- Email: [email protected]
Does labor influence neonatal and neurodevelopmental outcomes of extremely-low-birth-weight infants who are born by cesarean delivery?
Does labor influence neonatal and neurodevelopmental outcomes of extremely-low-birth-weight infants who are born by cesarean delivery? Rajan Wadhawan, MD, Betty R. Vohr, MD, Avroy A. Fanaroff, MD, Rebecca L. Perritt, MS, Shahnaz Duara, MD, Barbara J. Stoll, MD, Ronald Goldberg, MD, Abbot Laptook, MD, Kenneth Poole, PhD, Linda L. Wright, MD, and William Oh, MD Bethesda, Md OBJECTIVE: The purpose of this study was to examine the influence of labor on extremely-low-birth-weight infants who were born by cesarean delivery with reference to neonatal and neurodevelopmental outcomes. We hypothesized that infants who are born by cesarean delivery without labor will have better outcomes than those infants who are born by cesarean delivery with labor. STUDY DESIGN: This was a retrospective cohort study of extremely-low-birth-weight infants (birth weight, 401-1000 g) who were born by cesarean delivery and cared for in the National Institute for Child Health and Human Development Neonatal Network, during calendar years 1995 to 1997. A total of 1606 extremely-lowbirth-weight infants were born by cesarean delivery and survived to discharge. Of these, 1273 infants (80.8%) were examined in the network follow-up clinics at 18 to 22 months of corrected age and had a complete data set (667 infants were born without labor, 606 infants were born with labor). Outcome variables that were examined include intraventricular hemorrhage grade 3 to 4, periventricular leukomalacia, and neurodevelopmental impairment. RESULTS: Mothers in the cesarean delivery without labor group were older (P < .001), more likely to be married (P < .05), less likely to be supported by Medicaid (P < .01), more likely to have preeclampsia/ hypertension (P < .001), more likely to receive prenatal steroids (P < .005), and less likely to have received antibiotics (P < .001). Infants who were born by cesarean delivery without labor had higher gestational age (P < .001), lower birth weight (P < .01), and were less likely to be outborn (P < .001). By univariate analysis, infants who were born by cesarean delivery with labor had a higher incidence of grade 3 to 4 intraventricular hemorrhage (23.3% vs 12.1%, P < .001), periventricular leukomalacia (8.5% vs 4.7%, P < .02), and neurodevelopmental impairment (41.7% vs 34.6%, P < .02). Logistic regression analysis that controlled for all maternal and neonatal demographic and clinical variables that were statistically associated with labor or no labor revealed that the significant differences in grade 3 to 4 intraventricular hemorrhage, periventricular leukomalacia, and neurodevelopmental impairment were no longer evident. CONCLUSION: In extremely-low-birth-weight infants who were born by cesarean delivery and after control for other risk factors, labor does not appear to play a significant role in adverse neonatal outcomes and neurodevelopmental impairment at 18 to 22 months of corrected age. (Am J Obstet Gynecol 2003;189:501-6.)
Key words: Cesarean delivery, labor, extremely low birth weight
Of the nearly 4 million live births in the United States each year, approximately 0.3% have a birth weight of <1000 g.1 The survival rate for these extremely-low-birthweight (ELBW) infants has improved significantly over the past decade.2-4 Adverse neurodevelopmental out-
From the National Institute for Child Health and Human Development Neonatal Research Network. Received for publication November 25, 2002; revised January 15, 2003; accepted March 12, 2003. Reprint requests: Rajan Wadhawan, MD, 101 Dudley St, Providence, RI 02905. E-mail: [email protected] Ó 2003, Mosby, Inc. All rights reserved. 0002-9378/2003 $30.00 + 0 doi:10.1067/S0002-9378(03)00360-0
come, including cerebral palsy, is a common problem of ELBW infants.5-7 With better survival, the emphasis in neonatology has shifted toward attempts at improving outcomes of these infants. Intraventricular hemorrhage (IVH) occurs in as many as 25% of infants who were born at <32 weeks of gestation.8 An inverse relationship exists between gestational age and IVH, with the most immature infants being at the greatest risk.9 This, along with the presence of periventricular leukomalacia (PVL), is correlated strongly with adverse neurodevelopmental outcome.10 The cause of IVH and PVL is multifactorial; the stress of labor is quoted often as one of the contributing factors.9 The easily deformed, particularly compliant skull of the 501
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Table I. Study subjects Without labor (No.) With labor (No.) Born by cesarean delivery Died in first 12 h Discharged alive Died after discharge Eligible for follow-up Lost to follow-up Seen in follow-up visit Outcome data missing Complete data set
1041 37 (3.6%) 826 (79.3%) 17 809 126 683 (84.4%) 18 667
1031 46 (4.5%) 780 (75.7%) 14 766 149 617 (80.5%) 11 606
Table II. Maternal demographic and clinical characteristics Cesarean delivery without labor (No.)* Mother <20 years old Unmarried mother Race African American White Hispanic Other Medicaid Preeclampsia/ hypertension Antibiotic therapy Prenatal steroids ($1 dose)
Cesarean delivery with labor (No.)y
73 (11.0%) 282 (42.3%)
107 (17.7%) 296 (48.9%)
260 300 84 23 322 398
245 270 65 26 338 87
(39.0%) (45.0%) (12.6%) (3.4%) (48.4%) (59.7%)
295 (44.2%) 544 (81.6%)
P value <.001 <.05 NS
(40.4%) (44.6%) (10.7%) (4.3%) (55.9%) (14.2%)
<.01 <.001
422 (70.0%) 453 (75.0%)
<.001 <.005
NS, Not significant. *n = 667 women. yn = 606 women.
