Early Human Development 90 (2014) 821–827

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Population-based trends in mortality and neonatal morbidities among singleton, very preterm, very low birth weight infants over 16 years☆,☆☆ Sorina Grisaru-Granovsky a,⁎, Brian Reichman c,d, Liat Lerner-Geva c,d, Valentina Boyko c, Cathy Hammerman b, Arnon Samueloff a, Michael S. Schimmel b, The Israel Neonatal Network a

Department of Obstetrics and Gynecology, Shaare Zedek Medical Center, Jerusalem, affiliated with the Hebrew University Medical School of Jerusalem Department of Neonatology, Shaare Zedek Medical Center, Jerusalem, affiliated with the Hebrew University Medical School of Jerusalem c Women & Children's Health Research Unit, Gertner Institute, Tel Hashomer, Tel Aviv University, Tel Aviv, Israel d Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel b

a r t i c l e

i n f o

Article history: Received 28 May 2014 Received in revised form 11 August 2014 Accepted 19 August 2014 Available online xxxx Keywords: Very preterm and VLBW Neonatal mortality Neonatal morbidity Composite morbidity Trend

a b s t r a c t Background: Improved survival of singleton very preterm, very low birth weight (VPTVLBW) infants has been associated with increasing rates of severe neonatal morbidities. Aim: To assess changes in mortality and neonatal morbidities among singleton VPT-VLBW infants. Study design: Population-based observational study of data collected by the Israel Neonatal Network. Subjects: 10,705 singleton VPT-VLBW infants born at 24–32 gestational weeks in 1995–2010. Outcome measures: Mortality and major neonatal morbidities over 3 time periods: 1995–2000, 2001–2005, and 2006–2010. Major neurological morbidities comprised intraventricular hemorrhage grades 3–4, periventricular leukomalacia and retinopathy of prematurity grades 3–4. Results: The mortality rate decreased over time from 20.2% to 13.8% for all birth weight and gestational age groups. Compared to the 1995–2000 period, the adjusted odds ratios (aORs) (95% confidence intervals,) for mortality in 2001–2005 and 2006–2010 were 0.78 (0.67–0.90) and 0.72 (0.62–0.84), respectively. The combined outcomes of death or major neurological morbidities, aOR 0.74 (0.65–0.84) and death or major neurological morbidities and/or bronchopulmonary dysplasia aOR 0.85 (0.75–0.96) decreased significantly between the first and last periods. A significant improvement in mortality rates and survival without one or more major neonatal morbidity was observed for all birth weight and gestational age groups. Among 8,886 surviving infants the rates of major neurological morbidities decreased from 16.4% to 12.8%, aOR 0.80 (0.68–0.95). Conclusion: The improving survival of singleton VTP-VLBW infants was not associated with a concomitant increase in the risk for major neonatal neurological morbidities among surviving infants. Bronchopulmonary dysplasia, however, remained a significant burden. This analysis emphasizes the need to direct efforts towards the prevention and treatment of adverse respiratory sequelae. © 2014 Elsevier Ireland Ltd. All rights reserved.

1. Introduction Research efforts in perinatal and neonatal medicine over the last two decades have been directed at reducing the mortality and morbidity in very preterm, very low birth weight (VPT-VLBW) infants. They have ☆ The Israel National Very Low Birth Weight Infant database is partially supported by the Israel Center for Disease Control and the Ministry of Health. ☆☆ Disclaimer: No conflicts of interests are noted for any of the authors which may have impacted the reporting of the results of this study. ⁎ Corresponding author at: Department of Obstetrics and Gynecology, Division of Maternal and Fetal Medicine, One Bazak Road, Shaare Zedek Medical Center, Jerusalem, Israel 91031. Tel.: +972 2 6555111; fax: +972 2 6666053. E-mail address: [email protected] (S. Grisaru-Granovsky).

http://dx.doi.org/10.1016/j.earlhumdev.2014.08.009 0378-3782/© 2014 Elsevier Ireland Ltd. All rights reserved.

been focused on improving medical care for pregnant women, identifying and reducing risk factors and improving perinatal care. It is generally accepted that neonatal survival rates have substantially increased, even in extremely preterm infants [1]. A high proportion of survivors however, experience neonatal morbidities which may be associated with adverse long-term outcomes [2–7]. Population-based studies have recently reported varying trends for mortality and morbidity of VLBW infants [2–5,8–10]. Comparative studies have shown great variability in VLBW neonatal outcomes within the same geo-economical regions [6] and between different care systems of developed countries [11,12]. We hypothesized that the improving survival of VPT-VLBW infants was not associated with an increased risk of major neurological or

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respiratory morbidity in the survivors. This study aimed to assess the trends in mortality and morbidity in a national cohort of singleton VPT-VLBW infants born in Israel between 1995 and 2010.

