created a multivariate model including all univariate covariates with p-value of ≤ 0.10.

Results: In our cohort (n=229), when adjusted for non-white race, younger maternal age and increased BMI were independent predictors of clinically significant IVH (OR=1.4 CI 1.04- 1.79, p=0.03; OR 1.2 CI 1.04-1.33, p=0.01, respectively). Female gender was also found to be an independent predictor of poor 5 minute APGAR (OR=2.3 CI 1.06-5.28, p=0.04).

Conclusions: In our cohort, infants born to younger mothers or mothers with higher BMI appear to be at increased risk for clinically significant IVH. Interestingly, on further analysis, we found that female newborns had a 2-fold greater risk of poor 5 minute APGAR of less than 7. Given these data, larger studies are warranted to examine modifiable and non-modifiable risk pregnancy that may be associated with IVH and subsequent adverse neurological outcomes in pregnancies complicated by early PPROM


Intra-ventricular, Hemorrhage, Preterm birth, Pregnancy


Preterm birth continues to be a significant problem with clear impact on morbidity and mortality of the newborn. Preterm birth affects 12% of live births in the United States and is a leading cause of infant mortality [1,2]. Currently, over one third of all infant deaths are attributed to preterm related causes [3]. Further, preterm birth is a major cause of adverse perinatal outcomes, including intraventricular hemorrhage (IVH). It has been shown that severe IVH (grade III or IV) alone portends poor neurological outcome in the premature infant regardless of other factors of prematurity [4].

Although there are numerous studies addressing the outcomes of premature birth and the role of neonatal factors, such as respiratory distress syndrome, gestational age, and early sepsis in the development of IVH, [5,6] it remains unclear if maternal or pregnancy factors may also contribute to the development of this adverse neurological outcome. Moreover, there is little data examining potentially modifiable variables of the pre-conception and pregnancy periods that may reduce the risk of developing clinically significant IVH in the premature newborn.

Despite accounting for 30%-40% of preterm deliveries, preterm premature rupture of membranes (PPROM) is understudied and presents a unique challenge considering that all PPROM pregnancies are at risk of preterm birth and thus the risks associated with early delivery, including IVH [7,8]. Consequently, investigating the possible predictors of IVH in pregnancies complicated by PPROM is a pertinent and important question considering that PPROM occurs in 1%-2% of all pregnancies in the United States. Additionally, these mothers have upwards of a 30% increased risk of having preterm delivery and up to a 21% risk of PPROM in subsequent pregnancies [7,9].

We sought to determine maternal, pregnancy related, and fetal risk factors that contribute to the development of clinically significant IVH in the PPROM population. This information would allow for potential improvement in the counseling and management of these obstetric patients and their newborns given that IVH is known to contribute to lasting neurological disability and that these risk factors for IVH may be modifiable, andthus, mitigated.


We performed a retrospective cohort study of all singleton pregnancies with PPROM born at the University of Colorado Hospital (UCH) from January 1, 2007 through December 31, 2011. The protocol for this study was approved by the Colorado Multiple Institutional Review Board (COMIRB), and the University of Colorado Hospital.

Our cohort included cases identified through the UCH Perinatal Database. This database collects maternal, pregnancy, delivery, and neonate data on all pregnancies delivering at the UCH. Data is collected by direct patient interview, performed by trained research nurses, and medical chart abstraction. Cases were confirmed by independent chart review of all patients (W.G.), with confirmation by a neonatal neurologist (J.A.).

Inclusion criteria for PPROM in this study were rupture of membranes <32 weeks gestational age without active labor and cases were verified by abstraction of the medical chart for diagnosis of PPROM as recorded by the treating physician.

Variables captured by the Perinatal Database included for analysis were maternal factors: racial background, ethnicity, age, smoking, hypertension (HTN) diabetes, prepregnancy body mass index (BMI), primigravida status; pregnancy factors: chorioamnionitis, and fetal factors: neonatal weight, sex, hypoglycemia, respiratory distress, 1 minute and 5 minute APGAR scores of less than 5 and 7, and disposition (NICU, well baby, demise). Also included were data on GA at time of PPROM, GA at delivery, and latency period from PPROM to delivery (days). These variables were chosen as they look at both the modifiable and non-modifiable risk factors in the pre-conception, pregnancy, and post-partum periods that may contribute to IVH in the newborn. The primary outcome of this study was established a priori and defined as intraventricular hemorrhage in the newborn of grade III or IV as identified by cranial ultrasound.

Data analysis included cases of PPROM as previously defined. We compared dichotomous variables by using χ2 analysis (or Fisher's exact test when an expected cell size was <5) and continuous variables by using the t test. To assess predictors of IVH we calculated odds ratios (ORs) and 95% confidence intervals (CIs) using logistic regression. GA at time of PPROM, maternal age, and maternal BMI were treated as both continuous and trichotomous variables. GA at time of PPROM was trichotomized as <24, 24 to 28, and >28 to 32 wks. Maternal age was defined as <18, 18 to 30, and >30 years, and pre-pregnancy BMI was classified as <20, 20 to 30, and >30. Additionally, GA at delivery was treated as a continuous and quartiled variable defined by 22 to 24, >24 to 28, >28 to 32, and >32 wks.

To determine independent predictors of grade III or IV IVH we created a multivariate model, including all univariate covariates with a P value of ≤ .10. We used Stata 12.1 (Stata Corp, College Station, TX) to perform all statistical calculations, with p<0.05 considered significant.


We identified 229 eligible cases of PPROM, representing approximately 10% of all deliveries (Table 1). The cohort demographics were representative of the Rocky Mountain Region with 188 (82%) of maternal fetal dyads being white and 94 (41%) of Hispanic ethnicity. Mean maternal age was 27 years. Mean gestational age at time of PPROM and at time of delivery were 27 and 29 weeks respectively, with a mean latency from time of PPROM to delivery of 13.9 days. Almost 50% of the pregnancies were complicated by clinical chorioamnionitis (n=107). The majority of newborns were male (n=141; 60%). Less than 5% (n=9) of newborns transitioned to the well-baby unit post-partum. Of all 229 deliveries, 31 (14%) resulted in neonatal demise, either at the time of delivery or prior to disposition from the NICU or the well-baby unit. In the 31 deliveries that ultimately resulted in neonatal demise the median GA at delivery was 241/7, with a range from 220/7 to 314/7 weeks.

Maternal Characteristics (%)
Age, mean (SD) 27 (6.43)
White 188/229 (82)
Non-white 41/229 (18)
Hispanic 94/228 (41)
Non-Hispanic 134/228 (59)
Primigravida 64/229 (28)


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