premature infant may be the reason for possibly dangerous elevations in venous pressure during labor. This has led to the idea that cesarean delivery might reduce these complications by minimizing the ‘‘trauma’’ that is associated with vaginal birth. Although cesarean delivery soon after the onset of labor may be associated with a lower incidence of grade 3/4 IVH,9 several reports have shown that the avoidance of vaginal delivery conferred no advantage to the preterm fetus with cephalic presentation.11-13 The purpose of this study was to test the hypothesis that labor has a significant impact on neonatal neurologic morbidities and neurodevelopmental outcomes of ELBW infants who were born by cesarean delivery. Methods This is a retrospective cohort study of ELBW infants who were admitted to 12 neonatal intensive care units in the National Institute for Child Health and Human Development (NICHHD) Neonatal Research Network. During calendar years 1995 to 1997, 2072 ELBW infants were admitted to the Network centers after cesarean delivery, including 1031 infants who were born after labor
Table III. Infant clinical and demographic characteristics Cesarean delivery without labor (n = 676)
Cesarean delivery with labor (n = 614)
Male (No.) 297 (44.5%) 306 (50.5%) 26.2 ± 1.73 Gestational age (wk)* 27.4 ± 2.13 Birth weight (g)* 789.7 ± 143.4 812.9 ± 127.2 Multiple gestation 99 (14.8%) 211 (34.8%) (No.) Outborn (No.) 25 (3.8%) 69 (11.4%) 1-min Apgar score 149 (22.4%) 164 (27.1%) <3 (No.) 5-min Apgar score 20 (3.0%) 22 (3.6%) <3 (No.) Need for respiratory 623 (94.1%) 587 (97.4%) support (No.) 39.7 ± 24.1 Durationofrespiratory 30.6 ± 24.6 support (d)* Surfactant therapy 481 (72.3%) 494 (81.8%) (No.) Early indomethacin 224 (34.7%) 227 (39.1%) usage (No.) NS, Not significant. *Data are given as mean
P value NS <.001 .002 <.001 <.001 NS NS <.005 <.001 <.001 NS
± SD.
and 1041 who born without labor. Infants were included in the study if they were born by cesarean delivery (with or without labor) and survived until the neurodevelopmental assessment was performed at 18 to 22 months of corrected age. Data were collected on all infants who were born with a birth weight between 401 and 1000 g and who were admitted to the NICHHD network neonatal intensive care units. Trained research nurses obtained the data that were used for this study during the infants’ hospital stays using a specific definition of each item in the Manual of Operations that was developed by the Generic Data Base committee of the NICHHD. For instance, the presence or absence of IVH and PVL was recorded, on the basis of the cranial ultrasound finding that was interpreted by local radiologists at each center, who used the Papile classification of IVH.14 Labor was defined as at least four contractions that occurred in 20 minutes and cervical dilatation of $2 cm with 80% effacement in primiparous women. Multiparous women were said to be in labor if there were at least four contractions in 20 minutes and a cervical dilatation of $3 cm. These data are transmitted to the Research Triangle Institute in North Carolina on a weekly basis. Follow-up assessments of these infants were conducted at 18 to 22 months corrected age in each center’s follow-up clinic, which is staffed by trained and certified individuals who evaluate the infants under the supervision of a developmental pediatrician. The Bayley Scale of Infant Development II,15 a neurologic examination,16 a standard history and physical examination, and an assessment of hearing and visual functional status were performed. A
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Fig 1. Results of univariate analysis for adverse neurologic outcomes. Open bars, ‘‘Without labor’’ group; closed bars, ‘‘with labor’’ group. Asterisk, Probability value of <.05.
composite score called neurodevelopment impairment (NDI) was obtained. The NDI includes the presence of any of the following elements: Bayley motor development index or Bayley psychomotor index of <70, moderate or severe cerebral palsy, and bilateral blindness or bilateral deafness that requires amplification. Data analysis was performed by the Research Triangle Institute statisticians on the basis of the hypothesis that was generated by the investigators and approved by the Network Steering Committee. Statistical analyses. Statistical comparisons were performed with the use of the Student t test for continuous variables and the v2 test for categoric variables. Multivariable logistic regression was performed to determine the odds ratios for the influences of labor on adverse outcomes, after controlling for various maternal and neonatal factors known to be associated with these outcomes. Probability values of <.05 were considered significant. Results As shown in Table I, 2072 infants were born by cesarean delivery and admitted to the network centers. Of these, 1575 infants were eligible for follow-up at 18 to 22 months corrected age (809 of the infants were delivered without labor, 766 of the infants were delivered with previous labor). The compliance rate for follow-up was high (infants who were delivered without labor, 84.4% [n = 683]; infants who were delivered with labor, 80.5% [n = 617]). However, many of the infants had missing data. Thus, the cohort with a complete data set for analysis was 667 and 606 for those without and with labor, respectively. As shown in Table II, the mothers of infants in the cesarean delivery without labor group were less likely to be < 20 years of age (11.0% vs 17.7%), to be unmarried (42.3% vs 48.9%), to be insured by Medicaid (48.4% vs 55.9%), and to have received antibiotics (44.2% vs 70.0%) compared with the labor group. They were more likely to have received prenatal glucocorticoids (81.6% vs 75.0%)
Fig 2. Logistic regression for severe IVH, grade 3 or 4. Closed diamonds, Odds ratio; horizontal bars, 95% CIs.
