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Risk Factors for Intraventricular Hemorrhage in Very Low Birth Weight Premature Infants: A Retrospective Case-Control Study

Nehama Linder, MD^*,, Orli Haskin, MD^*,, Orli Levit, MD^*,, Gil Klinger, MD^*,, Tal Prince, MD^*,, Nora Naor, MD^*,, Pol Turner, MD^*,, Boaz Karmazyn, MD^, and Lea Sirota, MD^*,

^* Department of Neonatology
Radiology, Schneider Children’s Medical Center of Israel, Petah Tikva, Israel
Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

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	ABSTRACT

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Objective. High-grade intraventricular hemorrhage (IVH) is an important cause of severe cognitive and motor neurologic impairment in very low birth weight infants and is associated with a high mortality rate. The risk of IVH is inversely related to gestational age and birth weight. Previous studies have proposed a number of risk factors for IVH; however, lack of adequate matching for gestational age and birth weight may have confounded the results. The purpose of this study was to identify variables that affect the risk of high-grade IVH, using a retrospective and case-control clinical study.

Methods. From a cohort of 641 consecutive preterm infants with a birth weight of <1500 g, 36 infants with IVH grade 3 and/or 4 were identified. A control group of 69 infants, closely matched for gestational age and birth weight, was selected. Maternal factors, labor and delivery characteristics, and neonatal parameters were collected in both groups. Results of cranial ultrasound examinations, whether routine or performed in presence of clinical suspicion, were also collected. Univariate analysis and multivariate logistic regression analysis were performed.

Results. High fraction of inspired oxygen in the first 24 hours, pneumothorax, fertility treatment (mostly IVF), and early sepsis were associated with an increased risk of IVH. A higher number of suctioning procedures, a higher first hematocrit, and a relatively low arterial pressure of carbon dioxide during the first 24 hours of life were associated with a lower occurrence. In the multivariate logistic regression model, early sepsis (odds ratio [OR]: 8.19; 95% confidence interval [CI]: 1.55–43.1) and fertility treatment (OR: 4.34; 95% CI: 1.42–13.3) were associated with a greater risk of high-grade IVH, whereas for every dose of antenatal steroid treatment there was a lower risk of high-grade IVH (OR: 0.52; 95% CI: 0.30–0.90) and each decrease in a mmHg unit of arterial pressure of carbon dioxide during the first 24 hours was associated with a lower risk of IVH (OR: 0.91; 95% CI: 0.83–0.98). This multivariate model had a sensitivity of 77%, a specificity of 75%, and a positive predictive value of 76%. The area under the curve derived from the receiver operator characteristic plots is 0.82.

Conclusions. Our results confirm that the development of IVH is associated with early sepsis and failure to give antenatal steroid treatment. We propose that fertility treatment (and especially IVF) may be a new risk factor, and more research is needed to assess its role.

Key Words: intraventricular hemorrhage • premature infants • risk factors

Abbreviations: IVH, intraventricular hemorrhage • VLBW, very low birth weight • Fio₂, fraction of inspired oxygen • Paco₂, arterial pressure of carbon dioxide • HMD, hyaline membrane disease • OR, odds ratio • CI, confidence interval

	INTRODUCTION

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Intraventricular hemorrhage (IVH) is an important cause of morbidity and mortality in very low birth weight (VLBW) infants. More than 50% of bleeding episodes occur during the first 24 hours of life, with <5% occurring after day 4/5.^1,2 Although the incidence of IVH is decreasing,³ it remains a serious problem in the VLBW infant.

A number of risk factors have been proposed for the development of IVH: low birth weight and gestational age,^1–3,5–8 maternal smoking,⁹ breech presentation,⁵ gender,^5,7,10 premature rupture of membranes,^6,11 intrauterine infection,^6,11–13 mode of delivery,^{5,10,11,14,15} prolonged labor,^1,16 postnatal resuscitation and intubation,^1,7,16 transferal from one unit to another,^7,16 early onset of sepsis,^17,18 development of respiratory distress syndrome^7,11 or pneumothorax,² recurrent endotracheal suctioning,^1,16 metabolic acidosis and rapid bicarbonate infusion,^10,16 and high-frequency ventilation.¹⁹ Pregnancy-induced hypertension is associated with a lower rate of IVH.^5,20 For reducing the incidence of IVH, several pharmacological interventions have been proposed, including antenatal steroids,^{5,8,10,15,21,22} prenatal tocolytic therapy,^8,23 postnatal administration of low-dose indomethacin,^24,25 and surfactant.^26,27

However, many of the above studies failed to undertake multivariate analysis to identify independent risk factors for IVH. Furthermore, although low birth weight and low gestational age are major risk factors, they may simply describe a population at higher risk. Many studies have not adequately controlled for this, and their results may have been confounded by these 2 variables. We therefore performed a retrospective, case-control study with a high degree of matching for birth weight and gestational age to increase the sensitivity of detection of potential risk and protective factors that could be altered by medical intervention, in the hope of reducing the incidence of IVH.

