http://informahealthcare.com/jmf ISSN: 1476-7058 (print), 1476-4954 (electronic) J Matern Fetal Neonatal Med, 2015; 28(6): 666–673 ! 2014 Informa UK Ltd. DOI: 10.3109/14767058.2014.928851
ORIGINAL ARTICLE
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Outcome of singleton preterm small for gestational age infants born to mothers with pregnancy-induced hypertension. A population-based study Rivka H. Regev1,2, Shmuel Arnon1,2, Ita Litmanovitz1,2, Sofia Bauer-Rusek1, Valentina Boyko3, Liat Lerner-Geva2,3, Brian Reichman2,3; In collaboration with the Israel Neonatal Network* 1
Department of Neonatology, Meir Hospital, Sapir Medical Center, Kfar Saba, Israel, 2Women and Children’s Health Research Unit, Gertner Institute, Tel Hashomer, Israel, and 3Sackler Medical School, Tel Aviv University, Tel Aviv, Israel Abstract
Keywords
Background: Pregnancy-induced hypertension (PIH) has been associated with a decreased risk of infant mortality in small for gestational age (SGA) preterm infants. Objective: To evaluate the influence of PIH on mortality and major neonatal morbidities in singleton preterm SGA infants, in the presence and absence of acute pregnancy complications. Methods: Population-based observational study of singleton SGA infants, born at 24 to 32 weeks gestation in the period 1995–2010 (n ¼ 2139). Multivariable logistic regression analyses were used to assess the independent effect of PIH on mortality and neonatal morbidities. Acute pregnancy complications comprised premature labor, premature rupture of membranes 46 h, antepartum hemorrhage and clinical chorioamnionitis. Results: In the absence of pregnancy complications, the odds ratio (95% confidence interval) for mortality (0.77; 0.50–1.16), survival without severe neurological morbidity (1.14; 0.79–1.65) and survival without bronchopulmonary dysplasia (BPD) (0.85; 0.59–1.21) were similar in the PIH versus no-PIH groups. In the presence of pregnancy complications, mortality (0.76; 0.40–1.44), survival without severe neurological morbidity (1.16; 0.64–2.12) and survival without BPD (1.04; 0.58–1.86) were also similar in the PIH versus no-PIH groups. Conclusions: PIH was not associated with improved outcome in preterm SGA infants, both in the presence and absence of acute pregnancy complications.
Acute pregnancy complications, outcome, pregnancy-induced hypertension, premature infants, small for gestational age, very-low-birth-weight
Introduction Small for gestational age (SGA) preterm infants are at excess risk for mortality and major morbidities including necrotising enterocolitis (NEC), bronchopulmonary dysplasia (BPD) and retinopathy of prematurity (ROP) [1–4]. In a recent metaanalysis, Damodaram et al. demonstrated that preterm growth retarded fetuses are at an additional increased postnatal risk for intracranial hemorrhage and sepsis, compared with a normally grown cohort [5]. Hypertensive disorders of pregnancy complicate 5–10% of pregnancies [6,7], and are associated with increased risks of preterm birth, low birth weight and SGA infants [8]. The risk of perinatal mortality associated with pregnancy-induced hypertension (PIH), in singleton preterm infants, has been reported to be increased
*See Appendix A. Address for correspondence: Dr. Rivka H. Regev, Department of Neonatalogy, Meir Hospital, Sapir Medical Center, 59 Tchernichovsky, Kfar Saba 44410, Israel. E-mail: [email protected]
History Received 29 November 2013 Revised 31 March 2014 Accepted 25 May 2014 Published online 27 June 2014
[4,10], similar [11,12], as well as decreased [7,13]. Piper et al. reported that maternal hypertension was independently associated with a 39% reduction in perinatal mortality in preterm SGA infants [14]. Chen et al. [15], using a large USA infant birth/death database, reported that PIH was associated with a 46% decreased risk of infant mortality in SGA preterm infants. Despite the strength of this association, the authors comment that the data might overestimate the protective effect of PIH on infant mortality since the control group for SGA and preterm births did not necessarily represent a ‘‘normal’’ control group. In the control groups without PIH, the presence of additional acute pregnancy complications such as preterm premature contractions, antepartum hemorrhage, rupture of membranes and amnionitis, may necessitate early delivery and influence the outcome of premature verylow-birth-weight (VLBW) infants [16]. The purpose of this population-based study was to evaluate the influence of maternal PIH on mortality and major neonatal morbidities in preterm SGA infants, taking into consideration the presence or absence of acute pregnancy complications.
Preterm SGA infants and pregnancy-induced hypertension
DOI: 10.3109/14767058.2014.928851
Methods
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VLBW infant database This study was based on analysis of data collected by the Israel Neonatal Network on VLBW newborn infants (birth weight 1500 g) born in Israel from 1995 through 2010. All 28 neonatal departments in Israel participated in the data collection, which comprises the Israel National VLBW Infant database (Appendix A). The data collected included parental demographic details, maternal pregnancy history and antenatal care, details of the delivery, infants’ status at delivery, diagnoses, procedures and complications during hospitalisation and outcome at discharge [1,3]. A pre-structured form was completed for each infant. Each form was checked for logic errors and if necessary returned to the participating center for clarification. All live-born infants in Israel receive a unique identification number at birth. Patient information received by the database coordinator was cross checked with the national birth registry, and data from any missing infant were requested from the birth hospital. Birth hospital and patient identification subsequently remain confidential. Data were collected on all infants until death or discharge home. The study was approved by the Helsinki committee of the Sheba Medical Center. (SMC-9613-12). Study population From 1995 through 2010, the database included records of 24 250 infants, which comprise over 99% of all VLBW live Figure 1. Schematic summary – study population.
births in Israel. From these infants we excluded multiple births (n ¼ 10 332), appropriate and large for gestational age (GA) infants (n ¼ 9611), infants 524 or 432 weeks of gestation (n ¼ 1689), congenital malformations (n ¼ 317), infants born to mothers with chronic hypertension (n ¼ 145) and infants with missing data (n ¼ 17; Figure 1). The final study population comprised 2139 singleton, SGA infants without congenital malformations, born at 24 to 32 weeks gestation. Definitions All departments used operating manual and standard definitions. The definitions were based on those of the VermontOxford Trials Network, and have been previously reported [1,3,17]. The GA, in completed weeks, was defined as the attending neonatologist’s best estimate of gestational age based on last menstrual period, obstetric history and examination, prenatal ultrasound and postnatal physical examination performed in the first hours of life. Gender-specific birth weight z-scores and percentiles were determined according to the intrauterine growth charts of Kramer et al. [18]. SGA was determined as birth weight below the 10th percentile for gestational age. Delivery room resuscitation included endotracheal intubation, chest compressions or epinephrine administration. Ethnic origin was defined as Jewish or other ethnic groups including Muslim, Druze or Christian, according to the mother’s ethnic origin as reported on the infant’s birth certificate. PIH was defined as a systolic blood pressure VLBW infants born 1995-2010 N=24,250 Excluded: Multiple births (n= 10,332) AGA and LGA (n=9,611) GA 32 weeks (n= 1,689) Malformations (n=317) Chronic hypertension (n=145) Missing data (n=17)
Study Population n = 2,139
No Acute Pregnancy Complications* n= 1,471
No PIH n=539
667
PIH n=932
Acute Pregnancy Complications* n= 668
No PIH n=512
PIH n=156
* Pregnancy complications include premature labor, premature rupture of membranes) >6 hours, chorioamnionitis and antepartum hemorrhage. PIH- pregnancy induced hypertension
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equal or greater than 145-mm mercury or diastolic blood pressure equal or greater than 95-mm mercury as recorded on at least two separate measurements, with at least 4 h between them, first occurring after the 20th week of gestation of the current pregnancy. Chronic hypertension was defined as a persistent elevation of blood pressure before 20 weeks gestation or prior to pregnancy. PROM was defined as membrane rupture more than 6 h before the onset of regular spontaneous uterine contractions. Diagnosis of clinical chorioamnionitis was based on high maternal temperature (437.8 C orally or 438 C rectally) recorded twice in 1 h, during the rupture of membranes or during the first 6 h after delivery, provided no other cause for the fever was found. Premature labor was considered as the occurrence of uterine contractions prior to 35 weeks gestation together with cervical effacement and dilatation. Antepartum vaginal hemorrhage included hemorrhage due to either placenta praevia or placental abruption. Acute pregnancy complications were considered as the presence of one or more of the following conditions: premature labor, PROM 46 h, chorioamnionitis, and antepartum hemorrhage. Outcomes Death was defined as death before discharge home. Respiratory distress syndrome (RDS) was diagnosed by a chest radiography consistent with RDS together with supplementary oxygen or mechanical ventilation therapy. Bronchopulmonary dysplasia (BPD) was diagnosed according to the criteria of Bancalari et al. [19] including clinical and radiologic features, together with the requirement of oxygen supplementation at 36 weeks post menstrual age. Intraventricular hemorrhage (IVH) was diagnosed by ultrasound examination and graded according to Papile et al. [20]. Cystic periventicular leukomalacia (PVL) was diagnosed by the presence of multiple periventricular cysts identified by cranial ultrasound examination after 28 d of life. The diagnosis of NEC was made in the presence of clinical and radiologic features according to the criteria of Bell et al. [21]. Only definite NEC (Bell stages II and III) was included. Since mortality and major neonatal morbidities may be considered as competing outcomes, survival without major neurological morbidity (grade 3–4 IVH and/or PVL) and survival without BPD were also determined. Statistical analyses Differences between the no PIH and PIH groups, in the groups without or with acute pregnancy complications, were tested by chi-square test for categorical variables and t-test for continuous variables. p values50.05 were considered statistically significant. All tests were two-sided. Multivariable logistic regression analyses were used to assess the independent effect of PIH on mortality and major neonatal morbidities, adjusting for confounding variables including: maternal age, parity, ethnicity, GA at start of prenatal care, infertility treatment, antenatal steroids, mode of delivery, GA, birth weight z-score, gender, delivery room resuscitation and year of birth. Results of the logistic regression analyses are presented as odds ratios (OR) and 95% confidence intervals (CI). Since significant collinearity was present between birth
J Matern Fetal Neonatal Med, 2015; 28(6): 666–673
weight (BW) and GA, BW was not included in the analysis. Statistical analyses were performed using the SAS statistical software Version 9.2 (SAS Institute, Inc., Cary, NC).
