- Email: [email protected]
Risk factors for neonatal mortality among extremely-low-birth-weight infants
American Journal of Obstetrics and Gynecology (2005) 192, 862e7
www.ajog.org
Risk factors for neonatal mortality among extremely-low-birth-weight infants Stephen J. Bacak, MPH,a Kesha Baptiste-Roberts, MPH,a Erol Amon, MD,b Belinda Ireland, MD,a Terry Leet, PhDa,b Department of Community Health, Saint Louis University School of Public Health,a and Department of Obstetrics, Gynecology, and Women’s Health, Saint Louis University School of Medicine, St Louis, Mob Received for publication February 19, 2004; revised June 25, 2004; accepted July 19, 2004
KEY WORDS Extremely low birth weight Neonatal mortality Risk factors
Objective: The purpose of this study was to examine characteristics associated with neonatal mortality among extremely low-birth-weight infants (%1000 g). Study design: A population-based, case-control study using linked Missouri birth and death certificates from 1989 to 1997 was conducted. Cases (n = 835) were defined as extremely lowbirth-weight infants that died within 28 days of birth. Controls (n = 907) were randomly selected from extremely low-birth-weight infants that were alive at 1 year and were frequency matched to subjects by birth year and birth weight. Results: Infants born with severe congenital anomalies and at the youngest gestational ages were at greatest risk for neonatal mortality. Other significant risk factors included maternal age (!18 and >34 years), vaginal delivery, nontertiary hospital care, malpresentation, male gender, and small for gestational age. Black race and preeclampsia were protective against early death. Conclusions: The risk of neonatal mortality among extremely low-birth-weight infants was associated with several maternal, infant, and obstetric factors, some of which may be preventable. Ó 2005 Elsevier Inc. All rights reserved.
In 2002 extremely low-birth-weight (ELBW, %1000 g) infants accounted for less than 1% of all births in the United States.1 Although numerically small, ELBW infants represent nearly 50% of all perinatal mortality.2,3 Data on risk factors for neonatal mortality are limited for ELBW infants. Recently Shankaran et al4 compared risk factors for mortality among ELBW infants who died within the first 12 hours after birth with those who died after 12 hours using a populationbased cohort study. However, most of the previous Presented at the 21st Annual Meeting of the Society for MaternalFetal Medicine, Reno, Nev, February 5-10, 2001. Reprints not available from the authors. 0002-9378/$ - see front matter Ó 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.ajog.2004.07.029
studies have been observational or have reported data from single perinatal centers.5-7 The objective of the present study was to examine maternal, infant, and obstetric characteristics associated with an increased risk for neonatal mortality among ELBW infants using a population-based, case-control study design.
Material and methods We conducted a population-based, case-control study of neonatal mortality for all single live-born ELBW babies delivered among Missouri residents from 1989 to 1997. Linked birth and death certificates were used to identify cases and controls and to ensure Missouri residency of
Bacak et al Table I
863
Maternal characteristics for neonatal mortality among extremely low-birth-weight infants, 1989-1997 Cases (n = 835)
Characteristics Maternal age (y) !18 18-34 O34 Maternal race Black Other Education !High school RHigh school Tobacco use
Controls (n = 907)
No.
%
No.
%
Adjusted OR (95%CI)*
150 601 82
18.0 72.1 9.8
119 701 87
13.1 77.3 9.6
1.4 (1.0-2.1) Reference 1.6 (1.0-2.5)
292 539
35.1 64.9
332 574
36.6 63.4
0.7 (0.5-0.9) Reference
241 557 218
30.2 69.8 27.0
232 631 250
26.9 73.1 28.1
1.0 (0.8-1.5) Reference 0.8 (0.6-1.1)
OR, Odds ratio. * Adjusted odds ratio (adjusted for all covariates in Tables I, II, and III by logistic regression analysis).
the mother. We defined cases as single live-born ELBW infants who died within 28 days of birth. Prior studies have suggested that 90% of ELBW mortality occurs within the first 28 days of life and that the majority of mortality occurs within the first 72 hours after birth.4,8 Only 8% of ELBW infants died between days 28 and 365 and were excluded from our study. Controls were randomly selected from single liveborn ELBW infants who lived for at least 1 year. Although multiple births represent an increasing proportion of ELBW infants, we excluded them from our study population because they do not represent independent events. Controls were frequency matched to the cases by birth year and birth weight categories (350 to 499, 500 to 599, 600 to 699, 700 to 799, 800 to 899, and 900 to 99 g). A total of 2728 ELBW births were identified during this period. Infants were also excluded from the study population if their clinical gestational age estimate was less than 23 weeks or greater than 32 weeks or they had missing data for key variables of interest (n = 986). Twenty-three weeks is often considered the lower end of fetal viability.9,10 Thirty-two weeks was selected as the upper limit because of the small number of ELBW infants born at or beyond this gestational age in our sample. The final study population included 1742 infants, comprising 835 cases and 907 controls. All potential risk factors for neonatal mortality occurring in more than 10 cases in our study population were grouped into 1 of 3 categories: maternal, medical/ obstetric, and newborn characteristics (yes/no response unless otherwise indicated). Maternal characteristics included age (!18, 18 to 34, O34 years), race (black, other), education (less than high school, high school or beyond), and tobacco use. Medical/obstetric characteristics included mode of delivery (vaginal, cesarean section), level of hospital care (levels I and II, III) at birth, diabetes, hypertension, preeclampsia (includes
eclampsia), incompetent cervix, previous preterm birth, renal disease, placental abruption, premature rupture of membranes, precipitous labor, and malpresentation (includes breech malpresentation). Infant characteristics included gender, clinical gestational age at birth (23 to 24, 25 to 26, and 27 to 32 weeks), respiratory distress syndrome, severe congenital anomalies (includes anencephalus, renal agenesis, spina bifida, meningocele, hydrocephalus, microcephalus, other central nervous system malformations, other circulatory and respiratory anomalies), and small for gestational age (SGA, defined as %10th percentile of fetal growth).11 We performed univariate analysis to calculate the crude odds ratio (OR), comparing cases and controls for each potential risk factor. All statistically significant (P ! .05) variables from the univariate analysis and potential clinically relevant and previously cited risk factors were entered into a multivariate logistic regression model. The adjusted OR and 95% confidence interval (CI) were calculated for each risk factor. Diagnostic tests for collinearity, outliers, and interaction were conducted. All statistical analyses were performed using SPSS software version 10.0 (SPSS, Inc, Chicago, Ill). This study was reviewed by the Saint Louis University Institutional Review Board and was classified as exempt under 45 CFR 46.101(b) from the US Department of Health and Human Services regulations for the protection of human subjects.