	METHODS

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The neonatal department at the Rabin Medical Center prospectively collects data on all VLBW infants. The data include prenatal demographic details, maternal pregnancy history and antenatal care, details of the delivery, the infant’s status at delivery, diagnoses, procedures and complications during hospitalization, and outcome at discharge. A total of 641 VLBW preterm infants (<1500 g) were born at the Rabin Medical Center during the 5-year period from January 1, 1995, to December, 31 1999. From the cohort, we retrospectively identified all 36 premature infants (5.6%) with IVH grades 3 and/or 4, which composed our study group. A control group composed of 2 infants for each case, matched for gestational age (±1 week) and birth weight (±100 g), was selected on the basis of the first compatible live-born infant before and after each study infant.

In 3 cases, only a single control infant could be matched according to our criteria; hence, the control group consists of 69 infants. Data regarding maternal attributes, labor and delivery characteristics, and postnatal parameters were collected retrospectively from the fertility unit, high-risk pregnancy department delivery room, and neonatal charts in both groups. Maternal attributes included maternal age, fertility treatment (including clomiphene, Pergonal, and IVF), smoking during pregnancy, amniocentesis, cervical incompetence and cervical encerclage suture, maternal hypertension and the presence of preeclampsia, maternal steroids/antibiotics/tocolytic therapy/other medication (type, week of gestation when commenced, number of doses and dosage, reason for treatment), reason for induction of premature labor, reason for early delivery (premature contractions, premature rupture of membranes), placental abruption, placenta previa, and amnionitis (diagnosis on the basis of maternal fever >37.8°C orally or 38°C rectally, measured twice within 1 hour with no other source of fever identified, supported either by a positive culture result from amniotic fluid or by a high white blood cell count with elevated neutrophils in the amniotic fluid).

Labor, delivery, and newborn characteristics were: gender; singleton or twin or triplet; mode of delivery (vaginal, C-section, breech, instrumental: forceps and vacuum); gestational age (determined according to at least 2 of the following parameters: last menstrual period, first prenatal ultrasound, and Dubowitz score); birth weight; appropriateness for gestational age; Apgar score at 5 minutes; cord blood pH, bicarbonate and base excess; and delivery room resuscitation (use of oxygen, bag and mask or mechanical ventilation, intubation, cardiac massage, and epinephrine). Parameters for the first 24 hours of life included highest fraction of inspired oxygen (Fio₂); highest mean airway pressure; blood gases (highest and lowest arterial pressure of carbon dioxide [Paco₂], arterial oxygen pressure, pH); highest and lowest mean blood pressure; first hematocrit, lowest hemoglobin; lowest platelet count; treatment with bicarbonate (dose); and number of suction procedures per day. For the neonatal course, the presence of any of the following neonatal diagnoses was recorded: hyaline membrane disease (HMD; diagnosed in infants who required either supplemental O₂ or mechanical ventilation, together with radiographic evidence of HMD), respiratory support (requirement for O₂, nasal continuous positive airway pressure, intermittent mandatory ventilation, high-frequency ventilation, use of nitric oxide), pneumothorax, patent ductus arteriosus (if present, mode of treatment), necrotizing enterocolitis, retinopathy of prematurity (stage, zone), and presence of sepsis (early or late sepsis; early defined as within 72 hours of birth¹⁸). Sepsis was defined as positive microbial growth on 1 or more bloodstream cultures with accompanying clinical signs of sepsis. The diagnosis of sepsis caused by Staphylococcus-coagulase-negative was determined according to the Vermont Oxford Network Database²⁸; bacterial growth and antibiotics given (type, dosage); requirement for inotropes; requirement for surfactant (type, dosage); prophylactic indomethacin treatment (0.1 mg/kg given as a bolus during the first 72 hours); and administration of vitamins (type, dosage, age when commenced). Ultrasound evaluations were assessed by 2 independent radiologists. When present, the grade of IVH was determined according to Papile et al,²⁹ together with any posthemorrhagic hydrocephalus or periventricular leukomalacia. The routine protocol in the neonatal intensive care unit was for the first ultrasound scan to be performed on the third day of life, with follow-up scans at 14 and 28 days, and then monthly until discharge.³⁰ When there was clinical suspicion of bleeding, additional ultrasound examinations were performed. The first day of bleeding and day of maximal hemorrhage were defined as the days on which hemorrhage was first identified or highest degree of hemorrhage seen, respectively. Any pathologic or neurologic findings were noted, including the occurrence of convulsions and results of brainstem-evoked potential tests. The need for recurrent lumbar punctures or ventricular taps, ventriculoperitoneal shunt insertion, or ventriculostomy was recorded. Outcome data were also obtained, either discharge data (day of discharge, age, weight, height, head circumference, medical treatment at time of discharge, and all neurologic findings) or age and cause of death. At discharge, a physical neurologic examination performed by a qualified neurologist and brainstem-evoked responses were obtained from all infants.