and have preeclampsia/hypertension (59.7% vs 14.2%). Infants who were born by cesarean delivery without labor had older gestational age and lower birth weight. The lower birth weight of these infants may be a reflection of the higher incidence of preeclampsia in their mothers. Infants in this group were less likely to be outborn (3.8% vs 11.4%) or to be the result of multiple gestation (14.8% vs 34.8%, Table III). The cesarean delivery without labor group also had fewer infants with an Apgar score of <3 at 1 minute and a lesser need and duration of respiratory support. They were also less likely to receive surfactant therapy. Fig 1 shows that, by univariate analysis, the incidence of grade 3/4 IVH was lower in the cesarean delivery without labor group (12.1% vs 23.3%). The incidence of PVL was similarly lower in the cesarean delivery without labor group (4.7% vs 8.5%). NDI prevalence at 18 to 22 months’ corrected age was lower in the cesarean delivery without labor group (34.6% vs 41.7%). Logistic regression analysis, adjusting for various risk factors associated with adverse neurologic outcomes, showed that there were no differences in outcomes (IVH, PVL, and NDI) in the two groups (Figs 2 to 4). Comment Several reports have suggested that cesarean delivery affects neonatal outcomes, particularly with reference to grade 3/4 IVH. A meta-analysis of several of these studies failed to demonstrate a reduction in IVH in infants who were born by cesarean delivery compared with those infants who were born vaginally.11,12 One of the possible reasons for the failure of these studies to show any difference in outcomes may be related to the influence of a number of risk factors, which include labor on the occurrence of IVH and/or PVL. Underlying infection is thought to be responsible for a large proportion of preterm deliveries.17 For women in preterm labor, this may be associated with release of inflammatory cytokines.18
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Fig 3. Logistic regression for PVL. Closed diamonds, Odds ratio; horizontal bars, 95% CIs.
Elevated cytokine levels have been shown to be associated with both IVH and PVL during the neonatal period. Thus, in any attempt to examine the effect of mode of delivery on the neurologic complications in high-risk infants, risk factors including labor must be considered. Anderson et al19 prospectively studied the influence of labor in 89 ELBW infants who were born by cesarean delivery. In their study, infants of mothers for whom cesarean delivery was performed after the onset of the active phase of labor had a higher incidence of grade 3/4 IVH compared with infants who were born by cesarean delivery before undergoing the active phase of labor. They also showed that most IVH in infants who were born with or without cesarean delivery after the onset of active phase of labor occurred at <1 hour of age. In contrast, IVH that occurred in infants who were born by cesarean delivery before the active phase of labor occurred after the first hour of life. This suggested a possible role of the active phase of labor in the development of early IVH. The occurrence of PVL or adverse neurodevelopmental outcomes was not, however studied in these infants. This issue has also been addressed by Murphy et al,5 who performed a case-control study to identify factors that were associated with cerebral palsy in 59 prematurely born infants compared with 234 randomly selected control infants. They showed cesarean delivery after the onset of preterm labor to be a risk factor for cerebral palsy. Birth by elective cesarean delivery without labor, on the other hand, was shown to be protective. This study only looked at cerebral palsy and had the usual shortcomings of a casecontrol study that involves a relatively small sample size. Our results also showed that, without controlling for confounding factors, cesarean delivery after the onset of labor is associated with adverse neurologic outcomes. These outcomes, however, must be considered in relation to several other factors that may play a role. Ment et al20
August 2003 Am J Obstet Gynecol
Fig 4. Logistic regression for NDI. Closed diamonds, Odds ratio; horizontal bars, 95% CIs.
have reported that antenatal glucocorticoids that are given for fetal lung maturation protect against IVH. Similar results have been shown by Shankaran et al.21 Social environment has been shown to have a strong correlation with long-term neurodevelopmental outcomes.22 It is well known that the incidence of multiple births that result from assisted reproductive technology is increasing23 and that increased short- and long-term morbidities are associated with higher order multiple gestations. A large proportion of multiple gestations are born by cesarean delivery after the onset of preterm labor. We have incorporated all of these risk factors into multivariable logistic regression in analyzing the data in our study. The differences in outcomes in the group of infants who were born with or without labor were no longer evident after we controlled for all these factors. The ideal way to study this issue, however, would be to randomize women, who will inevitably be delivered prematurely, to a cesarean delivery before or after the onset of labor and then to follow the infants for adverse outcomes. To our knowledge, no prospective studies that address this issue are available. Because it is not feasible to identify prospectively pregnancies that are likely to result in a preterm delivery and because several of these women may be experiencing preterm labor, such a study is technically and ethically impossible. We conducted this retrospective cohort study because of the availability of large data sets with prospectively collected demographic and clinical characteristics. The cohort that was examined in this study was relatively recent, with a uniform approach to neurodevelopmental follow-up across the Network centers. This allowed us to analyze the impact of labor in cesarean delivery subjects with reference to selected neurologic complications, taking into account the other risk factors that have been shown to be correlated with these complications9 and poor neurodevelopmental outcomes in later life.
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Our study has certain limitations. Because of the retrospective nature of the study, we did not have information on the indications for cesarean delivery in these infants. The stage of labor at which the cesarean delivery was performed was also not known. If labor has an effect on neonatal outcomes, it is possible that it might be related to the duration of labor. Because of the lack of data on the duration of labor, we cannot make any conclusions in this regard. The time at which the cytokine release occurs in relation to preterm labor is also not known, and this fact may account for a lack of difference in outcomes in the 2 groups. Chorioamnionitis has been shown as a risk factor for cerebral palsy. We could not evaluate its influence on NDI because of lack of data pertaining to its occurrence in the study group. We also did not have any information on fetal distress and perinatal asphyxia, which have a role in the onset of IVH.24 We, however, controlled for both 1- and 5-minute Apgar scores as a surrogate marker of the infants’ conditions at birth, by including these in the regression model. We did not have information on intrauterine growth restriction on the study infants. The presence of maternal hypertension/ preeclampsia, a frequent reason for indicated preterm birth and fetal growth restriction was also controlled for in the logistic regression model, however. Nonetheless, we believe that our study demonstrates that labor is not a key factor in the eventual development of adverse neurologic outcomes. Subjecting mothers who are at risk of preterm delivery to cesarean delivery may not be warranted, and it should be reserved for pregnancies with usual indications for an operative delivery. Several new treatment techniques, nursing care protocols, and ventilation styles in neonatal intensive care have continued to evolve and to adapt to the needs of smaller infants, thereby improving their survival. Aggressive attempts to prevent premature labor and preterm birth, however, remain the most important component of the prevention approach.