Results The maternal characteristics associated with neonatal mortality among ELBW infants are shown in Table I. Infants born to women younger than 18 years (adjusted OR 1.4, 95% CI 1.0 to 2.1) and to women older than 34 years (adjusted OR 1.6, 95% CI 1.0 to 2.5) were more
864 Table II
Bacak et al Medical and obstetric characteristics for neonatal mortality among extremely low-birth-weight infants, 1989-1997 Cases (n = 835)
Characteristics Mode of delivery Vaginal Cesarean section Hospital care Level I or II Level III Diabetes Hypertension Preeclampsia Incompetent cervix Previous preterm infant Renal disease Placental abruption Premature rupture of membranes Precipitous labor Malpresentation
Controls (n = 907)
No.
%
No.
%
Adjusted OR (95% CI)*
535 298
64.2 35.8
604 293
67.3 32.7
1.4 (1.0-1.9) Reference
232 570 17 17 64 59 55 11 118 248
28.9 71.1 2.0 2.0 7.7 7.1 6.6 1.3 14.2 29.8
313 557 12 36 129 48 67 7 97 184
36.0 64.0 1.3 4.0 14.3 5.3 7.4 0.8 10.7 20.4
1.5 (1.1-2.0) Reference 1.2 (0.4-3.3) 0.6 (0.3-1.5) 0.6 (0.4-1.0) 0.9 (0.5-1.4) 0.8 (0.5-1.2) 3.7 (0.9-15.9) 1.5 (1.0-2.2) 1.0 (0.8-1.4)
53 283
6.4 34.1
35 240
3.9 26.6
1.2 (0.7-2.2) 1.6 (1.2-2.1)
OR, Odds ratio. * Adjusted odds ratio (adjusted for all covariates in Tables I, II, and III by logistic regression analysis).
Table III
Newborn characteristics for neonatal mortality among extremely low-birth-weight infants, 1989-1997 Cases (n = 835)
Characteristics Sex of infant Male Female Gestational age (wk) 23-24 25-26 27-32 Respiratory distress syndrome Severe congenital anomalies Small for gestational age
Controls (n = 907)
No.
%
No.
%
Adjusted OR (95% CI)*
484 351
58.0 42.0
428 479
47.2 52.8
1.7 (1.4-2.3) Reference
496 217 122 180 55 149
59.4 26.0 14.6 21.7 6.6 17.8
332 307 268 132 54 326
36.6 33.8 29.5 25.7 6.0 35.9
4.3 (2.9-6.4) 1.3 (0.9-1.8) Reference 0.8 (0.6-1.1) 4.9 (2.2-10.7) 1.6 (1.1-2.2)
OR, Odds ratio. * Adjusted odds ratio (adjusted for all covariates in Tables I, II, and III by logistic regression analysis).
likely to die than infants born to mothers 18 to 34 years of age. Black infants were 30% more likely to survive than infants of another race (adjusted OR 0.7, 95% CI 0.5 to 0.9). Several medical and obstetric characteristics were significantly associated with neonatal mortality (Table II). Malpresentation of the infant (adjusted OR 1.6, 95% CI 1.2 to 2.1), birth in a level I or II hospital (adjusted OR 1.5, 95% CI 1.1 to 2.0), and infants whose mothers experienced placental abruption (adjusted OR 1.5, 95% CI 1.0 to 2.2) were most likely to die during the neonatal period. Vaginally delivered ELBW infants (adjusted OR 1.4, 95% CI 1.0 to 1.9) were also at a higher risk of neonatal mortality. Infants born to
mothers diagnosed with preeclampsia (adjusted OR 0.6, 95% CI 0.4 to 1.0) were protected against neonatal mortality. Infants born with any severe congenital anomalies conferred the highest risk for neonatal mortality (adjusted OR 4.9, 95% CI 2.2 to 10.7) among all risk factors (Table III). Infants born at 23 to 24 weeks’ gestation (adjusted OR 4.3, 95% CI 2.9 to 6.4) were 4 times more likely to die than those delivered at older gestational ages. Other infant characteristics significantly associated with neonatal mortality were male gender (adjusted OR 1.7, 95% CI 1.4 to 2.3) and infants born SGA (adjusted OR 1.6, 95% CI 1.1 to 2.2). Because severe congenital anomalies may be underreported on
Bacak et al the birth certificate, we reanalyzed our data excluding this variable from our logistic model and found no difference in any of the risk estimates shown in Tables I through III.