Results In this population-based cohort of singleton SGA infants born at 24–32 weeks of gestation, 51% (1088/2139) were products of pregnancies complicated by PIH. In 668 (31%) of the births, acute pregnancy complications comprising premature labor, PROM 46 h, chorioamnionitis, and antepartum hemorrhage were reported (Figure 1). This group included 512 births with no maternal PIH and 156 with PIH. The group with none of the acute pregnancy complications (n ¼ 1471) comprised 539 births with no maternal PIH and 932 with PIH. The prenatal characteristics and demographic characteristics of the no PIH and PIH births in the pregnancies without and with acute pregnancy complications are compared in Table 1. In the group without acute pregnancy complications, the infants in the maternal PIH group were of lower mean GA (29.6 ± 2.2 versus 30.2 ± 1.9 weeks; p50.0001) and a higher proportion were of GA528 weeks (19.9% versus 9.5%; p50.001). This group had higher mean birth weight z-scores, and a significantly lower proportion were of birth weight53rd percentile (25.7% versus 42.3%; p50.0001). Over 95% of infants in both the no PIH and PIH groups were delivered by cesarean section. Among the 668 deliveries with acute pregnancy complications, PIH was reported in 156 mothers. The rates of premature labor and antepartum hemorrhage were similar in the no PIH and PIH groups, however the PIH group had significantly lower rates of PROM 46 h (8.3% versus 26.6%; p50.0001) and chorioamnionitis (3.2% versus 10.7%; p50.004). In the PIH group, a higher proportion had received complete or partial antenatal steroid therapy and 89.7% were cesarean deliveries compared to 67% in the no PIH group (p50.0001). In the no PIH group, 15.2% were of 24–25 weeks gestation compared to 5.1% in the PIH group (p ¼ 0.01). The percent mortality and neonatal morbidities in the no PIH and PIH groups in pregnancies without and with acute pregnancy complications are shown in Table 2. In the group without acute pregnancy complications, the PIH group had significantly higher rates of RDS and BPD. Mortality rates and major neurological morbidities were similar in the no PIH and PIH groups. In the group with acute pregnancy complications, the PIH group had a significantly lower rate of grades 3–4 IVH (2.7% versus 11.6%; p50.001) and a slightly lower mortality rate (18.6% versus 26.0%; p ¼ 0.06). The multivariable logistic regression analyses evaluating the independent effect of PIH on mortality and major neonatal morbidities in pregnancies with and without acute complications are shown in Table 3. In the absence of acute pregnancy complications the odds for mortality (OR 0.77; 95% CI 0.50– 1.16), survival without severe neurological morbidity (OR 1.14; 95% CI 0.79–1.65) and survival without BPD (OR 0.85; 95% CI 0.59–1.21) were similar in the PIH compared to the no-PIH group. In the presence of acute pregnancy complications, outcomes were also similar in the PIH compared to the no-PIH group: mortality (OR 0.76; 95% CI 0.40–1.44),
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Table 1. Demographic and perinatal characteristics of the study groups. No acute pregnancy complications*
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Variables Maternal age (years) 19 20–29 30–39 40 Mean ± SD Parity 0 1 2 Infertility treatment Non-Jewish Male Starting prenatal care: 0–12 weeks 13–20 weeks 420 weeks Unknown Antenatal steroids: Complete course Partial course None Cesarean delivery Gestational age 24–25 26–27 28–29 30–31 32 Mean ± SD Birth weight (g) 5750 750–999 1000–1249 1250–1500 Mean ± SD BW53rd percentile z-score (mean ± SD) Delivery room resuscitation Premature labor PROM46 h Chorioamnionitis APH Year of birth 1995–2000 2001–2005 2006–2010
No PIH N ¼ 539 n (%)
PIH N ¼ 932 n (%)
6 (1.1) 238 (44.2) 252 (46.7) 43 (8.0) 30.5 ± 6.0
15 (1.6) 454 (48.7) 405 (43.5) 58 (6.2) 30.1 ± 6.0
Acute pregnancy complications* p value
No PIH N ¼ 512 n (%)
PIH N ¼ 156 n (%)
18 (3.5) 275 (53.8) 194 (38.0) 24 (4.7) 28.7 ± 6.1
4 (2.6) 74 (48.0) 69 (44.8) 7 (4.6) 29.7 ± 6.0
0.22
0.48
0.19
0.43 218 110 211 95 123 292
(40.4) (20.4) (39.2) (17.7) (22.9) (54.2)
409 183 340 140 251 468
(43.9) (19.6) (36.5) (15.1) (26.9) (50.2)
451 34 27 27
(83.7) (6.3) (5) (5)
779 83 36 34
(83.6) (8.9) (3.9) (3.6)
285 71 181 516
(53.1) (13.2) (33.7) (95.7)
536 153 239 893
(57.8) (16.5) (25.7) (95.8)
0.19 0.08 0.14 0.14
0.004 0.94 5.0001
9 (1.7) 42 (7.8) 107 (19.8) 203 (37.7) 178 (33) 30.2 ± 1.9
49 (5.3) 136 (14.6) 210 (22.5) 290 (31.1) 247 (26.5) 29.6 ± 2.2
139 (25.8) 179 (33.2) 154 (28.6) 67 (12.4) 937 ± 243 228 (42.3) 1.88 ± 0.43 167 (31) _ _ _ _
270 (29) 262 (28.1) 280 (30) 120 (12.9) 922 ± 266 240 (25.7) 1.72 ± 0.37 383 (41.1) _ _ _ _
168 (31.2) 195 (36.2) 176 (32.6)
321 (34.4) 316 (33.9) 295 (31.7)
p value
5.0001 0.21
0.27 5.0001 5.0001 0.0001
155 104 251 59 165 323
(30.4) (20.4) (49.2) (11.6) (32.4) (63.1)
60 34 62 30 43 91
(38.5) (21.8) (39.7) (19.3) (27.7) (58.3)
393 48 49 22
(76.7) (9.4) (9.6) (4.3)
123 17 4 12
(78.8) (10.9) (2.6) (7.7)
225 68 217 343
(44.1) (13.3) (42.6) (67)
87 26 43 140
(55.8) (16.7) (27.5) (89.7)
78 (15.2) 61 (11.9) 85 (16.6) 120 (23.5) 168 (32.8) 29.3 ± 2.7
8 (5.1) 27 (17.3) 32 (20.5) 40 (25.7) 49 (31.4) 29.6 ± 2.3
167 (32.6) 120 (23.4) 119 (23.3) 106 (20.7) 937 ± 300 92 (18) 1.64 ± 0.37 240 (46.9) 328 (64.1) 136 (26.6) 55 (10.7) 192 (37.5)
49 (31.4) 38 (24.4) 44 (28.2) 25 (16) 936 ± 275 35 (22.4) 1.70 ± 0.36 60 (38.5) 95 (60.9) 13 (8.3) 5 (3.2) 65 (41.7)
216 (42.2) 167 (32.6) 129 (25.2)
63 (40.4) 57 (36.5) 36 (23.1)
0.42
0.07 0.09
0.01 0.27 0.28 0.02
0.004 50.0001 0.009
0.15 0.45
0.96 0.21 0.04 0.06 0.47 50.0001 0.004 0.35 0.65
*Pregnancy complications include premature labor, premature rupture of membranes (PROM) 46 h, chorioamnionitis and antepartum hemorrhage (APH).