REFERENCES 1. Avery GB, Fletcher MA, Macdonald MG. Neonatology: pathophysiology and management of the newborn. 5th ed. Philadelphia: Lippincott, Wlliams and Wilkins; 1999. p. 446. 2. Fanaroff AA, Wright LL, Stevenson DK, Shankaran S, Donovan EF, Ehrenkranz RA, et al. Very low birth weight outcomes of the National Institute of Child Health and Human Development Neonatal Research Network, May 1991-December 1992. Am J Obstet Gynecol 1995;173:1423-31. 3. 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. Pediatrics 2001;107(Suppl):E1. 4. Tudehope D, Burns YR, Grey TA, Mohay HA, O’Callaghan MJ, Rogers YM. Changing patterns of survival and outcome at 4 years, of children who weighed 500-999 g at birth. J Pediatr Child Health 1995;31:451-6. 5. Murphy D, Sellers S, MacKenzie I, Yudkin PL, Johnson AM. Casecontrol study of antenatal and intrapartum risk factors for cerebral palsy in very preterm singleton babies. Lancet 1995;346:1449-54.
6. Vohr B, Wright LL, Dusick AM, Mele L, Verter J, Steichen JJ, et al. Neurodevelopmental and functional outcomes of extremely low birth weight infants in the National Institute of Child Health and Human Development Neonatal Research Network, 1993-1994. Pediatrics 2000;105:1216-26. 7. Wood NS, Marlow N, Costeloe K, Gibson AT, Wilkinson AR. Neurologic and developmental disability after extremely preterm birth. N Engl J Med 2000;343:378-84. 8. Philip AG, Alan WC, Tito AM, Wheeler LR. Intraventricular hemorrhage in preterm infants: declining incidence in the 1980s. Pediatrics 1989;84:797-801. 9. Ment LR, Oh W, Phillip AG, Ehrenkranz RA, Duncan CC, Allan W, et al. Risk factors for early intraventricular hemorrhage for low birth weight infants. J Pediatr 1992;121:776-83. 10. Allan WC, Vohr B, Makuch RW, Katz KH, Ment LR. Antecedents of cerebral palsy in a multicenter trial of indomethacin for intraventricular hemorrhage. Arch Pediatr Adolesc Med 1997; 151:580-5. 11. Grant A. Elective versus selective cesarean section for delivery of the small baby. Cochrane Database Syst Rev 2000:CD 000078 (online update software). 12. Grant A, Glazener CM. Elective cesarean section versus expectant management for delivery of the small baby. Cochrane Database Syst Rev 2001:CD 000078 (online update software). 13. Malloy MH, Onstad L, Wright E. The effect of cesarean delivery on birth outcome in very low birth weight infants. Obstet Gynecol 1991;77:498-503. 14. Papile LA, Burstein J, Burstein R, Koffler H. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1,500 gm. J Pediatr 1978;92:529-34. 15. Bayley N. Bayley scales of infant development-II. San Antonio (TX): Psychological Corporation; 1993. 16. Taeusch HW, Yogman MW, editors. Follow-up management of the high-risk infant. Boston: Little, Brown; 1987. 17. Gonclaves LF, Chaiworaponsga T, Romero R. Intrauterine infection and prematurity. Ment Retard Dev Disabil Res Rev 2002;8: 3-13. 18. Coultrip LL, Lien JM, Gomez R, Kapernick P, Khoury A, Grossman JH. The value of amniotic fluid interleukin-6 determination in patients with preterm labor and intact membranes in the detection of microbial invasion of the amniotic cavity. Am J Obstet Gynecol 1994;171:901-11. 19. Anderson GD, Bada HS, Sibai BM, Harvey C, Korones SB, Magill HL, et al. The relationship between labor and route of delivery in the preterm infant. Am J Obstet Gynecol 1988;158:1382-90. 20. Ment LR, Oh W, Ehrenkranz RA, Philip AG, Duncan CC, Makuch RW. Antenatal steroids, delivery mode and intraventricular hemorrhage in preterm infants. Am J Obstet Gynecol 1995;172: 795-800. 21. Shankaran S, Bauer CR, Bain R, Wright LL, Zachary J. Prenatal and perinatal risk and protective factors for neonatal intracranial hemorrhage: National Institute of Child Health and Human Development Neonatal Research Network. Arch Pediatr Adolesc Med 1996;150:491-7. 22. Vohr B, Garcia-Coll C, Flanagan P, Oh W. Effects of intraventricular hemorrhage and socioeconomic status on perceptual, cognitive, and neurological status of low birth weight infants at 5 years of age. J Pediatr 1992;121:280-5. 23. Stevenson DK, Wright LL, Lemons JA, Oh W, Korones SB, Papile LA, et al. Very low birth weight outcomes of the National Institute of Child Health and Human Development Neonatal Research Network, January 1993 through December 1994. Am J Obstet Gynecol 1998;179:1632-9. 24. Vohr B, Ment LR. Intraventricular hemorrhage in the preterm infant. Early Hum Dev 1996;44:1-16.