Comment We identified several maternal, infant, and obstetric risk factors associated with neonatal mortality among ELBW infants. Infants born with severe congenital anomalies were at highest risk for neonatal death. Although not specific for early death among ELBW infants, our finding is consistent with Druschel et al,12 who reported that infants born with congenital malformations have a 6-fold increase for mortality than the general population. As expected, infants born at a lower gestational age were at much higher risk for neonatal mortality. Gestational age is often considered the foremost predictor of neonatal survival, with most clinicians acknowledging 23 to 24 weeks’ gestation as the lowest end of viability. Infant survival at 23 weeks is estimated between 10% and 30% and increases to 25% to 50% survival for infants at 24 weeks.10,13 In our study, 36% of infants born 23 to 24 weeks lived at least 1 year after birth. Gestational age and congenital anomalies are also closely associated with a physician’s willingness to provide aggressive intervention. Often physicians decide a priori threshold values for estimated fetal weight, birth weight, gestational age, and nature of specific congenital anomalies for which they are unwilling to aggressively intervene. These decisions balance heightened concerns for maternal morbidity and mortality and parental autonomy, in contrast to potential improvement in newborn outcomes. We did not identify another study that examined maternal age !18 years as an independent risk factor for neonatal mortality. Shankaran et al4 reported mothers of infants who died within the first 12 hours of life were younger than mothers whose infants survived but presented only a mean age of only 25.7 years. Younger mothers may not be completely biologically developed and thus more likely to experience preterm labor and delivery.14 However, this does not explain why ELBW infants born to younger mothers would be more likely to die within the first month of life. Additionally, there is no clear explanation for the increased risk of neonatal mortality born to women older than 34 years. This relationship should be further examined because the percentage of women older than 35 years giving birth continues to increase.15 Our finding that male ELBW infants have a higher risk of neonatal mortality than females was also similar to the findings of Shankaran et al (OR 1.7, 95% CI 1.2 to 2.3) and consistent with several other studies.4,16,17 This phenomenon, known as the male disadvantage, has been
865 recognized for decades; however, the biological mechanisms are not well understood. Recently Stevenson et al18 found that relative differences persist between males and females, with males having a higher mortality rate, lower Apgar scores, and a higher risk for most adverse neonatal outcomes. Tyson et al17 found that SGA was protective in infants weighing 501 to 800 g and being treated with mechanical ventilation. However, we did not have information on mechanical ventilation in our study. Another study found infants with intrauterine growth restriction almost 3 times as likely to die within the first month of life after adjustment for antenatal corticosteroid use, gestational age, and several other covariates.19 Although SGA is a function of both gestational age and birth weight, we included it in our regression model because it is a unique variable. When adjusted for potential confounders, including gestational age, SGA infants were 50% more likely to die early. This suggests that even the youngest infants have a better chance of survival if their weights are appropriate for gestational age. Prior population-based studies have found a significant association between vaginal delivery and neonatal mortality.20-22 Redman and Gonik20 reported significantly lower mortality rates in 22- and 23-week infants delivered by cesarean section, compared with vaginal delivery. The risk of neonatal mortality may not actually be due to mode of delivery but rather related to physicians’ unwillingness to intervene aggressively on behalf of the fetus, such as classic cesarean section, antenatal steroids, neonatal resuscitation, and other therapeutic modalities, especially if they perceive the infant to be too young or too small to survive.3,20 The mother’s willingness to undergo a cesarean section or permit other neonatal procedures should also be considered in all decision making regarding obstetric and neonatal ethical issues at the cusp of viability. We combined breech presentation with other malpresentations into one category because of small numbers. One possible explanation for the increased mortality rate in this group is their increased susceptibility to trauma and morbidity from events that we could not adjust for (eg, head entrapment), compared with vertex-presenting fetuses.21 Yeast et al23 reported that ELBW infants born in level I and II centers were 3 to 5 times more likely to die than infants born in level III facilities. However, the authors adjusted only for birth weight, race, and number of infants born, which may explain the higher risk estimates, compared with our results. Level III hospitals have a greater frequency of high-risk births and are equipped with more services, such as maternalfetal medicine specialists, neonatologists, and intensive care units that promote the chance of survival of these infants. Finally, neonatal mortality was higher among infants whose mothers had a placental abruption during
866 delivery. Perinatal mortality in births with placental abruption is approximately 12% in the United States.24 Our finding that black infants were more likely to survive than infants of another race agrees with Shankaran et al.4 It has been previously suggested that African Americans have a higher survival rate among low-birth-weight populations; however, recent evidence indicates that this advantage is declining, even at the lower end of perinatal viability.25 The biological mechanisms for race disparities are not completely understood. Factors such as access to health care and responsiveness to medical treatments may be affecting the racial gap in neonatal mortality. The protective association of preeclampsia has been found in several other population-based and single-center studies.4,5,7 One possible explanation for this finding may be the increased use of seizure prophylaxis, including magnesium sulfate, which has been shown in some studies to decrease the risk of adverse birth outcomes.5 The major limitation to our study was the inability to determine why the infant was delivered prematurely. Furthermore, we do not know what level of intervention was offered to keep the infant alive. We are, however, fairly certain that our population does not include late elective terminations. Legal abortions are available up to 20 weeks in Missouri and generally do not occur unless they are associated with lethal congenital anomalies. The reliability of birth and death certificate data varies considerably for specific covariates. Maternal demographics, pregnancy outcomes, and some congenital anomalies tend to have a higher sensitivity (reporting of a condition on both the birth certificate and hospital record) than other risk factors and comorbidities.26 Access to information not included on the birth certificate (eg, medical records) may have provided us with important clinical information, such as surfactant use, intubation, and resuscitation. Neonatal transfer after birth may also have had an impact on survival; however, we did not include this variable in our model because 60% of our population was missing information. A final limitation was that our study was restricted to Missouri births. However, comparisons can be made to a population with similar demographics as our study population. Despite the limitations, our study had several strengths. We were able to control more carefully for the confounding effects of birth weight on neonatal mortality by frequency matching on 100-g intervals of birth weight. The mean birth weight of the cases and controls were 664 g (SD = 146 g) and 655 g (SD = 152 g), respectively. Although cases were slightly younger than controls, mean gestational age of 24.7 weeks (SD = 1.9), compared with a mean of 25.6 (SD = 2.1) for controls, this was not significant. Frequency matching on birth year also accounted for the possibility that cases and controls may have received different medical
Bacak et al interventions. Finally, our study was one of the few population-based studies that have identified risk factors for neonatal mortality, specifically among ELBW infants. Neonatal mortality continues to be a significant public health burden in the United States. Over the last 2 decades, improvements in perinatal and neonatal care have led to great success in the survival of the smallest infants. Despite these advances, it is important that we continue to identify characteristics associated with early death as well as develop a better understanding of the etiology of preterm births. Our findings add to the current knowledge of risk factors associated with neonatal mortality among ELBW infants. Clinicians must be aware of the wide range of risk factors, some of which may be preventable (eg, mode of delivery, level of hospital care at birth), in counseling mothers and choosing appropriate medical interventions to ensure the survival of these infants.