Table 2. Percent mortality and major neonatal morbidities associated with PIH in the presence or absence of acute pregnancy complications in singleton SGA preterm infants. No acute pregnancy complications No PIH n/N (%) Mortality IVH grades 3–4 PVL NEC RDS BPD Survival without major neurological morbidityy Survival without BPD
67/539 22/516 14/416 48/538 248/538 46/480 374/458 431/537
(12.4) (4.3) (3.4) (8.9) (46.1) (9.6) (81.7) (80.3)
PIH n/N (%) 126/932 41/866 25/724 60/923 576/923 126/801 644/808 673/913
(13.5) (2.7) (3.4) (6.5) (62.4) (15.7) (79.7) (73.7)
p value 0.55 0.68 0.94 0.09 50.0001 0.002 0.40 0.005
Acute pregnancy complications* No PIH n/N (%) 133/512 52/450 26/352 35/499 287/499 59/384 290/450 324/507
(26) (11.6) (7.4) (7.0) (57.5) (15.4) (64.4) (63.9)
PIH n/N (%) 29/156 4/148 6/115 11/155 84/155 20/128 96/130 106/152
(18.6) (2.7) (5.2) (7.1) (54.2) (15.6) (73.8) (69.7)
*Pregnancy complications include premature labor, premature rupture of membranes 46 h, chorioamnionitis and antepartum hemorrhage. yMajor neurological morbidities includes IVH grades 3–4 and PVL.
p value 0.06 0.001 0.42 0.97 0.47 0.94 0.05 0.18
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J Matern Fetal Neonatal Med, 2015; 28(6): 666–673
Table 3. Adjusted odds ratios (95% confidence interval) for mortality and major morbidities associated with PIH in the presence or absence of acute pregnancy complications in singleton, SGA preterm infants. No acute pregnancy complications No PIH
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Mortality Severe IVH PVL NEC RDS BPD Survival without major neurological morbiditz Survival without BPDô
1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0
PIH ORy (95% CI) 0.77 0.93 0.80 0.64 1.61 1.53 1.14 0.85
(0.50–1.16) (0.52–1.65) (0.39–1.64) (0.42–0.98) (1.23–2.10) (0.99–2.34) (0.79–1.65) (0.59–1.21)
Acute pregnancy complications* No PIH 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0
PIH ORy (95% CI) 0.76 0.26 0.71 0.95 1.04 1.16 1.09 1.04
(0.40–1.44) (0.08–0.84) (0.25–1.98) (0.43–2.07) (0.64–2.07) (0.64–2.12) (0.61–1.96) (0.58–1.86)
*Pregnancy complications include premature labor, premature rupture of membranes 46 h, chorioamnionitis and antepartum hemorrhage. yAdjusted for: maternal age, parity, ethnicity, GA of starting prenatal care, infertility treatment, antenatal steroids, cesarean section, GA, birth weight z-score, gender, delivery room resuscitation and year of birth. zMajor neurological morbidities include IVH grades 3–4 and PVL. ôAdjusted also for RDS. OR, odds ratio; CI, confidence interval.
survival without severe neurological morbidity (OR1.16; 95% CI 0.64–2.12) and survival without BPD (OR 1.04; 95% CI 0.58–1.86). In the absence of acute pregnancy complications the PIH group had a significantly lower odds for NEC (OR 0.64; 95% CI 0.42–0.98) and a higher odds for RDS (OR1.61; 95% CI 1.21–2.06). In the presence of acute pregnancy complications, the PIH group had a significantly lower odds for severe IVH (OR 0.26; 95% CI 0.08–0.84).
Discussion In this population-based study of very preterm SGA infants, approximately half of the pregnancies were complicated by maternal PIH and in 31% acute pregnancy complications, including premature labor, PROM 46 h, chorioamnionitis and antepartum hemorrhage, were reported. The results of this study did not show a significant protective effect of maternal PIH on infant mortality or on survival without major neurological or respiratory morbidities among preterm SGA infants, both the presence and absence of acute pregnancy complications. In preterm infants, the risk of perinatal mortality associated with PIH has been reported to be either increased [22], similar [11,12] or decreased [7,13,14]. The protective effect on mortality was present mainly in the early preterm deliveries of SGA infants (510th percentile) [13,15]. Chen et al. considered that the improved outcome may be due to a selective intervention bias where PIH pregnancies and neonates were managed more intensely [13] and were more likely to have earlier and more closely monitored prenatal care, receive a full course of steroids and be treated with magnesium sulphate. The more meticulous maternal and fetal assessments, might lead to delivery upon evidence of worsening of fetal compromise of infants [13,15]. A similar favorable effect of hypertension on infant survival was also shown by von Dadelszen et al. who reported a protective effect in premature SGA infants born 5 28 weeks gestation, resulting in almost doubling of survival among SGA infants admitted to the NICU [7]. These studies did not however account for the presence of other pregnancy complications which may influence the outcome in the non-hypertensive pregnancies.