2. Methods 2.1. Data collection This population-based observational study was based on the analysis of data collected by the Israel Neonatal Network on VLBW infants (≤1500 g) born in Israel between January 1995 and December 2010. Data were collected on all live births of infants with a birth weight of ≤ 1500 g. All 28 neonatal units in Israel, comprising the Israel national VLBW infant database, were included in data collection (see Appendix A). Data were recorded on a structured form which includes parental demographic information, maternal pregnancy history and antenatal care, details of delivery, infant status at delivery, diagnoses, procedures, complications during hospitalization, and status at discharge. The database procedures and definitions have previously been described [13]. All live born infants receive an identification number at birth. Patient information received by the database coordinator is cross-checked with the National Birth Registry, and data from any missing infant are requested from the birth hospital. Hospital and patient identification subsequently remain confidential by consensus agreement of all participating centers. Data are reported on all infants until death or discharge home. This study was approved by the Institutional Review Board (Helsinki Committee) of the Sheba Medical Center, Tel Hashomer, Israel (SMC 9612-12).

2.2. Definitions The gestational age in completed weeks was defined as the attending neonatologist's best estimate of the gestational age according to the reported last menstrual period, obstetric history and examination, prenatal ultrasound, and postnatal clinical examination performed during the first hours after birth. Birth weight (BW) percentiles were determined from the gender-specific charts of Kramer et al [14], and small for gestational age (SGA) was defined as a BW b 10th percentile. Delivery room resuscitation included endotracheal intubation, chest compression and/or administration of epinephrine. The evaluated outcomes were defined as follows: mortality was considered as death occurring prior to discharge home, late-onset sepsis was determined by positive microbial growth on ≥ 1 blood cultures obtained after72 hours of age, respiratory distress syndrome (RDS) was diagnosed by a chest radiograph consistent with RDS together with the need for supplementary oxygen therapy, intraventricular hemorrhage (IVH) was diagnosed by ultrasound examination and graded according to Papile et al [15], periventricular leukomalacia (PVL) was diagnosed by the presence of multiple periventricular cysts identified by ultrasound after 28 days of life, and retinopathy of prematurity (ROP) was determined according to the international classification [16]. Necrotizing enterocolitis (NEC) was diagnosed according to the clinical and radiological criteria of Bell et al [17], and only definite NEC (Bell stages II–III) was included. Bronchopulmonary dysplasia (BPD) was diagnosed according to the criteria of Bancalari et al including clinical and radiologic features [18] together with the requirement of oxygen therapy at 36 weeks postmenstrual age. For the purpose of this study we also defined combined outcomes of death or major neurological morbidity including IVH grades 3–4, PVL and/or ROP grades 3–4; death or BPD; death or ≥ 1 of the major morbidities, specifically, IVH grades 3–4, PVL, ROP grades 3–4 or BPD, as well as survival without ≥ 1 of these major morbidities.

2.3. Study population Between 1995 and 2010, the database included records of 24,250 infants, representing N99% of all live born VLBW infants in Israel. For the purpose of the present analysis, we excluded 10,338 infants from multiple births, 630 infants b 24 weeks' gestation, 1,654 infants N32 weeks' gestation and 923 infants with congenital malformations. Infants from multiple births were excluded from this analysis due to the different maternal, fetal and neonatal factors and different neonatal outcomes in multiple births [1,19,20]. A total of 13,545 infants were excluded, resulting in a study population of 10,705 singleton VPT-VLBW neonates of 24–32 weeks' gestation. Three consecutive time periods were studied: 1995–2000 (n = 3,846 infants), 2001–2005 (n = 3,475 infants) and 2006–2010 (n = 3,384 infants). A secondary analysis of major neurological and respiratory morbidities by time period was undertaken for 8,886 infant survivors: 1995–2000 (n = 3,069 infants), 2001–2005 (n = 2,902 infants) and 2006–2010 (n = 2,915 infants). 2.4. Statistical analysis Distribution of perinatal and neonatal characteristics and outcomes throughout the three time periods were tested by the chi-square test, the Mantel–Haenszel test for trends and ANOVA. All tests were two-sided. A p value of b 0.05 was considered significant. Multivariable logistic regression analyses were employed to study the influence of the three time periods on the odds for mortality and morbidity. Results of the logistic regression analyses are presented as adjusted odds ratios (aORs) with appropriate 95% confidence intervals (CIs), after adjusting for maternal age, ethnicity, initiation of prenatal care, infertility treatment, maternal hypertensive disorders, diabetes mellitus, premature labor, antepartum hemorrhage, preterm premature rupture of membranes (PPROM) N24 hours, clinical chorioamnionitis, antenatal steroids (including "partial" if delivery occurred within 24 hours after the first dose or "complete" if delivery occurred from 24 hours to 7 days after completion of the course), mode of delivery, gestational age at birth (completed weeks), gender, SGA and delivery room resuscitation. The statistical analyses were performed using SAS software version 9.2 (SAS Institute, Cary, NC). 3. Results 3.1. Perinatal and neonatal characteristics The study population comprised 10,705 singleton VPT-VLBW infants born at 24–32 weeks' gestation over three time periods, 1995–2000 (n = 3,846 infants), 2001–2005 (n = 3,475 infants) and 2006–2010 (n = 3, 384 infants). The demographic and perinatal characteristics are shown in Table 1. There were significant increases over time in maternal age (p = 0.0001) and maternal education N12 years (p b 0.0001), earlier initiation of antenatal care (≤ 12 weeks, p b 0.0001), infertility therapy (p = 0.0003), diabetes mellitus (p = 0.005) and significantly lower rates of PPROM (p b 0.0001) and clinical chorioamnionitis (p b 0.0001). A significant increase in antenatal steroid therapy (p b 0.0001) and cesarean deliveries (p b 0.0001) was observed. Over the three time periods there was a significant decrease in the percent of newborns with 5' Apgar scores b7 (p = 0.0006) and in the percent of infants receiving delivery room resuscitation (p b 0.0001). 3.2. Infant mortality and morbidities The multiple regression analyses assessed the odds for mortality and morbidities for the population of singleton VPT-VLBW infants in the latter two study periods compared to 1995–2000, adjusting for potential confounders (Table 2). Mortality decreased significantly in