Acknowledgments We thank Garland Land, Joseph Stockbauer, and Janice Bakewell from the Missouri Department of Health and Senior Services for their helpful comments and for providing the data for this study.
References 1. Martin JA, Hamilton BE, Sutton PD, Ventura SJ, Menacker F, Munson ML. Births: final data for 2002. Natl Vital Stat Rep 2003;52:1-116. 2. Amon E. Limits of fetal viability. Obstetric considerations regarding the management and delivery of the extremely premature baby. Obstet Gynecol Clin North Am 1988;15:321-38. 3. Bottoms SF, Paul RH, Iams JD, Mercer BM, Thom EA, Roberts JM, et al. Obstetric determinants of neonatal survival: influence of willingness to perform cesarean delivery on survival of extremely low-birth-weight infants: National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units. Am J Obstet Gynecol 1997;176:960-6. 4. Shankaran S, Fanaroff AA, Wright LL, Stevenson DK, Donovan EF, Ehrenkranz RA, et al. Risk factors for early death among extremely low-birth-weight infants. Am J Obstet Gynecol 2002;186:796-802. 5. Bottoms SF, Paul RH, Mercer BM, MacPherson CA, Caritis SN, Moawad AH, et al. Obstetric determinants of neonatal survival: antenatal predictors of neonatal survival and morbidity in extremely low birth weight infants. Am J Obstet Gynecol 1999;180:665-9. 6. Holtrop PC, Ertzbischoff LM, Roberts CL, Batton DG, Lorenz RP. Survival and short-term outcome in newborns of 23 to 25 weeks’ gestation. Am J Obstet Gynecol 1994;170:1266-70. 7. Amon E, Sibai BM, Anderson GD, Mabie WC. Obstetric variables predicting survival of the immature newborn (less than or equal to 1000 gm): a five-year experience at a single perinatal center. Am J Obstet Gynecol 1987;156:1380-9. 8. Philip AG. Neonatal mortality rate is further improvement possible? J Pediatr 1995;126:427-33.
Bacak et al 9. McElrath TF, Norwitz ER, Nour N, Robinson JN. Contemporary trends in the management of delivery at 23 weeks’ gestation. Am J Perinatol 2002;19:9-15. 10. American College of Obstetrics and Gynecology. Perinatal care at the threshold of viability (practice bulletin). Int J Gynaecol Obstet 2002;79:181-8. 11. Alexander GR, Himes JH, Kaufman RB, Mor J, Kogan M. A United States national reference for fetal growth. Obstet Gynecol 1996;87:163-8. 12. Druschel C, Hughes JP, Olsen C. Mortality among infants with congenital malformations, New York State, 1983 to 1988. Public Health Rep 1996;111:359-65. 13. MacDonald H. Perinatal care at the threshold of viability. Pediatrics 2002;110:1024-7. 14. Stevens-Simon C, Beach RK, McGregor JA. Does incomplete growth and development predispose teenagers to preterm delivery? A template for research. J Perinatol 2002;22:315-23. 15. Center of Disease Control and Prevention. Preterm singleton birthsdUnited States, 1989-1996. MMWR Morb Mortal Wkly Rep 1999;48:185-9. 16. Lemons JA, Bauer CR, Oh W, Korones SB, Papile LA, Stoll BJ, et al. Very low birth weight outcomes of the National Institute of Child Health and Human Development Neonatal Research Network, January 1995 through December 1996. NICHD Neonatal Research Network. Pediatrics 2001;107:E1. 17. Tyson JE, Younes N, Verter J, Wright LL. Viability, morbidity, and resource use among newborns of 501- to 800-g birth weight. NICHD Neonatal Research Network. JAMA 1996; 276:1645-51.
867 18. Stevenson DK, Verter J, Fanaroff AA, Oh W, Ehrenkranz RA, Shankaran S, et al. Sex differences in outcomes of very low birthweight infants: the newborn male disadvantage. Arch Dis Child Fetal Neonatal Ed 2000;83:F182-5. 19. Bernstein IM, Horbar JD, Badger GJ, Ohlsson A, Golan A. Morbidity and mortality among very-low-birth-weight neonates with intrauterine growth restriction: the Vermont Oxford Network. Am J Obstet Gynecol 2000;182:198-206. 20. Redman ME, Gonik B. Cesarean delivery rates at the threshold of viability. Am J Obstet Gynecol 2002;187:873-6. 21. Lee KS, Khoshnood B, Sriram S, Hsieh HL, Singh J, Mittendorf R. Relationship of cesarean delivery to lower birth weight-specific neonatal mortality in singleton breech infants in the United States. Obstet Gynecol 1998;92:769-74. 22. Jonas HA, Khalid N, Schwartz SM. The relationship between Caesarean section and neonatal mortality in very-low-birth weight infants born in Washington State, USA. Paediatr Perinat Epidemiol 1999;13:170-89. 23. Yeast JD, Poskin M, Stockbauer JW, Shaffer S. Changing patterns in regionalization of perinatal care and the impact on neonatal mortality. Am J Obstet Gynecol 1998;178:131-5. 24. Ananth CV, Wilcox AJ. Placental abruption and perinatal mortality in the United States. Am J Epidemiol 2001;153:332-7. 25. Allen MC, Alexander GR, Tompkins ME, Hulsey TC. Racial differences in temporal changes in newborn viability and survival by gestational age. Paediatr Perinat Epidemiol 2000;14:152-8. 26. Schramm W. Data quality: new certificates. Association for Vital Records and Health Statistics/Vital Statistics Cooperative Program Project Directors Meeting, May 1991, San Francisco, Calif.