Chen et al. [13] note that their data might thus overestimate the protective effect of PIH on infant mortality in SGA and preterm births. The presence of acute co-morbidities such as APH, chorioamnionitis and PROM has been reported to be associated with increased neonatal morbidity and mortality [23,24]. These conditions are both significant contributors to preterm birth, as well as a significant cause of gestational agedependent neonatal morbidity and mortality. In non-PIH pregnancies, preterm delivery associated with acute pregnancy complications may predispose to higher infant mortality and morbidity and hence explain the reported relatively better neonatal outcome in the PIH-complicated pregnancies. The impact of PIH, pregnancy co-morbidities and BW percentiles in very preterm infants was considered by Zeitlin et al. [4] who demonstrated adverse infant outcomes when pregnancy complications and SGA were both present. BW 510th percentile was associated with a 16-fold excess odds for mortality and 5-fold excess odds for BPD in the presence of maternal hypertension or fetal growth restriction. In the presence of pregnancy complications including maternal hemorrhage, PROM and infection, the odds for mortality and for BPD were approximately 4-fold higher in infants with a BW 510th percentile. This further supports the importance and necessity of accounting for the impact of associated pregnancy complications when evaluating the outcomes of preterm infants. A recent meta-analysis [5] reported significantly increased respiratory complications in preterm growth-restricted infants. In the presence of PIH, the risk of BPD was found to be either increased [4,24,25] similar [26,27], or reduced [28]. Our study showed an approximately 1.5-fold excess risk for RDS and BPD in the PIH group, further suggesting that PIH was not associated with accelerated fetal lung maturation. Tang et al. [29] have suggested that in infants born to mothers with pre-eclampsia, impaired vascular endothelial growth factor (VGEF) signalling in-utero, due to high amniotic fluid levels of soluble VGEF receptor-1, disrupts lung growth and contributes to the increased risk of BPD. NEC is a major morbidity in preterm infants, caused by the combination of mucosal injury, bacteria and metabolic substrates on an immature intestine. The redistribution of
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DOI: 10.3109/14767058.2014.928851
blood to vital organs in an intrauterine adaptive mechanism in growth retarded fetuses which persists postnatally [30], and may cause feeding intolerance and subsequent NEC. Two reports [31,32] suggested maternal hypertension to be a risk factor for NEC in VLBW infants. Others did not support this observation, stating that even in the presence of compromised fetal blood distribution these changes are insufficient to induce NEC [9,33]. Our analysis found preterm SGA infants in the PIH group to be at a lower risk for NEC. This reduced risk could be due to the suggested protective effect of the superior mesenteric artery flow on the splanchnic circulation previously described in growth-retarded fetuses [34], and probably to the changes in enteral feeding strategies in premature infants [35]. The possible impact of PIH on the risk of brain injury in preterm SGA infants is of interest. Conflicting reports suggest higher, lower or similar rates of both IVH and PVL [17,36– 39]. In the EPIPAGE study, Ancel et al. [40] reported that both SGA and maternal hypertension without SGA were not associated with higher rates of both IVH and PVL. The impact of the cause of preterm delivery and neonatal outcomes was assessed by Baud et al. [36] who showed that the presence of intrauterine growth restriction/pre-eclampsia was associated with a decreased risk of cystic PVL, compared with intrauterine infection. von Dadelszen et al. [7] suggested that PIH may serve some adaptive role for the fetus in the face of uteroplacental dysfunction. Activation of hypothalamic– pituitary–adrenal axis with increased levels of ACTH and adrenal corticosteroids may contribute to the maturation of organ systems including the brain [41]. However, despite the suggested protective mechanisms, our study did not find a reduced risk of IVH and PVL in the PIH group without acute pregnancy complications. We did however find a reduced risk of IVH in the group with both PIH and acute pregnancy complications. This finding may rather reflect the especially poor outcome in the group of infants from pregnancies with acute complications and no PIH, since this latter group was significantly less mature, had less antenatal corticosteroid treatment and lower rates of cesarean deliveries than all other groups studied. In considering the results of this study a number of limitations should be accounted for. First, the study population of SGA infants was determined using a birth weight percentile reference [1,3,18]. The use of a population-based birth weight references rather than fetal growth standards or customized standards for the diagnosis of abnormal fetal growth or small size for gestational age is controversial and may impact the results of this study [42–46]. Neonatal growth standards derived from whole populations tend to lower the cut-off points for the identification of SGA infants [45]. Conversely, the use of the 10th percentile from fetal growth standards would represent a liberal definition of SGA and hence a large number of false-positive cases [42], potentially labelling many healthy infants as being ‘‘at risk’’ [44]. The use of customized charts in order to account for variations in fetal growth associated with differences in maternal characteristics [43], or for maternal diseases that adversely affect fetal weight [45], may improve identification of newborn infants at increased risk for adverse perinatal outcomes [45]. The improved predictive ability of these charts may however
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be the consequence of an artifactual identification of preterm infants as SGA [42], and it has not been determined whether the use of customized criteria for fetal SGA would result in improved outcomes [43]. Ehrenkranz [46] concludes that at the present time it is preferable to continue to use reference intrauterine growth curves based on body weight in clinical practice. A further limitation of the study is that it is observational in design. The database does not include information related to the severity of PIH or other acute pregnancy complications, as well as variations in both obstetric and neonatal management which may influence the outcomes reported. The database does not provide information pertaining to the complex assessment of fetal well-being and management decisions required in the presence of fetal growth restriction. It was therefore not possible to determine the precise etiology of the preterm deliveries. Changes in practice over time, especially in respect to provider indicated deliveries, may influence the outcomes studied. Adjustment for year of birth did not affect the results of the study, however. The database however comprises 499% of all VLBW infants born in Israel, and the study population reflects a total national population of very preterm SGA infants without any selection bias. The database includes prospectively collected information on major pregnancy complications which enabled more accurate characterisation of the ‘‘control groups’’ of the non-PIH pregnancies. The size of our sample made it possible to examine outcome in singleton SGA premature infants born to mothers with PIH both in the presence and absence of acute pregnancy complications, and control for multiple confounding factors.
Conclusion The present study does not support a protective effect of maternal PIH on the combined outcomes of infant survival without major neurological morbidity and survival without BPD, in preterm SGA infants, both in the presence and absence of acute pregnancy complications. It is however possible that the management of these pregnancies including close prenatal care, antenatal steroid therapy, magnesium sulphate treatment together with meticulous maternal and fetal assessments and optimal timing of delivery, might ameliorated the potentially detrimental outcome in the PIHcomplicated pregnancies.
Declaration of interest The Israel National Very-Low-Birth-Weight Infant Database is partially funded by the Israel center for Disease Control and the Ministry of Health.
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27. Cheng SW, Chou HC, Tsou KI, et al. Delivery before 32 weeks of gestation for maternal pre-eclampsia: neonatal outcome and 2-year developmental outcome. Early Hum Dev 2004;76:39–46. 28. O’Shea JE, Davis PG, Doyle LW. Maternal preeclampsia and risk of bronchopulmonary dysplasia in preterm infants. Pediatr Res 2012;71:210–14. 29. Tang JR, Karumanchi SA, Seedorf G, et al. Excess soluble vascular endothelial growth factor receptor-1 in amniotic fluid impairs lung growth in rats: linking preeclampsia with bronchopulmonary dysplasia. Am J Physiol Lung Cell Mol Physiol 2012;302:L36–46. 30. Bora R, Mukhopadhyay K, Saxena AK, et al. Prediction of feed intolerance and necrotizing enterocolitis in neonates with absent end diastolic flow in umbilical artery and the correlation of feed intolerance with postnatal superior mesenteric artery flow. J Matern Fetal Neonatal Med 2009;22:1092–6. 31. Bashiri A, Zmora E, Sheiner E, et al. Maternal hypertensive disorders are an independent risk factor for the development of necrotizing enterocolitis in very low birth weight infants. Fetal Diagn Ther 2003;18:404–7. 32. Cetinkaya M, Ozkan H, Koksal N. Maternal preeclampsia is associated with increased risk of necrotizing enterocolitis in preterm infants. Early Hum Dev 2012;88:893–8. 33. Simchen MJ, Beiner ME, Strauss-Liviathan N, et al. Neonatal outcome in growth-restricted versus appropriately grown preterm infants. Am J Perinatol 2000;17:187–92. 34. Achiron R, Mazkereth R, Orvieto R, et al. Echogenic bowel in intrauterine growth restriction fetuses: does this jeopardize the gut? Obstet Gynecol 2002;100:120–5. 35. Baud O, Zupan V, Lacaze-Masmonteil T, et al. The relationships between antenatal management, the cause of delivery and neonatal outcome in a large cohort of very preterm singleton infants. BJOG 2000;107:877–84. 36. O’Shea M, Savitz DA, Hage ML, Feinstein KA. Prenatal events and the risk of subependymal/intraventricular haemorrhage in very low birthweight neonates. Paediatr Perinat Epidemiol 1992;6:352–62. 37. Kuban KC, Leviton A, Pagano M, et al. Maternal toxemia is associated with reduced incidence of germinal matrix hemorrhage in premature babies. J Child Neurol 1992;7:70–6. 38. Perlman JM, Risser RC, Gee JB. Pregnancy-induced hypertension and reduced intraventricular hemorrhage in preterm infants. Pediatr Neurol 1997;17:29–33. 39. Ancel PY, Marret S, Larroque B, et al. Are maternal hypertension and small-for-gestational age risk factors for severe intraventricular hemorrhage and cystic periventricular leukomalacia? Results of the EPIPAGE cohort study. Am J Obstet Gynecol 2005;193:178–84. 40. Kapoor A, Dunn E, Kostaki A, et al. Fetal programming of hypothalamo-pituitary-adrenal function: prenatal stress and glucocorticoids. J Physiol 2006;572:31–44. 41. Morgan J, Young L, McGuire W. Slow advancement of enteral feed volumes to prevent necrotising enterocolitis in very low birth weight infants. Cochrane Database Syst Rev 2013; Issue 3. 42. Mayer C, Joshef KS. Fetal growth: a review of terms, concepts and issues relevant to obstetrics. Ultrasound Obstet Gynecol 2013;41: 136–45. 43. Larkin JC, Hill LM, Speer PD, Simhan HN. Risk of morbid perinatal outcomes in small-for-gestational-age pregnancies: customized compared with conventional standards of fetal growth. Obstet Gynecol 2012;119:21–7. 44. Hemming K, Bonellie S, Hutton JL. Fetal growth and birthweight standards as screening tools: methods for evaluating performance. BJOG 2011;118:1477–83. 45. Ferdynus C, Quantin C, Abrahamowicz M, et al. Comparison of the ability of alternative birthweight and fetal weight standards to identify preterm newborns at increased risk of perinatal death. BJOG 2013;120:1456–64. 46. Ehrenkranz RA. Estimated fetal weights versus birth weights: should the reference intrauterine growth curves based on birth weights be retired? Arch Dis Child Fetal Neonatal Ed 2007;92: F161–2.