Appendix Members of the NICHHD Neonatal Research Network. Alan Jobe, MD, PhD, Chairman, University of
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Cincinnati; Neil N. Finer, MD,* and Chris Henderson, AS, University of California at San Diego (U10 HD40461); Avroy A. Fanaroff, MB, BCh,* Michele Walsh, MD, and Nancy Newman, RN, Case Western Reserve University (U10 HD21364); Edward F. Donovan, MD,* Vivek Narendran, MD, MRCP, and Marcia Mersmann, RN, University of Cincinnati (U10 HD27853, M01 RR 08084); Barbara J. Stoll, MD,* and Ellen Hale, RN, Emory University (U10 HD27851); James A. Lemons, MD,* Brenda Poindexter, MD, and Lucy Miller, RN, Indiana University (U10 HD27856, M01 RR 00750); Charles R. Bauer, MD,* Shahnaz Duara, MD, and Ruth Everett, RN, University of Miami (U10 HD21397); Linda L. Wright, MD,* Sumner J. Yaffe, MD, and Elizabeth M. McClure, MEd, National Institute of Child Health and Human Development; Lu-Ann Papile, MD,* and Conra Backstrom, RN, University of New Mexico (U10 HD27881, M01 RR00997); W. Kenneth Poole, PhD,* Research Triangle Institute (U01 HD36790); David K. Stevenson, MD,* and Bethany Ball, BS, Stanford University (U10
August 2003 Am J Obstet Gynecol
HD27880, M01 RR 00070); Sheldon B. Korones, MD,* Henrietta Bada, MD, and Tina Hudson, RN, University of Tennessee at Memphis (U10 HD21415); Jon E. Tyson, MD, MPH,* Kathleen Kennedy, MD, MPH, and Georgia McDavid, RN, University of Texas Health Science Center at Houston (U10 HD21373); Abbot R. Laptook, MD,* and Susie Madison, RN, University of Texas Southwestern Medical Center (U10 HD40689); Seetha Shankaran, MD,* Ganesh Konduri, MD, and Geraldine Muran, RN, Wayne State University (U10 HD21385); William Oh, MD,* Barbara Stonestreet, MD, and Angelita Hensman, RN, Women and Infants Hospital (U10 HD27904); Richard A. Ehrenkranz, MD,* and Patricia Gettner, RN, Yale University (U10 HD27871, M01 RR 06022); and Waldemar A. Carlo, MD,* Namasivayam Ambalavanan, MD, and Monica V. Collins, RN, University of Alabama at Birmingham (U10 HD34216).
*Principal Investigator.
Key words: Cesarean delivery, labor, extremely low birth weight
Of the nearly 4 million live births in the United States each year, approximately 0.3% have a birth weight of <1000 g.1 The survival rate for these extremely-low-birthweight (ELBW) infants has improved significantly over the past decade.2-4 Adverse neurodevelopmental out-
From the National Institute for Child Health and Human Development Neonatal Research Network. Received for publication November 25, 2002; revised January 15, 2003; accepted March 12, 2003. Reprint requests: Rajan Wadhawan, MD, 101 Dudley St, Providence, RI 02905. E-mail: [email protected] Ó 2003, Mosby, Inc. All rights reserved. 0002-9378/2003 $30.00 + 0 doi:10.1067/S0002-9378(03)00360-0
come, including cerebral palsy, is a common problem of ELBW infants.5-7 With better survival, the emphasis in neonatology has shifted toward attempts at improving outcomes of these infants. Intraventricular hemorrhage (IVH) occurs in as many as 25% of infants who were born at <32 weeks of gestation.8 An inverse relationship exists between gestational age and IVH, with the most immature infants being at the greatest risk.9 This, along with the presence of periventricular leukomalacia (PVL), is correlated strongly with adverse neurodevelopmental outcome.10 The cause of IVH and PVL is multifactorial; the stress of labor is quoted often as one of the contributing factors.9 The easily deformed, particularly compliant skull of the 501
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Table I. Study subjects Without labor (No.) With labor (No.) Born by cesarean delivery Died in first 12 h Discharged alive Died after discharge Eligible for follow-up Lost to follow-up Seen in follow-up visit Outcome data missing Complete data set
1041 37 (3.6%) 826 (79.3%) 17 809 126 683 (84.4%) 18 667
1031 46 (4.5%) 780 (75.7%) 14 766 149 617 (80.5%) 11 606
Table II. Maternal demographic and clinical characteristics Cesarean delivery without labor (No.)* Mother <20 years old Unmarried mother Race African American White Hispanic Other Medicaid Preeclampsia/ hypertension Antibiotic therapy Prenatal steroids ($1 dose)
Cesarean delivery with labor (No.)y
73 (11.0%) 282 (42.3%)
107 (17.7%) 296 (48.9%)
260 300 84 23 322 398
245 270 65 26 338 87
(39.0%) (45.0%) (12.6%) (3.4%) (48.4%) (59.7%)
295 (44.2%) 544 (81.6%)
P value <.001 <.05 NS
(40.4%) (44.6%) (10.7%) (4.3%) (55.9%) (14.2%)
<.01 <.001
422 (70.0%) 453 (75.0%)
<.001 <.005
NS, Not significant. *n = 667 women. yn = 606 women.
premature infant may be the reason for possibly dangerous elevations in venous pressure during labor. This has led to the idea that cesarean delivery might reduce these complications by minimizing the ‘‘trauma’’ that is associated with vaginal birth. Although cesarean delivery soon after the onset of labor may be associated with a lower incidence of grade 3/4 IVH,9 several reports have shown that the avoidance of vaginal delivery conferred no advantage to the preterm fetus with cephalic presentation.11-13 The purpose of this study was to test the hypothesis that labor has a significant impact on neonatal neurologic morbidities and neurodevelopmental outcomes of ELBW infants who were born by cesarean delivery. Methods This is a retrospective cohort study of ELBW infants who were admitted to 12 neonatal intensive care units in the National Institute for Child Health and Human Development (NICHHD) Neonatal Research Network. During calendar years 1995 to 1997, 2072 ELBW infants were admitted to the Network centers after cesarean delivery, including 1031 infants who were born after labor
Table III. Infant clinical and demographic characteristics Cesarean delivery without labor (n = 676)
Cesarean delivery with labor (n = 614)
Male (No.) 297 (44.5%) 306 (50.5%) 26.2 ± 1.73 Gestational age (wk)* 27.4 ± 2.13 Birth weight (g)* 789.7 ± 143.4 812.9 ± 127.2 Multiple gestation 99 (14.8%) 211 (34.8%) (No.) Outborn (No.) 25 (3.8%) 69 (11.4%) 1-min Apgar score 149 (22.4%) 164 (27.1%) <3 (No.) 5-min Apgar score 20 (3.0%) 22 (3.6%) <3 (No.) Need for respiratory 623 (94.1%) 587 (97.4%) support (No.) 39.7 ± 24.1 Durationofrespiratory 30.6 ± 24.6 support (d)* Surfactant therapy 481 (72.3%) 494 (81.8%) (No.) Early indomethacin 224 (34.7%) 227 (39.1%) usage (No.) NS, Not significant. *Data are given as mean
P value NS <.001 .002 <.001 <.001 NS NS <.005 <.001 <.001 NS
± SD.