www.ajog.org
Risk factors for neonatal mortality among extremely-low-birth-weight infants Stephen J. Bacak, MPH,a Kesha Baptiste-Roberts, MPH,a Erol Amon, MD,b Belinda Ireland, MD,a Terry Leet, PhDa,b Department of Community Health, Saint Louis University School of Public Health,a and Department of Obstetrics, Gynecology, and Women’s Health, Saint Louis University School of Medicine, St Louis, Mob Received for publication February 19, 2004; revised June 25, 2004; accepted July 19, 2004
KEY WORDS Extremely low birth weight Neonatal mortality Risk factors
Objective: The purpose of this study was to examine characteristics associated with neonatal mortality among extremely low-birth-weight infants (%1000 g). Study design: A population-based, case-control study using linked Missouri birth and death certificates from 1989 to 1997 was conducted. Cases (n = 835) were defined as extremely lowbirth-weight infants that died within 28 days of birth. Controls (n = 907) were randomly selected from extremely low-birth-weight infants that were alive at 1 year and were frequency matched to subjects by birth year and birth weight. Results: Infants born with severe congenital anomalies and at the youngest gestational ages were at greatest risk for neonatal mortality. Other significant risk factors included maternal age (!18 and >34 years), vaginal delivery, nontertiary hospital care, malpresentation, male gender, and small for gestational age. Black race and preeclampsia were protective against early death. Conclusions: The risk of neonatal mortality among extremely low-birth-weight infants was associated with several maternal, infant, and obstetric factors, some of which may be preventable. Ó 2005 Elsevier Inc. All rights reserved.
In 2002 extremely low-birth-weight (ELBW, %1000 g) infants accounted for less than 1% of all births in the United States.1 Although numerically small, ELBW infants represent nearly 50% of all perinatal mortality.2,3 Data on risk factors for neonatal mortality are limited for ELBW infants. Recently Shankaran et al4 compared risk factors for mortality among ELBW infants who died within the first 12 hours after birth with those who died after 12 hours using a populationbased cohort study. However, most of the previous Presented at the 21st Annual Meeting of the Society for MaternalFetal Medicine, Reno, Nev, February 5-10, 2001. Reprints not available from the authors. 0002-9378/$ - see front matter Ó 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.ajog.2004.07.029
studies have been observational or have reported data from single perinatal centers.5-7 The objective of the present study was to examine maternal, infant, and obstetric characteristics associated with an increased risk for neonatal mortality among ELBW infants using a population-based, case-control study design.
Material and methods We conducted a population-based, case-control study of neonatal mortality for all single live-born ELBW babies delivered among Missouri residents from 1989 to 1997. Linked birth and death certificates were used to identify cases and controls and to ensure Missouri residency of
Bacak et al Table I
863
Maternal characteristics for neonatal mortality among extremely low-birth-weight infants, 1989-1997 Cases (n = 835)
Characteristics Maternal age (y) !18 18-34 O34 Maternal race Black Other Education !High school RHigh school Tobacco use
Controls (n = 907)
No.
%
No.
%
Adjusted OR (95%CI)*
150 601 82
18.0 72.1 9.8
119 701 87
13.1 77.3 9.6
1.4 (1.0-2.1) Reference 1.6 (1.0-2.5)
292 539
35.1 64.9
332 574
36.6 63.4
0.7 (0.5-0.9) Reference
241 557 218
30.2 69.8 27.0
232 631 250
26.9 73.1 28.1
1.0 (0.8-1.5) Reference 0.8 (0.6-1.1)
OR, Odds ratio. * Adjusted odds ratio (adjusted for all covariates in Tables I, II, and III by logistic regression analysis).
the mother. We defined cases as single live-born ELBW infants who died within 28 days of birth. Prior studies have suggested that 90% of ELBW mortality occurs within the first 28 days of life and that the majority of mortality occurs within the first 72 hours after birth.4,8 Only 8% of ELBW infants died between days 28 and 365 and were excluded from our study. Controls were randomly selected from single liveborn ELBW infants who lived for at least 1 year. Although multiple births represent an increasing proportion of ELBW infants, we excluded them from our study population because they do not represent independent events. Controls were frequency matched to the cases by birth year and birth weight categories (350 to 499, 500 to 599, 600 to 699, 700 to 799, 800 to 899, and 900 to 99 g). A total of 2728 ELBW births were identified during this period. Infants were also excluded from the study population if their clinical gestational age estimate was less than 23 weeks or greater than 32 weeks or they had missing data for key variables of interest (n = 986). Twenty-three weeks is often considered the lower end of fetal viability.9,10 Thirty-two weeks was selected as the upper limit because of the small number of ELBW infants born at or beyond this gestational age in our sample. The final study population included 1742 infants, comprising 835 cases and 907 controls. All potential risk factors for neonatal mortality occurring in more than 10 cases in our study population were grouped into 1 of 3 categories: maternal, medical/ obstetric, and newborn characteristics (yes/no response unless otherwise indicated). Maternal characteristics included age (!18, 18 to 34, O34 years), race (black, other), education (less than high school, high school or beyond), and tobacco use. Medical/obstetric characteristics included mode of delivery (vaginal, cesarean section), level of hospital care (levels I and II, III) at birth, diabetes, hypertension, preeclampsia (includes
eclampsia), incompetent cervix, previous preterm birth, renal disease, placental abruption, premature rupture of membranes, precipitous labor, and malpresentation (includes breech malpresentation). Infant characteristics included gender, clinical gestational age at birth (23 to 24, 25 to 26, and 27 to 32 weeks), respiratory distress syndrome, severe congenital anomalies (includes anencephalus, renal agenesis, spina bifida, meningocele, hydrocephalus, microcephalus, other central nervous system malformations, other circulatory and respiratory anomalies), and small for gestational age (SGA, defined as %10th percentile of fetal growth).11 We performed univariate analysis to calculate the crude odds ratio (OR), comparing cases and controls for each potential risk factor. All statistically significant (P ! .05) variables from the univariate analysis and potential clinically relevant and previously cited risk factors were entered into a multivariate logistic regression model. The adjusted OR and 95% confidence interval (CI) were calculated for each risk factor. Diagnostic tests for collinearity, outliers, and interaction were conducted. All statistical analyses were performed using SPSS software version 10.0 (SPSS, Inc, Chicago, Ill). This study was reviewed by the Saint Louis University Institutional Review Board and was classified as exempt under 45 CFR 46.101(b) from the US Department of Health and Human Services regulations for the protection of human subjects.