Statistical Analysis
Statistical analysis was performed with the BMDP Statistical Software.³¹ Univariate analysis was performed to identify differences between the study and control groups, using the t test, Pearson ² test, and Mann-Whitney nonparametric test, as appropriate. Statistical significance was defined as P .05. Those variables in which the univariate analysis was demonstrated as P < .1 were entered into a stepwise logistic regression model. Because we had only 36 infants with high-grade IVH and 69 controls with no possibility of enlarging these 2 groups, we did only the power analysis regarding survival with a result of 97%.

	RESULTS

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Between 1995 and 1999, 36 infants developed IVH grade 3 and/or 4, an incidence of 5.6%. Eleven of these (31%) developed posthemorrhagic hydrocephalus, with 1 infant requiring ventriculoperitoneal shunt insertion. In 86% of cases, the hemorrhage occurred during the first week of life, with 70% of cases diagnosed before or on the third day. In 31%, propagation of the bleed occurred during the first week. The overall mortality of infants born at <1500 g during the 5-year period was 13.4%. Among infants with IVH grades 3/4, the mortality was 75%, with a rate of 20.5% in the control group. None of the infants died within the first 24 hours. In the IVH group, 8 infants (22%) died within the first 3 days and 17 (47%) died within the first week compared with 2 (2.9%) within the first 3 days and 3 (4.3%) within the first week in the control group. Periventricular leukomalacia was present in 19.4% of infants with IVH, compared with 5.8% in the control group (P = .05). There were 9 survivors in the study group, 2 of whom had abnormal neurologic findings at discharge, whereas only 2 (of 52 survivors) in the control group had similar findings. Table 1 includes the important parameters and ultrasound findings of the study subjects, control subjects, and total population. There were no differences between the study and control groups in terms of demographic data, including gestational age and birth weight, as shown in Table 2. The results of the univariate analysis are shown in Tables 2–5. The factors found to be associated with a statistically significantly higher incidence of IVH were fertility treatment (63.9% vs 39.1% in controls; P = .02), which usually was through IVF treatment (P < .03). Ninety-two percent of all of the fertility treatments and 94% of the IVF treatments were performed by specialists of the fertility unit at the Rabin medical center. The percentage of twins and triplets and the incidence of infants who were small for gestational age was found to be similar in the 2 groups (Table 2). In 2 pregnancies, fetal death was recorded, 1 in each group; a higher incidence of early sepsis (19.4% vs 5.8%; P < .05); 86% of patients with early sepsis had Gram-negative sepsis all identified by positive blood cultures; only 1 infant had positive cerebrospinal fluid culture (early sepsis rate in the VLBW population was 3%), and pneumothorax (41.7% vs 20.3%; P < .05) in the IVH group compared with controls; a relatively lower first hematocrit level during the first 24 hours (44.0 ± 7.9 vs 49.3 ± 11.2; P < .02); and a higher Fio₂ during the first 24 hours of life in the study group (P < .02). No difference was observed in the arterial oxygen pressure. Variables associated with a lower incidence of IVH were a lower Paco₂ during the first 24 hours (30.7 ± 6.6 in the controls vs 33.6 ± 5.8; P < .05) and a higher number of suctioning procedures during the first 24 hours (4.7 ± 2.9 in controls vs 3.3 ± 2.4; P < .05). There was no significant difference in maternal antenatal treatment with steroids between the 2 groups. Eighty percent of infants without IVH were born to mothers who had received antenatal steroid therapy, compared with 61% in the IVH group. However, a negative association was observed between the number of steroid doses and the occurrence of IVH grade 3 and/or 4 (P = .03).