and 1041 who born without labor. Infants were included in the study if they were born by cesarean delivery (with or without labor) and survived until the neurodevelopmental assessment was performed at 18 to 22 months of corrected age. Data were collected on all infants who were born with a birth weight between 401 and 1000 g and who were admitted to the NICHHD network neonatal intensive care units. Trained research nurses obtained the data that were used for this study during the infants’ hospital stays using a specific definition of each item in the Manual of Operations that was developed by the Generic Data Base committee of the NICHHD. For instance, the presence or absence of IVH and PVL was recorded, on the basis of the cranial ultrasound finding that was interpreted by local radiologists at each center, who used the Papile classification of IVH.14 Labor was defined as at least four contractions that occurred in 20 minutes and cervical dilatation of $2 cm with 80% effacement in primiparous women. Multiparous women were said to be in labor if there were at least four contractions in 20 minutes and a cervical dilatation of $3 cm. These data are transmitted to the Research Triangle Institute in North Carolina on a weekly basis. Follow-up assessments of these infants were conducted at 18 to 22 months corrected age in each center’s follow-up clinic, which is staffed by trained and certified individuals who evaluate the infants under the supervision of a developmental pediatrician. The Bayley Scale of Infant Development II,15 a neurologic examination,16 a standard history and physical examination, and an assessment of hearing and visual functional status were performed. A
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Fig 1. Results of univariate analysis for adverse neurologic outcomes. Open bars, ‘‘Without labor’’ group; closed bars, ‘‘with labor’’ group. Asterisk, Probability value of <.05.
composite score called neurodevelopment impairment (NDI) was obtained. The NDI includes the presence of any of the following elements: Bayley motor development index or Bayley psychomotor index of <70, moderate or severe cerebral palsy, and bilateral blindness or bilateral deafness that requires amplification. Data analysis was performed by the Research Triangle Institute statisticians on the basis of the hypothesis that was generated by the investigators and approved by the Network Steering Committee. Statistical analyses. Statistical comparisons were performed with the use of the Student t test for continuous variables and the v2 test for categoric variables. Multivariable logistic regression was performed to determine the odds ratios for the influences of labor on adverse outcomes, after controlling for various maternal and neonatal factors known to be associated with these outcomes. Probability values of <.05 were considered significant. Results As shown in Table I, 2072 infants were born by cesarean delivery and admitted to the network centers. Of these, 1575 infants were eligible for follow-up at 18 to 22 months corrected age (809 of the infants were delivered without labor, 766 of the infants were delivered with previous labor). The compliance rate for follow-up was high (infants who were delivered without labor, 84.4% [n = 683]; infants who were delivered with labor, 80.5% [n = 617]). However, many of the infants had missing data. Thus, the cohort with a complete data set for analysis was 667 and 606 for those without and with labor, respectively. As shown in Table II, the mothers of infants in the cesarean delivery without labor group were less likely to be < 20 years of age (11.0% vs 17.7%), to be unmarried (42.3% vs 48.9%), to be insured by Medicaid (48.4% vs 55.9%), and to have received antibiotics (44.2% vs 70.0%) compared with the labor group. They were more likely to have received prenatal glucocorticoids (81.6% vs 75.0%)
Fig 2. Logistic regression for severe IVH, grade 3 or 4. Closed diamonds, Odds ratio; horizontal bars, 95% CIs.
and have preeclampsia/hypertension (59.7% vs 14.2%). Infants who were born by cesarean delivery without labor had older gestational age and lower birth weight. The lower birth weight of these infants may be a reflection of the higher incidence of preeclampsia in their mothers. Infants in this group were less likely to be outborn (3.8% vs 11.4%) or to be the result of multiple gestation (14.8% vs 34.8%, Table III). The cesarean delivery without labor group also had fewer infants with an Apgar score of <3 at 1 minute and a lesser need and duration of respiratory support. They were also less likely to receive surfactant therapy. Fig 1 shows that, by univariate analysis, the incidence of grade 3/4 IVH was lower in the cesarean delivery without labor group (12.1% vs 23.3%). The incidence of PVL was similarly lower in the cesarean delivery without labor group (4.7% vs 8.5%). NDI prevalence at 18 to 22 months’ corrected age was lower in the cesarean delivery without labor group (34.6% vs 41.7%). Logistic regression analysis, adjusting for various risk factors associated with adverse neurologic outcomes, showed that there were no differences in outcomes (IVH, PVL, and NDI) in the two groups (Figs 2 to 4). Comment Several reports have suggested that cesarean delivery affects neonatal outcomes, particularly with reference to grade 3/4 IVH. A meta-analysis of several of these studies failed to demonstrate a reduction in IVH in infants who were born by cesarean delivery compared with those infants who were born vaginally.11,12 One of the possible reasons for the failure of these studies to show any difference in outcomes may be related to the influence of a number of risk factors, which include labor on the occurrence of IVH and/or PVL. Underlying infection is thought to be responsible for a large proportion of preterm deliveries.17 For women in preterm labor, this may be associated with release of inflammatory cytokines.18
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Fig 3. Logistic regression for PVL. Closed diamonds, Odds ratio; horizontal bars, 95% CIs.