Results The maternal characteristics associated with neonatal mortality among ELBW infants are shown in Table I. Infants born to women younger than 18 years (adjusted OR 1.4, 95% CI 1.0 to 2.1) and to women older than 34 years (adjusted OR 1.6, 95% CI 1.0 to 2.5) were more
864 Table II
Bacak et al Medical and obstetric characteristics for neonatal mortality among extremely low-birth-weight infants, 1989-1997 Cases (n = 835)
Characteristics Mode of delivery Vaginal Cesarean section Hospital care Level I or II Level III Diabetes Hypertension Preeclampsia Incompetent cervix Previous preterm infant Renal disease Placental abruption Premature rupture of membranes Precipitous labor Malpresentation
Controls (n = 907)
No.
%
No.
%
Adjusted OR (95% CI)*
535 298
64.2 35.8
604 293
67.3 32.7
1.4 (1.0-1.9) Reference
232 570 17 17 64 59 55 11 118 248
28.9 71.1 2.0 2.0 7.7 7.1 6.6 1.3 14.2 29.8
313 557 12 36 129 48 67 7 97 184
36.0 64.0 1.3 4.0 14.3 5.3 7.4 0.8 10.7 20.4
1.5 (1.1-2.0) Reference 1.2 (0.4-3.3) 0.6 (0.3-1.5) 0.6 (0.4-1.0) 0.9 (0.5-1.4) 0.8 (0.5-1.2) 3.7 (0.9-15.9) 1.5 (1.0-2.2) 1.0 (0.8-1.4)
53 283
6.4 34.1
35 240
3.9 26.6
1.2 (0.7-2.2) 1.6 (1.2-2.1)
OR, Odds ratio. * Adjusted odds ratio (adjusted for all covariates in Tables I, II, and III by logistic regression analysis).
Table III
Newborn characteristics for neonatal mortality among extremely low-birth-weight infants, 1989-1997 Cases (n = 835)
Characteristics Sex of infant Male Female Gestational age (wk) 23-24 25-26 27-32 Respiratory distress syndrome Severe congenital anomalies Small for gestational age
Controls (n = 907)
No.
%
No.
%
Adjusted OR (95% CI)*
484 351
58.0 42.0
428 479
47.2 52.8
1.7 (1.4-2.3) Reference
496 217 122 180 55 149
59.4 26.0 14.6 21.7 6.6 17.8
332 307 268 132 54 326
36.6 33.8 29.5 25.7 6.0 35.9
4.3 (2.9-6.4) 1.3 (0.9-1.8) Reference 0.8 (0.6-1.1) 4.9 (2.2-10.7) 1.6 (1.1-2.2)
OR, Odds ratio. * Adjusted odds ratio (adjusted for all covariates in Tables I, II, and III by logistic regression analysis).
likely to die than infants born to mothers 18 to 34 years of age. Black infants were 30% more likely to survive than infants of another race (adjusted OR 0.7, 95% CI 0.5 to 0.9). Several medical and obstetric characteristics were significantly associated with neonatal mortality (Table II). Malpresentation of the infant (adjusted OR 1.6, 95% CI 1.2 to 2.1), birth in a level I or II hospital (adjusted OR 1.5, 95% CI 1.1 to 2.0), and infants whose mothers experienced placental abruption (adjusted OR 1.5, 95% CI 1.0 to 2.2) were most likely to die during the neonatal period. Vaginally delivered ELBW infants (adjusted OR 1.4, 95% CI 1.0 to 1.9) were also at a higher risk of neonatal mortality. Infants born to
mothers diagnosed with preeclampsia (adjusted OR 0.6, 95% CI 0.4 to 1.0) were protected against neonatal mortality. Infants born with any severe congenital anomalies conferred the highest risk for neonatal mortality (adjusted OR 4.9, 95% CI 2.2 to 10.7) among all risk factors (Table III). Infants born at 23 to 24 weeks’ gestation (adjusted OR 4.3, 95% CI 2.9 to 6.4) were 4 times more likely to die than those delivered at older gestational ages. Other infant characteristics significantly associated with neonatal mortality were male gender (adjusted OR 1.7, 95% CI 1.4 to 2.3) and infants born SGA (adjusted OR 1.6, 95% CI 1.1 to 2.2). Because severe congenital anomalies may be underreported on
Bacak et al the birth certificate, we reanalyzed our data excluding this variable from our logistic model and found no difference in any of the risk estimates shown in Tables I through III.