Appendix A The Israel Neonatal Network participating centers in the Israel National VLBW infant database are: Assaf Harofeh Medical center, Rishon Le Zion; Barzilay Medical center, Ashkelon; Bikur Holim Hospital,
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Jerusalem; Bnai Zion Medical center, Haifa; Carmel Medical center, Haifa; English (Scottish) Hospital, Nazareth; French Hospital, Nazareth; Hadassah University Hospital Ein-Karem, Jerusalem; Hadassah University Hospital Har Hazofim, Jerusalem; Haemek Medical center, Afula; Hillel Yafe Medical center, Hadera; Italian Hospital, Nazareth; Kaplan Hospital, Rehovot; Laniado Hospital, Netanya; Maayanei Hayeshua Hospital, Bnei-Brak; Meir Medical center, Kefar Saba; Misgav Ladach Hospital, Jerusalem; Naharia Hospital, Naharia; Poria
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Hospital, Tiberias; Rambam Medical center, Haifa; Rivka Ziv Hospital, Zefat; Schneider Children’s Medical center of Israel and Rabin Medical center (Belinson Campus), Petach-Tikva; Shaare-Zedek Hospital, Jerusalem; Sheba Medical center, Tel-Hashomer; Soroka Medical center, Beer-Sheva; Sourasky Medical center, Tel-Aviv; Wolfson Medical center, Holon; Yoseftal Hospital, Eilat Coordinating center: Women and Children’s Health Research Unit, Gertner Institute, Tel Hashomer.
ORIGINAL ARTICLE
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Outcome of singleton preterm small for gestational age infants born to mothers with pregnancy-induced hypertension. A population-based study Rivka H. Regev1,2, Shmuel Arnon1,2, Ita Litmanovitz1,2, Sofia Bauer-Rusek1, Valentina Boyko3, Liat Lerner-Geva2,3, Brian Reichman2,3; In collaboration with the Israel Neonatal Network* 1
Department of Neonatology, Meir Hospital, Sapir Medical Center, Kfar Saba, Israel, 2Women and Children’s Health Research Unit, Gertner Institute, Tel Hashomer, Israel, and 3Sackler Medical School, Tel Aviv University, Tel Aviv, Israel Abstract
Keywords
Background: Pregnancy-induced hypertension (PIH) has been associated with a decreased risk of infant mortality in small for gestational age (SGA) preterm infants. Objective: To evaluate the influence of PIH on mortality and major neonatal morbidities in singleton preterm SGA infants, in the presence and absence of acute pregnancy complications. Methods: Population-based observational study of singleton SGA infants, born at 24 to 32 weeks gestation in the period 1995–2010 (n ¼ 2139). Multivariable logistic regression analyses were used to assess the independent effect of PIH on mortality and neonatal morbidities. Acute pregnancy complications comprised premature labor, premature rupture of membranes 46 h, antepartum hemorrhage and clinical chorioamnionitis. Results: In the absence of pregnancy complications, the odds ratio (95% confidence interval) for mortality (0.77; 0.50–1.16), survival without severe neurological morbidity (1.14; 0.79–1.65) and survival without bronchopulmonary dysplasia (BPD) (0.85; 0.59–1.21) were similar in the PIH versus no-PIH groups. In the presence of pregnancy complications, mortality (0.76; 0.40–1.44), survival without severe neurological morbidity (1.16; 0.64–2.12) and survival without BPD (1.04; 0.58–1.86) were also similar in the PIH versus no-PIH groups. Conclusions: PIH was not associated with improved outcome in preterm SGA infants, both in the presence and absence of acute pregnancy complications.
Acute pregnancy complications, outcome, pregnancy-induced hypertension, premature infants, small for gestational age, very-low-birth-weight
Introduction Small for gestational age (SGA) preterm infants are at excess risk for mortality and major morbidities including necrotising enterocolitis (NEC), bronchopulmonary dysplasia (BPD) and retinopathy of prematurity (ROP) [1–4]. In a recent metaanalysis, Damodaram et al. demonstrated that preterm growth retarded fetuses are at an additional increased postnatal risk for intracranial hemorrhage and sepsis, compared with a normally grown cohort [5]. Hypertensive disorders of pregnancy complicate 5–10% of pregnancies [6,7], and are associated with increased risks of preterm birth, low birth weight and SGA infants [8]. The risk of perinatal mortality associated with pregnancy-induced hypertension (PIH), in singleton preterm infants, has been reported to be increased
*See Appendix A. Address for correspondence: Dr. Rivka H. Regev, Department of Neonatalogy, Meir Hospital, Sapir Medical Center, 59 Tchernichovsky, Kfar Saba 44410, Israel. E-mail: [email protected]
History Received 29 November 2013 Revised 31 March 2014 Accepted 25 May 2014 Published online 27 June 2014
[4,10], similar [11,12], as well as decreased [7,13]. Piper et al. reported that maternal hypertension was independently associated with a 39% reduction in perinatal mortality in preterm SGA infants [14]. Chen et al. [15], using a large USA infant birth/death database, reported that PIH was associated with a 46% decreased risk of infant mortality in SGA preterm infants. Despite the strength of this association, the authors comment that the data might overestimate the protective effect of PIH on infant mortality since the control group for SGA and preterm births did not necessarily represent a ‘‘normal’’ control group. In the control groups without PIH, the presence of additional acute pregnancy complications such as preterm premature contractions, antepartum hemorrhage, rupture of membranes and amnionitis, may necessitate early delivery and influence the outcome of premature verylow-birth-weight (VLBW) infants [16]. The purpose of this population-based study was to evaluate the influence of maternal PIH on mortality and major neonatal morbidities in preterm SGA infants, taking into consideration the presence or absence of acute pregnancy complications.
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DOI: 10.3109/14767058.2014.928851
Methods
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VLBW infant database This study was based on analysis of data collected by the Israel Neonatal Network on VLBW newborn infants (birth weight 1500 g) born in Israel from 1995 through 2010. All 28 neonatal departments in Israel participated in the data collection, which comprises the Israel National VLBW Infant database (Appendix A). The data collected included parental demographic details, maternal pregnancy history and antenatal care, details of the delivery, infants’ status at delivery, diagnoses, procedures and complications during hospitalisation and outcome at discharge [1,3]. A pre-structured form was completed for each infant. Each form was checked for logic errors and if necessary returned to the participating center for clarification. All live-born infants in Israel receive a unique identification number at birth. Patient information received by the database coordinator was cross checked with the national birth registry, and data from any missing infant were requested from the birth hospital. Birth hospital and patient identification subsequently remain confidential. Data were collected on all infants until death or discharge home. The study was approved by the Helsinki committee of the Sheba Medical Center. (SMC-9613-12). Study population From 1995 through 2010, the database included records of 24 250 infants, which comprise over 99% of all VLBW live Figure 1. Schematic summary – study population.