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Table 1 Maternal demographic, perinatal and infant characteristics for three time periods. Characteristic

1995–2000n = 3846n (%)

2001–2005n = 3475n (%)

2006–2010n = 3384n (%)

p-Value

Maternal age, (mean ± SD years) Maternal education (years, n, %) 0–8 9–12 N12 Jewish population group (n, %) Week starting prenatal care (n, %) 0–12 N12 Infertility treatment (n, %) Chronic hypertension (n, %) PIH (n, %) Diabetes mellitus (n, %) Premature labor (n, %) Antepartum hemorrhage (n, %) PPROM (n, %) Clinical chorioamnionitis (n, %) Antenatal steroid therapy (complete/partial) (n, %) Cesarean section (n, %) Gestational age (mean ± SD, wks) Birth weight (mean ± SD, g) Birth weight b1000 g (n, %) Small for gestational age (n, %) Male gender (n, %) Delivery room resuscitation (n, %) 5' Apgar score b7 (n, %)

29.1 ± 6.2

29.5 ± 6.2

29.8 ± 6.4

0.0001 b0.0001

500 (13.7) 1991 (54.5) 1161 (31.8) 2681 (70.0)

314 (9.6) 1627 (49.5) 1343 (40.9) 2336 (67.3)

175 (5.5) 1618 (50.8) 1393 (43.7) 2268 (67.1)

2794 (72.6) 1052 (27.4) 360 (9.4) 137 (3.6) 809 (21.1) 143 (3.7) 2003 (52.2) 837 (21.8) 824 (21.7) 437 (11.4) 2268 (59.3) 2336 (60.8) 28.3 ± 2.3 1064 ± 269 1582 (41.1) 828 (21.5) 2040(53.1) 2093 (54.4) 909 (24.6)

2820 (81.2) 655 (18.8) 407 (11.8) 97 (2.8) 762 (22.0) 153 (4.4) 1576 (45.5) 756 (21.8) 563 (16.6) 299 (8.6) 2342 (67.7) 2293 (66.0) 28.3 ± 2.3 1055 ± 277 1471 (42.3) 782 (22.5) 1825 (52.2) 1601 (46.1) 726 (21.6)

2774 (82.0) 610 (18.0) 409 (12.1) 107 (3.2) 770 (22.8) 179 (5.3) 1417 (41.9) 751 (22.2) 461 (14.1) 259 (7.7) 2434 (72.0) 1085 (67.9) 28.4 ± 2.3 1073 ± 270 1321 (39.0) 683 (20.2) 1791 (52.9) 1434 (42.4) 688 (21.0)

2001–2005 and 2006–2010, with aOR's (95% CI) of 0.78 (0.67–0.90) and 0.72 (0.62–0.82), respectively. The odds for late onset sepsis decreased in the last period, aOR 0.79 (0.70–0.88). The odds for RDS were significantly increased in 2001–2005 and 2006–2010 with aOR's of 1.36 (1.21–1.53) and 1.76 (1.56–1.99), respectively. This increase was paralleled by increased odds for BPD in 2001–2005, aOR 1.45 (1.23–1.71). There was a marked and significant decrease in the odds for severe ROP in 2006–2010, aOR 0.57 (0.45–0.73). Although the rates of severe neurological morbidities (IVH grades 3–4 and PVL)