Elevated cytokine levels have been shown to be associated with both IVH and PVL during the neonatal period. Thus, in any attempt to examine the effect of mode of delivery on the neurologic complications in high-risk infants, risk factors including labor must be considered. Anderson et al19 prospectively studied the influence of labor in 89 ELBW infants who were born by cesarean delivery. In their study, infants of mothers for whom cesarean delivery was performed after the onset of the active phase of labor had a higher incidence of grade 3/4 IVH compared with infants who were born by cesarean delivery before undergoing the active phase of labor. They also showed that most IVH in infants who were born with or without cesarean delivery after the onset of active phase of labor occurred at <1 hour of age. In contrast, IVH that occurred in infants who were born by cesarean delivery before the active phase of labor occurred after the first hour of life. This suggested a possible role of the active phase of labor in the development of early IVH. The occurrence of PVL or adverse neurodevelopmental outcomes was not, however studied in these infants. This issue has also been addressed by Murphy et al,5 who performed a case-control study to identify factors that were associated with cerebral palsy in 59 prematurely born infants compared with 234 randomly selected control infants. They showed cesarean delivery after the onset of preterm labor to be a risk factor for cerebral palsy. Birth by elective cesarean delivery without labor, on the other hand, was shown to be protective. This study only looked at cerebral palsy and had the usual shortcomings of a casecontrol study that involves a relatively small sample size. Our results also showed that, without controlling for confounding factors, cesarean delivery after the onset of labor is associated with adverse neurologic outcomes. These outcomes, however, must be considered in relation to several other factors that may play a role. Ment et al20
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Fig 4. Logistic regression for NDI. Closed diamonds, Odds ratio; horizontal bars, 95% CIs.
have reported that antenatal glucocorticoids that are given for fetal lung maturation protect against IVH. Similar results have been shown by Shankaran et al.21 Social environment has been shown to have a strong correlation with long-term neurodevelopmental outcomes.22 It is well known that the incidence of multiple births that result from assisted reproductive technology is increasing23 and that increased short- and long-term morbidities are associated with higher order multiple gestations. A large proportion of multiple gestations are born by cesarean delivery after the onset of preterm labor. We have incorporated all of these risk factors into multivariable logistic regression in analyzing the data in our study. The differences in outcomes in the group of infants who were born with or without labor were no longer evident after we controlled for all these factors. The ideal way to study this issue, however, would be to randomize women, who will inevitably be delivered prematurely, to a cesarean delivery before or after the onset of labor and then to follow the infants for adverse outcomes. To our knowledge, no prospective studies that address this issue are available. Because it is not feasible to identify prospectively pregnancies that are likely to result in a preterm delivery and because several of these women may be experiencing preterm labor, such a study is technically and ethically impossible. We conducted this retrospective cohort study because of the availability of large data sets with prospectively collected demographic and clinical characteristics. The cohort that was examined in this study was relatively recent, with a uniform approach to neurodevelopmental follow-up across the Network centers. This allowed us to analyze the impact of labor in cesarean delivery subjects with reference to selected neurologic complications, taking into account the other risk factors that have been shown to be correlated with these complications9 and poor neurodevelopmental outcomes in later life.
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Our study has certain limitations. Because of the retrospective nature of the study, we did not have information on the indications for cesarean delivery in these infants. The stage of labor at which the cesarean delivery was performed was also not known. If labor has an effect on neonatal outcomes, it is possible that it might be related to the duration of labor. Because of the lack of data on the duration of labor, we cannot make any conclusions in this regard. The time at which the cytokine release occurs in relation to preterm labor is also not known, and this fact may account for a lack of difference in outcomes in the 2 groups. Chorioamnionitis has been shown as a risk factor for cerebral palsy. We could not evaluate its influence on NDI because of lack of data pertaining to its occurrence in the study group. We also did not have any information on fetal distress and perinatal asphyxia, which have a role in the onset of IVH.24 We, however, controlled for both 1- and 5-minute Apgar scores as a surrogate marker of the infants’ conditions at birth, by including these in the regression model. We did not have information on intrauterine growth restriction on the study infants. The presence of maternal hypertension/ preeclampsia, a frequent reason for indicated preterm birth and fetal growth restriction was also controlled for in the logistic regression model, however. Nonetheless, we believe that our study demonstrates that labor is not a key factor in the eventual development of adverse neurologic outcomes. Subjecting mothers who are at risk of preterm delivery to cesarean delivery may not be warranted, and it should be reserved for pregnancies with usual indications for an operative delivery. Several new treatment techniques, nursing care protocols, and ventilation styles in neonatal intensive care have continued to evolve and to adapt to the needs of smaller infants, thereby improving their survival. Aggressive attempts to prevent premature labor and preterm birth, however, remain the most important component of the prevention approach.
REFERENCES 1. Avery GB, Fletcher MA, Macdonald MG. Neonatology: pathophysiology and management of the newborn. 5th ed. Philadelphia: Lippincott, Wlliams and Wilkins; 1999. p. 446. 2. Fanaroff AA, Wright LL, Stevenson DK, Shankaran S, Donovan EF, Ehrenkranz RA, et al. Very low birth weight outcomes of the National Institute of Child Health and Human Development Neonatal Research Network, May 1991-December 1992. Am J Obstet Gynecol 1995;173:1423-31. 3. 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. Pediatrics 2001;107(Suppl):E1. 4. Tudehope D, Burns YR, Grey TA, Mohay HA, O’Callaghan MJ, Rogers YM. Changing patterns of survival and outcome at 4 years, of children who weighed 500-999 g at birth. J Pediatr Child Health 1995;31:451-6. 5. Murphy D, Sellers S, MacKenzie I, Yudkin PL, Johnson AM. Casecontrol study of antenatal and intrapartum risk factors for cerebral palsy in very preterm singleton babies. Lancet 1995;346:1449-54.