births in Israel. From these infants we excluded multiple births (n ¼ 10 332), appropriate and large for gestational age (GA) infants (n ¼ 9611), infants 524 or 432 weeks of gestation (n ¼ 1689), congenital malformations (n ¼ 317), infants born to mothers with chronic hypertension (n ¼ 145) and infants with missing data (n ¼ 17; Figure 1). The final study population comprised 2139 singleton, SGA infants without congenital malformations, born at 24 to 32 weeks gestation. Definitions All departments used operating manual and standard definitions. The definitions were based on those of the VermontOxford Trials Network, and have been previously reported [1,3,17]. The GA, in completed weeks, was defined as the attending neonatologist’s best estimate of gestational age based on last menstrual period, obstetric history and examination, prenatal ultrasound and postnatal physical examination performed in the first hours of life. Gender-specific birth weight z-scores and percentiles were determined according to the intrauterine growth charts of Kramer et al. [18]. SGA was determined as birth weight below the 10th percentile for gestational age. Delivery room resuscitation included endotracheal intubation, chest compressions or epinephrine administration. Ethnic origin was defined as Jewish or other ethnic groups including Muslim, Druze or Christian, according to the mother’s ethnic origin as reported on the infant’s birth certificate. PIH was defined as a systolic blood pressure VLBW infants born 1995-2010 N=24,250 Excluded: Multiple births (n= 10,332) AGA and LGA (n=9,611) GA 32 weeks (n= 1,689) Malformations (n=317) Chronic hypertension (n=145) Missing data (n=17)
Study Population n = 2,139
No Acute Pregnancy Complications* n= 1,471
No PIH n=539
667
PIH n=932
Acute Pregnancy Complications* n= 668
No PIH n=512
PIH n=156
* Pregnancy complications include premature labor, premature rupture of membranes) >6 hours, chorioamnionitis and antepartum hemorrhage. PIH- pregnancy induced hypertension
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equal or greater than 145-mm mercury or diastolic blood pressure equal or greater than 95-mm mercury as recorded on at least two separate measurements, with at least 4 h between them, first occurring after the 20th week of gestation of the current pregnancy. Chronic hypertension was defined as a persistent elevation of blood pressure before 20 weeks gestation or prior to pregnancy. PROM was defined as membrane rupture more than 6 h before the onset of regular spontaneous uterine contractions. Diagnosis of clinical chorioamnionitis was based on high maternal temperature (437.8 C orally or 438 C rectally) recorded twice in 1 h, during the rupture of membranes or during the first 6 h after delivery, provided no other cause for the fever was found. Premature labor was considered as the occurrence of uterine contractions prior to 35 weeks gestation together with cervical effacement and dilatation. Antepartum vaginal hemorrhage included hemorrhage due to either placenta praevia or placental abruption. Acute pregnancy complications were considered as the presence of one or more of the following conditions: premature labor, PROM 46 h, chorioamnionitis, and antepartum hemorrhage. Outcomes Death was defined as death before discharge home. Respiratory distress syndrome (RDS) was diagnosed by a chest radiography consistent with RDS together with supplementary oxygen or mechanical ventilation therapy. Bronchopulmonary dysplasia (BPD) was diagnosed according to the criteria of Bancalari et al. [19] including clinical and radiologic features, together with the requirement of oxygen supplementation at 36 weeks post menstrual age. Intraventricular hemorrhage (IVH) was diagnosed by ultrasound examination and graded according to Papile et al. [20]. Cystic periventicular leukomalacia (PVL) was diagnosed by the presence of multiple periventricular cysts identified by cranial ultrasound examination after 28 d of life. The diagnosis of NEC was made in the presence of clinical and radiologic features according to the criteria of Bell et al. [21]. Only definite NEC (Bell stages II and III) was included. Since mortality and major neonatal morbidities may be considered as competing outcomes, survival without major neurological morbidity (grade 3–4 IVH and/or PVL) and survival without BPD were also determined. Statistical analyses Differences between the no PIH and PIH groups, in the groups without or with acute pregnancy complications, were tested by chi-square test for categorical variables and t-test for continuous variables. p values50.05 were considered statistically significant. All tests were two-sided. Multivariable logistic regression analyses were used to assess the independent effect of PIH on mortality and major neonatal morbidities, adjusting for confounding variables including: maternal age, parity, ethnicity, GA at start of prenatal care, infertility treatment, antenatal steroids, mode of delivery, GA, birth weight z-score, gender, delivery room resuscitation and year of birth. Results of the logistic regression analyses are presented as odds ratios (OR) and 95% confidence intervals (CI). Since significant collinearity was present between birth
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weight (BW) and GA, BW was not included in the analysis. Statistical analyses were performed using the SAS statistical software Version 9.2 (SAS Institute, Inc., Cary, NC).
Results In this population-based cohort of singleton SGA infants born at 24–32 weeks of gestation, 51% (1088/2139) were products of pregnancies complicated by PIH. In 668 (31%) of the births, acute pregnancy complications comprising premature labor, PROM 46 h, chorioamnionitis, and antepartum hemorrhage were reported (Figure 1). This group included 512 births with no maternal PIH and 156 with PIH. The group with none of the acute pregnancy complications (n ¼ 1471) comprised 539 births with no maternal PIH and 932 with PIH. The prenatal characteristics and demographic characteristics of the no PIH and PIH births in the pregnancies without and with acute pregnancy complications are compared in Table 1. In the group without acute pregnancy complications, the infants in the maternal PIH group were of lower mean GA (29.6 ± 2.2 versus 30.2 ± 1.9 weeks; p50.0001) and a higher proportion were of GA528 weeks (19.9% versus 9.5%; p50.001). This group had higher mean birth weight z-scores, and a significantly lower proportion were of birth weight53rd percentile (25.7% versus 42.3%; p50.0001). Over 95% of infants in both the no PIH and PIH groups were delivered by cesarean section. Among the 668 deliveries with acute pregnancy complications, PIH was reported in 156 mothers. The rates of premature labor and antepartum hemorrhage were similar in the no PIH and PIH groups, however the PIH group had significantly lower rates of PROM 46 h (8.3% versus 26.6%; p50.0001) and chorioamnionitis (3.2% versus 10.7%; p50.004). In the PIH group, a higher proportion had received complete or partial antenatal steroid therapy and 89.7% were cesarean deliveries compared to 67% in the no PIH group (p50.0001). In the no PIH group, 15.2% were of 24–25 weeks gestation compared to 5.1% in the PIH group (p ¼ 0.01). The percent mortality and neonatal morbidities in the no PIH and PIH groups in pregnancies without and with acute pregnancy complications are shown in Table 2. In the group without acute pregnancy complications, the PIH group had significantly higher rates of RDS and BPD. Mortality rates and major neurological morbidities were similar in the no PIH and PIH groups. In the group with acute pregnancy complications, the PIH group had a significantly lower rate of grades 3–4 IVH (2.7% versus 11.6%; p50.001) and a slightly lower mortality rate (18.6% versus 26.0%; p ¼ 0.06). The multivariable logistic regression analyses evaluating the independent effect of PIH on mortality and major neonatal morbidities in pregnancies with and without acute complications are shown in Table 3. In the absence of acute pregnancy complications the odds for mortality (OR 0.77; 95% CI 0.50– 1.16), survival without severe neurological morbidity (OR 1.14; 95% CI 0.79–1.65) and survival without BPD (OR 0.85; 95% CI 0.59–1.21) were similar in the PIH compared to the no-PIH group. In the presence of acute pregnancy complications, outcomes were also similar in the PIH compared to the no-PIH group: mortality (OR 0.76; 95% CI 0.40–1.44),