Comment We identified several maternal, infant, and obstetric risk factors associated with neonatal mortality among ELBW infants. Infants born with severe congenital anomalies were at highest risk for neonatal death. Although not specific for early death among ELBW infants, our finding is consistent with Druschel et al,12 who reported that infants born with congenital malformations have a 6-fold increase for mortality than the general population. As expected, infants born at a lower gestational age were at much higher risk for neonatal mortality. Gestational age is often considered the foremost predictor of neonatal survival, with most clinicians acknowledging 23 to 24 weeks’ gestation as the lowest end of viability. Infant survival at 23 weeks is estimated between 10% and 30% and increases to 25% to 50% survival for infants at 24 weeks.10,13 In our study, 36% of infants born 23 to 24 weeks lived at least 1 year after birth. Gestational age and congenital anomalies are also closely associated with a physician’s willingness to provide aggressive intervention. Often physicians decide a priori threshold values for estimated fetal weight, birth weight, gestational age, and nature of specific congenital anomalies for which they are unwilling to aggressively intervene. These decisions balance heightened concerns for maternal morbidity and mortality and parental autonomy, in contrast to potential improvement in newborn outcomes. We did not identify another study that examined maternal age !18 years as an independent risk factor for neonatal mortality. Shankaran et al4 reported mothers of infants who died within the first 12 hours of life were younger than mothers whose infants survived but presented only a mean age of only 25.7 years. Younger mothers may not be completely biologically developed and thus more likely to experience preterm labor and delivery.14 However, this does not explain why ELBW infants born to younger mothers would be more likely to die within the first month of life. Additionally, there is no clear explanation for the increased risk of neonatal mortality born to women older than 34 years. This relationship should be further examined because the percentage of women older than 35 years giving birth continues to increase.15 Our finding that male ELBW infants have a higher risk of neonatal mortality than females was also similar to the findings of Shankaran et al (OR 1.7, 95% CI 1.2 to 2.3) and consistent with several other studies.4,16,17 This phenomenon, known as the male disadvantage, has been
865 recognized for decades; however, the biological mechanisms are not well understood. Recently Stevenson et al18 found that relative differences persist between males and females, with males having a higher mortality rate, lower Apgar scores, and a higher risk for most adverse neonatal outcomes. Tyson et al17 found that SGA was protective in infants weighing 501 to 800 g and being treated with mechanical ventilation. However, we did not have information on mechanical ventilation in our study. Another study found infants with intrauterine growth restriction almost 3 times as likely to die within the first month of life after adjustment for antenatal corticosteroid use, gestational age, and several other covariates.19 Although SGA is a function of both gestational age and birth weight, we included it in our regression model because it is a unique variable. When adjusted for potential confounders, including gestational age, SGA infants were 50% more likely to die early. This suggests that even the youngest infants have a better chance of survival if their weights are appropriate for gestational age. Prior population-based studies have found a significant association between vaginal delivery and neonatal mortality.20-22 Redman and Gonik20 reported significantly lower mortality rates in 22- and 23-week infants delivered by cesarean section, compared with vaginal delivery. The risk of neonatal mortality may not actually be due to mode of delivery but rather related to physicians’ unwillingness to intervene aggressively on behalf of the fetus, such as classic cesarean section, antenatal steroids, neonatal resuscitation, and other therapeutic modalities, especially if they perceive the infant to be too young or too small to survive.3,20 The mother’s willingness to undergo a cesarean section or permit other neonatal procedures should also be considered in all decision making regarding obstetric and neonatal ethical issues at the cusp of viability. We combined breech presentation with other malpresentations into one category because of small numbers. One possible explanation for the increased mortality rate in this group is their increased susceptibility to trauma and morbidity from events that we could not adjust for (eg, head entrapment), compared with vertex-presenting fetuses.21 Yeast et al23 reported that ELBW infants born in level I and II centers were 3 to 5 times more likely to die than infants born in level III facilities. However, the authors adjusted only for birth weight, race, and number of infants born, which may explain the higher risk estimates, compared with our results. Level III hospitals have a greater frequency of high-risk births and are equipped with more services, such as maternalfetal medicine specialists, neonatologists, and intensive care units that promote the chance of survival of these infants. Finally, neonatal mortality was higher among infants whose mothers had a placental abruption during
866 delivery. Perinatal mortality in births with placental abruption is approximately 12% in the United States.24 Our finding that black infants were more likely to survive than infants of another race agrees with Shankaran et al.4 It has been previously suggested that African Americans have a higher survival rate among low-birth-weight populations; however, recent evidence indicates that this advantage is declining, even at the lower end of perinatal viability.25 The biological mechanisms for race disparities are not completely understood. Factors such as access to health care and responsiveness to medical treatments may be affecting the racial gap in neonatal mortality. The protective association of preeclampsia has been found in several other population-based and single-center studies.4,5,7 One possible explanation for this finding may be the increased use of seizure prophylaxis, including magnesium sulfate, which has been shown in some studies to decrease the risk of adverse birth outcomes.5 The major limitation to our study was the inability to determine why the infant was delivered prematurely. Furthermore, we do not know what level of intervention was offered to keep the infant alive. We are, however, fairly certain that our population does not include late elective terminations. Legal abortions are available up to 20 weeks in Missouri and generally do not occur unless they are associated with lethal congenital anomalies. The reliability of birth and death certificate data varies considerably for specific covariates. Maternal demographics, pregnancy outcomes, and some congenital anomalies tend to have a higher sensitivity (reporting of a condition on both the birth certificate and hospital record) than other risk factors and comorbidities.26 Access to information not included on the birth certificate (eg, medical records) may have provided us with important clinical information, such as surfactant use, intubation, and resuscitation. Neonatal transfer after birth may also have had an impact on survival; however, we did not include this variable in our model because 60% of our population was missing information. A final limitation was that our study was restricted to Missouri births. However, comparisons can be made to a population with similar demographics as our study population. Despite the limitations, our study had several strengths. We were able to control more carefully for the confounding effects of birth weight on neonatal mortality by frequency matching on 100-g intervals of birth weight. The mean birth weight of the cases and controls were 664 g (SD = 146 g) and 655 g (SD = 152 g), respectively. Although cases were slightly younger than controls, mean gestational age of 24.7 weeks (SD = 1.9), compared with a mean of 25.6 (SD = 2.1) for controls, this was not significant. Frequency matching on birth year also accounted for the possibility that cases and controls may have received different medical
Bacak et al interventions. Finally, our study was one of the few population-based studies that have identified risk factors for neonatal mortality, specifically among ELBW infants. Neonatal mortality continues to be a significant public health burden in the United States. Over the last 2 decades, improvements in perinatal and neonatal care have led to great success in the survival of the smallest infants. Despite these advances, it is important that we continue to identify characteristics associated with early death as well as develop a better understanding of the etiology of preterm births. Our findings add to the current knowledge of risk factors associated with neonatal mortality among ELBW infants. Clinicians must be aware of the wide range of risk factors, some of which may be preventable (eg, mode of delivery, level of hospital care at birth), in counseling mothers and choosing appropriate medical interventions to ensure the survival of these infants.