	DISCUSSION

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Our main objective was to identify risk factors for the development of high-grade IVH. The prenatal factors associated with increased risk of IVH were fertility treatment and especially IVF, which was identified as an independent risk factor in the multivariate analysis, something previously unreported in the literature. A recent study found that infants born after IVF have a higher incidence of neurologic impairment, particularly cerebral palsy, and it was proposed that the higher rates of multiple pregnancies and prematurity in IVF pregnancies may account for this.³² Another study demonstrated an association between assisted conception and retinopathy of prematurity.³³ IVF is a known risk factor for prematurity, largely as a result of the higher occurrence of multiple pregnancies. However, in our study, controlled for birth weight and gestational age, there was no difference in the incidence of multiple pregnancies between the study and control groups, an observation consistent with previous findings,⁶ and an alternative explanation is necessary. It is possible that the maternal problem preventing spontaneous pregnancy is also influencing the environmental conditions of the embryo in utero, increasing the risk of IVH. Alternatively, medication used during IVF treatment may increase the risk of IVH, perhaps by an effect on vasoreactivity or platelet aggregation. During the 5-year period, various techniques for IVF were introduced. The database does not record the specific technology used in each individual case; hence, we are not able to ascribe the outcomes reported to any specific technology. A prospective study evaluating the outcome of infants in relation to the different therapeutic modalities is currently being undertaken. Additional investigation using larger, controlled prospective trials are needed to clarify this finding.

Antenatal steroid treatment has been reported as conferring protection against the development of IVH.^20,21 Although this study failed to corroborate this with statistical significance, we did observe that the protection provided by steroids may be related to the number of steroid doses received (Table 8). Therefore, repeated doses of maternal antenatal steroids may reduce the risk of IVH in high-risk populations, but the possible benefits of such an intervention need to be assessed further before any recommendations can be made. This study did not find any influence on the incidence of high-grade IVH by other maternal and perinatal factors such as preeclampsia, method of delivery, premature rupture of membranes, and chorioamnionitis.

Suctioning procedure has been reported to increase intracranial pressure and hence has been associated with an increased incidence of IVH. Our study, however, shows in the univariate analysis a significant inverse relationship between the incidence of IVH and the number of suction procedures performed during the first 24 hours of life. This contradicts the minimal handling theory recommended for very small premature infants,^2,15 and additional research is needed before proper recommendations as to airway suction procedures in very small infants during the first 24 hours of life can be made.

Infants who developed IVH required a higher Fio₂ during the first 24 hours to maintain the same degree of oxygenation as controls. This suggests that these infants may be commencing life with a more severe degree of respiratory compromise. This factor was not found to be an independent factor in the logistic regression analysis. The incidence of HMD in both groups was statistically similar. Lower Paco₂ during the first 24 hours of life was found to be associated with a lower incidence of IVH in the multivariate analysis, a finding reported elsewhere.³⁴ Potentially, a lower Paco₂ may reduce the risk of IVH by causing arterial vasoconstriction. However, low Paco₂ has been described as a risk factor for periventricular leukomalacia and a poor neurologic prognosis,¹⁹ so there is a need for caution in interpreting this finding.

A relatively lower first hematocrit during the first 24 hours of life correlated with a higher incidence of IVH, a finding consistent with previous reports.¹⁴ Although a low hematocrit might accelerate cerebral blood flow, thus contributing to the hemorrhage,¹⁴ it is difficult to determine whether the low hematocrit levels contributed to the development of IVH or were a consequence of the bleed itself.

This study is limited by its retrospective nature and the small sample size. However, to our knowledge, this is the first study in the literature in which study and control groups were closely matched for gestational age and birth weight, with similar rates of multiple pregnancies in both groups. By reducing the confounding effects of these factors, the sensitivity of this study to detect other independent variables that affect the incidence IVH was increased.

	CONCLUSIONS

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We have demonstrated that early sepsis and fertility treatment may be risk factors for the development of grade 3 and/or 4 IVH in VLBW infants, whereas antenatal steroids and a lower Paco₂ may confer a degree of protection. The relationship between IVF and IVH has not been mentioned previously, and a large prospective study is required to clarify this finding. If these factors can be validated further, then it may be possible for medical interventions to reduce the incidence of IVH, thus decreasing mortality and preventing the associated long-term severe neurologic sequelae in the VLBW neonate.

	ACKNOWLEDGMENTS

We thank Pearl Lilos, Department of Statistics, Tel Aviv University, for excellent statistical analysis.

	FOOTNOTES

 
Received for publication Jun 20, 2002; Accepted Dec 3, 2002.

Reprint requests to (N.L) Department of Neonatology, Schneider Children’s Medical Center of Israel, 14 Kaplan St, Petah Tikva 49202, Israel. E-mail: linderm{at}netvision.net.il

	REFERENCES

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