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Table 1. Demographic and perinatal characteristics of the study groups. No acute pregnancy complications*
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Variables Maternal age (years) 19 20–29 30–39 40 Mean ± SD Parity 0 1 2 Infertility treatment Non-Jewish Male Starting prenatal care: 0–12 weeks 13–20 weeks 420 weeks Unknown Antenatal steroids: Complete course Partial course None Cesarean delivery Gestational age 24–25 26–27 28–29 30–31 32 Mean ± SD Birth weight (g) 5750 750–999 1000–1249 1250–1500 Mean ± SD BW53rd percentile z-score (mean ± SD) Delivery room resuscitation Premature labor PROM46 h Chorioamnionitis APH Year of birth 1995–2000 2001–2005 2006–2010
No PIH N ¼ 539 n (%)
PIH N ¼ 932 n (%)
6 (1.1) 238 (44.2) 252 (46.7) 43 (8.0) 30.5 ± 6.0
15 (1.6) 454 (48.7) 405 (43.5) 58 (6.2) 30.1 ± 6.0
Acute pregnancy complications* p value
No PIH N ¼ 512 n (%)
PIH N ¼ 156 n (%)
18 (3.5) 275 (53.8) 194 (38.0) 24 (4.7) 28.7 ± 6.1
4 (2.6) 74 (48.0) 69 (44.8) 7 (4.6) 29.7 ± 6.0
0.22
0.48
0.19
0.43 218 110 211 95 123 292
(40.4) (20.4) (39.2) (17.7) (22.9) (54.2)
409 183 340 140 251 468
(43.9) (19.6) (36.5) (15.1) (26.9) (50.2)
451 34 27 27
(83.7) (6.3) (5) (5)
779 83 36 34
(83.6) (8.9) (3.9) (3.6)
285 71 181 516
(53.1) (13.2) (33.7) (95.7)
536 153 239 893
(57.8) (16.5) (25.7) (95.8)
0.19 0.08 0.14 0.14
0.004 0.94 5.0001
9 (1.7) 42 (7.8) 107 (19.8) 203 (37.7) 178 (33) 30.2 ± 1.9
49 (5.3) 136 (14.6) 210 (22.5) 290 (31.1) 247 (26.5) 29.6 ± 2.2
139 (25.8) 179 (33.2) 154 (28.6) 67 (12.4) 937 ± 243 228 (42.3) 1.88 ± 0.43 167 (31) _ _ _ _
270 (29) 262 (28.1) 280 (30) 120 (12.9) 922 ± 266 240 (25.7) 1.72 ± 0.37 383 (41.1) _ _ _ _
168 (31.2) 195 (36.2) 176 (32.6)
321 (34.4) 316 (33.9) 295 (31.7)
p value
5.0001 0.21
0.27 5.0001 5.0001 0.0001
155 104 251 59 165 323
(30.4) (20.4) (49.2) (11.6) (32.4) (63.1)
60 34 62 30 43 91
(38.5) (21.8) (39.7) (19.3) (27.7) (58.3)
393 48 49 22
(76.7) (9.4) (9.6) (4.3)
123 17 4 12
(78.8) (10.9) (2.6) (7.7)
225 68 217 343
(44.1) (13.3) (42.6) (67)
87 26 43 140
(55.8) (16.7) (27.5) (89.7)
78 (15.2) 61 (11.9) 85 (16.6) 120 (23.5) 168 (32.8) 29.3 ± 2.7
8 (5.1) 27 (17.3) 32 (20.5) 40 (25.7) 49 (31.4) 29.6 ± 2.3
167 (32.6) 120 (23.4) 119 (23.3) 106 (20.7) 937 ± 300 92 (18) 1.64 ± 0.37 240 (46.9) 328 (64.1) 136 (26.6) 55 (10.7) 192 (37.5)
49 (31.4) 38 (24.4) 44 (28.2) 25 (16) 936 ± 275 35 (22.4) 1.70 ± 0.36 60 (38.5) 95 (60.9) 13 (8.3) 5 (3.2) 65 (41.7)
216 (42.2) 167 (32.6) 129 (25.2)
63 (40.4) 57 (36.5) 36 (23.1)
0.42
0.07 0.09
0.01 0.27 0.28 0.02
0.004 50.0001 0.009
0.15 0.45
0.96 0.21 0.04 0.06 0.47 50.0001 0.004 0.35 0.65
*Pregnancy complications include premature labor, premature rupture of membranes (PROM) 46 h, chorioamnionitis and antepartum hemorrhage (APH).
Table 2. Percent mortality and major neonatal morbidities associated with PIH in the presence or absence of acute pregnancy complications in singleton SGA preterm infants. No acute pregnancy complications No PIH n/N (%) Mortality IVH grades 3–4 PVL NEC RDS BPD Survival without major neurological morbidityy Survival without BPD
67/539 22/516 14/416 48/538 248/538 46/480 374/458 431/537
(12.4) (4.3) (3.4) (8.9) (46.1) (9.6) (81.7) (80.3)
PIH n/N (%) 126/932 41/866 25/724 60/923 576/923 126/801 644/808 673/913
(13.5) (2.7) (3.4) (6.5) (62.4) (15.7) (79.7) (73.7)
p value 0.55 0.68 0.94 0.09 50.0001 0.002 0.40 0.005
Acute pregnancy complications* No PIH n/N (%) 133/512 52/450 26/352 35/499 287/499 59/384 290/450 324/507
(26) (11.6) (7.4) (7.0) (57.5) (15.4) (64.4) (63.9)
PIH n/N (%) 29/156 4/148 6/115 11/155 84/155 20/128 96/130 106/152
(18.6) (2.7) (5.2) (7.1) (54.2) (15.6) (73.8) (69.7)
*Pregnancy complications include premature labor, premature rupture of membranes 46 h, chorioamnionitis and antepartum hemorrhage. yMajor neurological morbidities includes IVH grades 3–4 and PVL.
p value 0.06 0.001 0.42 0.97 0.47 0.94 0.05 0.18
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Table 3. Adjusted odds ratios (95% confidence interval) for mortality and major morbidities associated with PIH in the presence or absence of acute pregnancy complications in singleton, SGA preterm infants. No acute pregnancy complications No PIH
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Mortality Severe IVH PVL NEC RDS BPD Survival without major neurological morbiditz Survival without BPDô
1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0
PIH ORy (95% CI) 0.77 0.93 0.80 0.64 1.61 1.53 1.14 0.85
(0.50–1.16) (0.52–1.65) (0.39–1.64) (0.42–0.98) (1.23–2.10) (0.99–2.34) (0.79–1.65) (0.59–1.21)
Acute pregnancy complications* No PIH 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0
PIH ORy (95% CI) 0.76 0.26 0.71 0.95 1.04 1.16 1.09 1.04
(0.40–1.44) (0.08–0.84) (0.25–1.98) (0.43–2.07) (0.64–2.07) (0.64–2.12) (0.61–1.96) (0.58–1.86)
*Pregnancy complications include premature labor, premature rupture of membranes 46 h, chorioamnionitis and antepartum hemorrhage. yAdjusted for: maternal age, parity, ethnicity, GA of starting prenatal care, infertility treatment, antenatal steroids, cesarean section, GA, birth weight z-score, gender, delivery room resuscitation and year of birth. zMajor neurological morbidities include IVH grades 3–4 and PVL. ôAdjusted also for RDS. OR, odds ratio; CI, confidence interval.
survival without severe neurological morbidity (OR1.16; 95% CI 0.64–2.12) and survival without BPD (OR 1.04; 95% CI 0.58–1.86). In the absence of acute pregnancy complications the PIH group had a significantly lower odds for NEC (OR 0.64; 95% CI 0.42–0.98) and a higher odds for RDS (OR1.61; 95% CI 1.21–2.06). In the presence of acute pregnancy complications, the PIH group had a significantly lower odds for severe IVH (OR 0.26; 95% CI 0.08–0.84).
Discussion In this population-based study of very preterm SGA infants, approximately half of the pregnancies were complicated by maternal PIH and in 31% acute pregnancy complications, including premature labor, PROM 46 h, chorioamnionitis and antepartum hemorrhage, were reported. The results of this study did not show a significant protective effect of maternal PIH on infant mortality or on survival without major neurological or respiratory morbidities among preterm SGA infants, both the presence and absence of acute pregnancy complications. In preterm infants, the risk of perinatal mortality associated with PIH has been reported to be either increased [22], similar [11,12] or decreased [7,13,14]. The protective effect on mortality was present mainly in the early preterm deliveries of SGA infants (510th percentile) [13,15]. Chen et al. considered that the improved outcome may be due to a selective intervention bias where PIH pregnancies and neonates were managed more intensely [13] and were more likely to have earlier and more closely monitored prenatal care, receive a full course of steroids and be treated with magnesium sulphate. The more meticulous maternal and fetal assessments, might lead to delivery upon evidence of worsening of fetal compromise of infants [13,15]. A similar favorable effect of hypertension on infant survival was also shown by von Dadelszen et al. who reported a protective effect in premature SGA infants born 5 28 weeks gestation, resulting in almost doubling of survival among SGA infants admitted to the NICU [7]. These studies did not however account for the presence of other pregnancy complications which may influence the outcome in the non-hypertensive pregnancies.