Acknowledgments We thank Garland Land, Joseph Stockbauer, and Janice Bakewell from the Missouri Department of Health and Senior Services for their helpful comments and for providing the data for this study.
References 1. Martin JA, Hamilton BE, Sutton PD, Ventura SJ, Menacker F, Munson ML. Births: final data for 2002. Natl Vital Stat Rep 2003;52:1-116. 2. Amon E. Limits of fetal viability. Obstetric considerations regarding the management and delivery of the extremely premature baby. Obstet Gynecol Clin North Am 1988;15:321-38. 3. Bottoms SF, Paul RH, Iams JD, Mercer BM, Thom EA, Roberts JM, et al. Obstetric determinants of neonatal survival: influence of willingness to perform cesarean delivery on survival of extremely low-birth-weight infants: National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units. Am J Obstet Gynecol 1997;176:960-6. 4. Shankaran S, Fanaroff AA, Wright LL, Stevenson DK, Donovan EF, Ehrenkranz RA, et al. Risk factors for early death among extremely low-birth-weight infants. Am J Obstet Gynecol 2002;186:796-802. 5. Bottoms SF, Paul RH, Mercer BM, MacPherson CA, Caritis SN, Moawad AH, et al. Obstetric determinants of neonatal survival: antenatal predictors of neonatal survival and morbidity in extremely low birth weight infants. Am J Obstet Gynecol 1999;180:665-9. 6. Holtrop PC, Ertzbischoff LM, Roberts CL, Batton DG, Lorenz RP. Survival and short-term outcome in newborns of 23 to 25 weeks’ gestation. Am J Obstet Gynecol 1994;170:1266-70. 7. Amon E, Sibai BM, Anderson GD, Mabie WC. Obstetric variables predicting survival of the immature newborn (less than or equal to 1000 gm): a five-year experience at a single perinatal center. Am J Obstet Gynecol 1987;156:1380-9. 8. Philip AG. Neonatal mortality rate is further improvement possible? J Pediatr 1995;126:427-33.
Bacak et al 9. McElrath TF, Norwitz ER, Nour N, Robinson JN. Contemporary trends in the management of delivery at 23 weeks’ gestation. Am J Perinatol 2002;19:9-15. 10. American College of Obstetrics and Gynecology. Perinatal care at the threshold of viability (practice bulletin). Int J Gynaecol Obstet 2002;79:181-8. 11. Alexander GR, Himes JH, Kaufman RB, Mor J, Kogan M. A United States national reference for fetal growth. Obstet Gynecol 1996;87:163-8. 12. Druschel C, Hughes JP, Olsen C. Mortality among infants with congenital malformations, New York State, 1983 to 1988. Public Health Rep 1996;111:359-65. 13. MacDonald H. Perinatal care at the threshold of viability. Pediatrics 2002;110:1024-7. 14. Stevens-Simon C, Beach RK, McGregor JA. Does incomplete growth and development predispose teenagers to preterm delivery? A template for research. J Perinatol 2002;22:315-23. 15. Center of Disease Control and Prevention. Preterm singleton birthsdUnited States, 1989-1996. MMWR Morb Mortal Wkly Rep 1999;48:185-9. 16. Lemons JA, Bauer CR, Oh W, Korones SB, Papile LA, Stoll BJ, et al. Very low birth weight outcomes of the National Institute of Child Health and Human Development Neonatal Research Network, January 1995 through December 1996. NICHD Neonatal Research Network. Pediatrics 2001;107:E1. 17. Tyson JE, Younes N, Verter J, Wright LL. Viability, morbidity, and resource use among newborns of 501- to 800-g birth weight. NICHD Neonatal Research Network. JAMA 1996; 276:1645-51.
867 18. Stevenson DK, Verter J, Fanaroff AA, Oh W, Ehrenkranz RA, Shankaran S, et al. Sex differences in outcomes of very low birthweight infants: the newborn male disadvantage. Arch Dis Child Fetal Neonatal Ed 2000;83:F182-5. 19. Bernstein IM, Horbar JD, Badger GJ, Ohlsson A, Golan A. Morbidity and mortality among very-low-birth-weight neonates with intrauterine growth restriction: the Vermont Oxford Network. Am J Obstet Gynecol 2000;182:198-206. 20. Redman ME, Gonik B. Cesarean delivery rates at the threshold of viability. Am J Obstet Gynecol 2002;187:873-6. 21. Lee KS, Khoshnood B, Sriram S, Hsieh HL, Singh J, Mittendorf R. Relationship of cesarean delivery to lower birth weight-specific neonatal mortality in singleton breech infants in the United States. Obstet Gynecol 1998;92:769-74. 22. Jonas HA, Khalid N, Schwartz SM. The relationship between Caesarean section and neonatal mortality in very-low-birth weight infants born in Washington State, USA. Paediatr Perinat Epidemiol 1999;13:170-89. 23. Yeast JD, Poskin M, Stockbauer JW, Shaffer S. Changing patterns in regionalization of perinatal care and the impact on neonatal mortality. Am J Obstet Gynecol 1998;178:131-5. 24. Ananth CV, Wilcox AJ. Placental abruption and perinatal mortality in the United States. Am J Epidemiol 2001;153:332-7. 25. Allen MC, Alexander GR, Tompkins ME, Hulsey TC. Racial differences in temporal changes in newborn viability and survival by gestational age. Paediatr Perinat Epidemiol 2000;14:152-8. 26. Schramm W. Data quality: new certificates. Association for Vital Records and Health Statistics/Vital Statistics Cooperative Program Project Directors Meeting, May 1991, San Francisco, Calif.