0.01 b0.0001

0.0003 0.17 0.23 0.005 b0.0001 0.89 b0.0001 b0.0001 b0.0001 b0.0001 0.16 0.02 0.02 0.06 0.89 b0.0001 0.0006

decreased significantly over the three time periods, these changes were not significant in the multivariable analyses. The significant decrease in mortality rates was observed in all birth weight (Fig. 1a) and gestational age groups (Fig. 1b). 3.3. Combined outcomes The combined outcome of death or major neurological morbidities (IVH grade 3–4, PVL or ROP grade 3–4) decreased significantly, from

Table 2 Rates and adjusted odds ratios⁎ (aOR) and 95% confidence intervals (CI) for mortality and neonatal morbidities among singleton very preterm very low birth weight infants by three time periods. Outcome

1995–2000

2001–2005

2006–2010

p Value for trend⁎⁎

Mortality, n/N (%) aOR (95% CI) RDS, n/N (%) aOR (95% CI) Late sepsis, n/N (%) aOR (95% CI) NEC, n/N (%) aOR (95% CI) BPD, n/N (%) aOR (95% CI) IVH grades 3–4, n/N (%) aOR (95% CI) PVL, n/N (%) aOR (95% CI) ROP grades 3–4, n/N (%) aOR (95% CI) Combined outcomes Death or IVH 3–4, PVL, ROP 3–4, n/N (%) aOR (95% CI) Death or BPD n/N (%) aOR (95% CI) Death or IVH 3–4, PVL, ROP 3–4, BPD, n/N (%) aOR (95% CI) Alive without IVH 3–4, PVL, ROP3-4 or BPD, n/N (%) aOR⁎(95% CI)

777/3846 (20.2) 1.0 2496/3796 (65.7) 1.0 1166/3488 (33.3) 1.0 242/3796 (6.4) 1.0 354/3030 (11.7) 1.0 454/3448(13.2) 1.0 223/2670(8.8) 1.0 229/2956 (7.7) 1.0

573/3745 (16.5) 0.78 (0.67–0.90) 2387/3447 (69.2) 1.36 (1.21–1.53) 1109/3233 (34.3) 1.02 (0.92–1.14) 263/3445 (7.6) 1.18 (0.98–1.43) 479/2917 (16.4) 1.45(1.23–1.71) 369/3237(11.4) 0.93(0.79–1.10) 171/2644(6.5) 0.87(0.70–1.08) 199/2774 (7.2) 0.88 (0.70–1.10)

468/3383(13.8) 0.72 (0.62–0.84) 2423/3350(72.3) 1.76 (1.56–1.99) 914/3194 (28.6) 0.79 (0.70–0.88) 237/3349(7.1) 1.10 (0.90–1.34) 382/2921(13.1) 1.15 (0.96–1.37) 350/3190(11.0) 1.00 (0.84–1.18) 162/2567(6.3) 0.85 (0.68–1.07) 136/2900 (4.7) 0.57 (0.45–0.73)

b0.0001

1280/3846 (33.3) 1.0 1091/3846 (28.4) 1.0 1465/3846 (38.1) 1.0 2381/3846 (61.9) 1.0

991/3745 (28.5) 0.82 (0.72–0.93) 1016/3745 (29.2) 1.12 (0.98–1.27) 1284/3745 (36.9) 1.03 (0.91–1.16) 2191/3745 (63.0) 0.97(0.86–1.10)

840/3383 (24.8) 0.74 (0.65–0.84) 822/3383 (24.3) 0.93 (0.82–1.07) 1067/3383 (31.5) 0.85 (0.75–0.96) 2316/3383 (68.5) 1.18 (1.04–1.34)

b0.0001 b0.0001 0.19 0.06 0.005 0.003 b0.0001

b0.0001 0.0003 b0.0001 b0.0001

⁎ Adjusted odds ratio adjusted for gestational age, gender, SGA, and delivery room resuscitation, maternal age, ethnicity, initiation of prenatal care, infertility treatment, hypertensive disorders, diabetes mellitus, premature labor, antepartum hemorrhage, PPROM N24 hours, clinical chorioamnionitis, antenatal steroids, cesarean section. ⁎⁎ p Value for trend refers to the univariate analysis.

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Percentage of VPT - VLBW Infants

a

1995-2000 70 60

2001-2005

2006-2010

p

Population-based trends in mortality and neonatal morbidities among singleton, very preterm, very low birth weight infants over 16 years.

Improved survival of singleton very preterm, very low birth weight (VPTVLBW) infants has been associated with increasing rates of severe neonatal morb...
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