Chen et al. [13] note that their data might thus overestimate the protective effect of PIH on infant mortality in SGA and preterm births. The presence of acute co-morbidities such as APH, chorioamnionitis and PROM has been reported to be associated with increased neonatal morbidity and mortality [23,24]. These conditions are both significant contributors to preterm birth, as well as a significant cause of gestational agedependent neonatal morbidity and mortality. In non-PIH pregnancies, preterm delivery associated with acute pregnancy complications may predispose to higher infant mortality and morbidity and hence explain the reported relatively better neonatal outcome in the PIH-complicated pregnancies. The impact of PIH, pregnancy co-morbidities and BW percentiles in very preterm infants was considered by Zeitlin et al. [4] who demonstrated adverse infant outcomes when pregnancy complications and SGA were both present. BW 510th percentile was associated with a 16-fold excess odds for mortality and 5-fold excess odds for BPD in the presence of maternal hypertension or fetal growth restriction. In the presence of pregnancy complications including maternal hemorrhage, PROM and infection, the odds for mortality and for BPD were approximately 4-fold higher in infants with a BW 510th percentile. This further supports the importance and necessity of accounting for the impact of associated pregnancy complications when evaluating the outcomes of preterm infants. A recent meta-analysis [5] reported significantly increased respiratory complications in preterm growth-restricted infants. In the presence of PIH, the risk of BPD was found to be either increased [4,24,25] similar [26,27], or reduced [28]. Our study showed an approximately 1.5-fold excess risk for RDS and BPD in the PIH group, further suggesting that PIH was not associated with accelerated fetal lung maturation. Tang et al. [29] have suggested that in infants born to mothers with pre-eclampsia, impaired vascular endothelial growth factor (VGEF) signalling in-utero, due to high amniotic fluid levels of soluble VGEF receptor-1, disrupts lung growth and contributes to the increased risk of BPD. NEC is a major morbidity in preterm infants, caused by the combination of mucosal injury, bacteria and metabolic substrates on an immature intestine. The redistribution of
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blood to vital organs in an intrauterine adaptive mechanism in growth retarded fetuses which persists postnatally [30], and may cause feeding intolerance and subsequent NEC. Two reports [31,32] suggested maternal hypertension to be a risk factor for NEC in VLBW infants. Others did not support this observation, stating that even in the presence of compromised fetal blood distribution these changes are insufficient to induce NEC [9,33]. Our analysis found preterm SGA infants in the PIH group to be at a lower risk for NEC. This reduced risk could be due to the suggested protective effect of the superior mesenteric artery flow on the splanchnic circulation previously described in growth-retarded fetuses [34], and probably to the changes in enteral feeding strategies in premature infants [35]. The possible impact of PIH on the risk of brain injury in preterm SGA infants is of interest. Conflicting reports suggest higher, lower or similar rates of both IVH and PVL [17,36– 39]. In the EPIPAGE study, Ancel et al. [40] reported that both SGA and maternal hypertension without SGA were not associated with higher rates of both IVH and PVL. The impact of the cause of preterm delivery and neonatal outcomes was assessed by Baud et al. [36] who showed that the presence of intrauterine growth restriction/pre-eclampsia was associated with a decreased risk of cystic PVL, compared with intrauterine infection. von Dadelszen et al. [7] suggested that PIH may serve some adaptive role for the fetus in the face of uteroplacental dysfunction. Activation of hypothalamic– pituitary–adrenal axis with increased levels of ACTH and adrenal corticosteroids may contribute to the maturation of organ systems including the brain [41]. However, despite the suggested protective mechanisms, our study did not find a reduced risk of IVH and PVL in the PIH group without acute pregnancy complications. We did however find a reduced risk of IVH in the group with both PIH and acute pregnancy complications. This finding may rather reflect the especially poor outcome in the group of infants from pregnancies with acute complications and no PIH, since this latter group was significantly less mature, had less antenatal corticosteroid treatment and lower rates of cesarean deliveries than all other groups studied. In considering the results of this study a number of limitations should be accounted for. First, the study population of SGA infants was determined using a birth weight percentile reference [1,3,18]. The use of a population-based birth weight references rather than fetal growth standards or customized standards for the diagnosis of abnormal fetal growth or small size for gestational age is controversial and may impact the results of this study [42–46]. Neonatal growth standards derived from whole populations tend to lower the cut-off points for the identification of SGA infants [45]. Conversely, the use of the 10th percentile from fetal growth standards would represent a liberal definition of SGA and hence a large number of false-positive cases [42], potentially labelling many healthy infants as being ‘‘at risk’’ [44]. The use of customized charts in order to account for variations in fetal growth associated with differences in maternal characteristics [43], or for maternal diseases that adversely affect fetal weight [45], may improve identification of newborn infants at increased risk for adverse perinatal outcomes [45]. The improved predictive ability of these charts may however
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be the consequence of an artifactual identification of preterm infants as SGA [42], and it has not been determined whether the use of customized criteria for fetal SGA would result in improved outcomes [43]. Ehrenkranz [46] concludes that at the present time it is preferable to continue to use reference intrauterine growth curves based on body weight in clinical practice. A further limitation of the study is that it is observational in design. The database does not include information related to the severity of PIH or other acute pregnancy complications, as well as variations in both obstetric and neonatal management which may influence the outcomes reported. The database does not provide information pertaining to the complex assessment of fetal well-being and management decisions required in the presence of fetal growth restriction. It was therefore not possible to determine the precise etiology of the preterm deliveries. Changes in practice over time, especially in respect to provider indicated deliveries, may influence the outcomes studied. Adjustment for year of birth did not affect the results of the study, however. The database however comprises 499% of all VLBW infants born in Israel, and the study population reflects a total national population of very preterm SGA infants without any selection bias. The database includes prospectively collected information on major pregnancy complications which enabled more accurate characterisation of the ‘‘control groups’’ of the non-PIH pregnancies. The size of our sample made it possible to examine outcome in singleton SGA premature infants born to mothers with PIH both in the presence and absence of acute pregnancy complications, and control for multiple confounding factors.
Conclusion The present study does not support a protective effect of maternal PIH on the combined outcomes of infant survival without major neurological morbidity and survival without BPD, in preterm SGA infants, both in the presence and absence of acute pregnancy complications. It is however possible that the management of these pregnancies including close prenatal care, antenatal steroid therapy, magnesium sulphate treatment together with meticulous maternal and fetal assessments and optimal timing of delivery, might ameliorated the potentially detrimental outcome in the PIHcomplicated pregnancies.
Declaration of interest The Israel National Very-Low-Birth-Weight Infant Database is partially funded by the Israel center for Disease Control and the Ministry of Health.
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Appendix A The Israel Neonatal Network participating centers in the Israel National VLBW infant database are: Assaf Harofeh Medical center, Rishon Le Zion; Barzilay Medical center, Ashkelon; Bikur Holim Hospital,
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Jerusalem; Bnai Zion Medical center, Haifa; Carmel Medical center, Haifa; English (Scottish) Hospital, Nazareth; French Hospital, Nazareth; Hadassah University Hospital Ein-Karem, Jerusalem; Hadassah University Hospital Har Hazofim, Jerusalem; Haemek Medical center, Afula; Hillel Yafe Medical center, Hadera; Italian Hospital, Nazareth; Kaplan Hospital, Rehovot; Laniado Hospital, Netanya; Maayanei Hayeshua Hospital, Bnei-Brak; Meir Medical center, Kefar Saba; Misgav Ladach Hospital, Jerusalem; Naharia Hospital, Naharia; Poria
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Hospital, Tiberias; Rambam Medical center, Haifa; Rivka Ziv Hospital, Zefat; Schneider Children’s Medical center of Israel and Rabin Medical center (Belinson Campus), Petach-Tikva; Shaare-Zedek Hospital, Jerusalem; Sheba Medical center, Tel-Hashomer; Soroka Medical center, Beer-Sheva; Sourasky Medical center, Tel-Aviv; Wolfson Medical center, Holon; Yoseftal Hospital, Eilat Coordinating center: Women and Children’s Health Research Unit, Gertner Institute, Tel Hashomer.