6. Vohr B, Wright LL, Dusick AM, Mele L, Verter J, Steichen JJ, et al. Neurodevelopmental and functional outcomes of extremely low birth weight infants in the National Institute of Child Health and Human Development Neonatal Research Network, 1993-1994. Pediatrics 2000;105:1216-26. 7. Wood NS, Marlow N, Costeloe K, Gibson AT, Wilkinson AR. Neurologic and developmental disability after extremely preterm birth. N Engl J Med 2000;343:378-84. 8. Philip AG, Alan WC, Tito AM, Wheeler LR. Intraventricular hemorrhage in preterm infants: declining incidence in the 1980s. Pediatrics 1989;84:797-801. 9. Ment LR, Oh W, Phillip AG, Ehrenkranz RA, Duncan CC, Allan W, et al. Risk factors for early intraventricular hemorrhage for low birth weight infants. J Pediatr 1992;121:776-83. 10. Allan WC, Vohr B, Makuch RW, Katz KH, Ment LR. Antecedents of cerebral palsy in a multicenter trial of indomethacin for intraventricular hemorrhage. Arch Pediatr Adolesc Med 1997; 151:580-5. 11. Grant A. Elective versus selective cesarean section for delivery of the small baby. Cochrane Database Syst Rev 2000:CD 000078 (online update software). 12. Grant A, Glazener CM. Elective cesarean section versus expectant management for delivery of the small baby. Cochrane Database Syst Rev 2001:CD 000078 (online update software). 13. Malloy MH, Onstad L, Wright E. The effect of cesarean delivery on birth outcome in very low birth weight infants. Obstet Gynecol 1991;77:498-503. 14. Papile LA, Burstein J, Burstein R, Koffler H. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1,500 gm. J Pediatr 1978;92:529-34. 15. Bayley N. Bayley scales of infant development-II. San Antonio (TX): Psychological Corporation; 1993. 16. Taeusch HW, Yogman MW, editors. Follow-up management of the high-risk infant. Boston: Little, Brown; 1987. 17. Gonclaves LF, Chaiworaponsga T, Romero R. Intrauterine infection and prematurity. Ment Retard Dev Disabil Res Rev 2002;8: 3-13. 18. Coultrip LL, Lien JM, Gomez R, Kapernick P, Khoury A, Grossman JH. The value of amniotic fluid interleukin-6 determination in patients with preterm labor and intact membranes in the detection of microbial invasion of the amniotic cavity. Am J Obstet Gynecol 1994;171:901-11. 19. Anderson GD, Bada HS, Sibai BM, Harvey C, Korones SB, Magill HL, et al. The relationship between labor and route of delivery in the preterm infant. Am J Obstet Gynecol 1988;158:1382-90. 20. Ment LR, Oh W, Ehrenkranz RA, Philip AG, Duncan CC, Makuch RW. Antenatal steroids, delivery mode and intraventricular hemorrhage in preterm infants. Am J Obstet Gynecol 1995;172: 795-800. 21. Shankaran S, Bauer CR, Bain R, Wright LL, Zachary J. Prenatal and perinatal risk and protective factors for neonatal intracranial hemorrhage: National Institute of Child Health and Human Development Neonatal Research Network. Arch Pediatr Adolesc Med 1996;150:491-7. 22. Vohr B, Garcia-Coll C, Flanagan P, Oh W. Effects of intraventricular hemorrhage and socioeconomic status on perceptual, cognitive, and neurological status of low birth weight infants at 5 years of age. J Pediatr 1992;121:280-5. 23. Stevenson DK, Wright LL, Lemons JA, Oh W, Korones SB, Papile LA, et al. Very low birth weight outcomes of the National Institute of Child Health and Human Development Neonatal Research Network, January 1993 through December 1994. Am J Obstet Gynecol 1998;179:1632-9. 24. Vohr B, Ment LR. Intraventricular hemorrhage in the preterm infant. Early Hum Dev 1996;44:1-16.
Appendix Members of the NICHHD Neonatal Research Network. Alan Jobe, MD, PhD, Chairman, University of
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Cincinnati; Neil N. Finer, MD,* and Chris Henderson, AS, University of California at San Diego (U10 HD40461); Avroy A. Fanaroff, MB, BCh,* Michele Walsh, MD, and Nancy Newman, RN, Case Western Reserve University (U10 HD21364); Edward F. Donovan, MD,* Vivek Narendran, MD, MRCP, and Marcia Mersmann, RN, University of Cincinnati (U10 HD27853, M01 RR 08084); Barbara J. Stoll, MD,* and Ellen Hale, RN, Emory University (U10 HD27851); James A. Lemons, MD,* Brenda Poindexter, MD, and Lucy Miller, RN, Indiana University (U10 HD27856, M01 RR 00750); Charles R. Bauer, MD,* Shahnaz Duara, MD, and Ruth Everett, RN, University of Miami (U10 HD21397); Linda L. Wright, MD,* Sumner J. Yaffe, MD, and Elizabeth M. McClure, MEd, National Institute of Child Health and Human Development; Lu-Ann Papile, MD,* and Conra Backstrom, RN, University of New Mexico (U10 HD27881, M01 RR00997); W. Kenneth Poole, PhD,* Research Triangle Institute (U01 HD36790); David K. Stevenson, MD,* and Bethany Ball, BS, Stanford University (U10
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HD27880, M01 RR 00070); Sheldon B. Korones, MD,* Henrietta Bada, MD, and Tina Hudson, RN, University of Tennessee at Memphis (U10 HD21415); Jon E. Tyson, MD, MPH,* Kathleen Kennedy, MD, MPH, and Georgia McDavid, RN, University of Texas Health Science Center at Houston (U10 HD21373); Abbot R. Laptook, MD,* and Susie Madison, RN, University of Texas Southwestern Medical Center (U10 HD40689); Seetha Shankaran, MD,* Ganesh Konduri, MD, and Geraldine Muran, RN, Wayne State University (U10 HD21385); William Oh, MD,* Barbara Stonestreet, MD, and Angelita Hensman, RN, Women and Infants Hospital (U10 HD27904); Richard A. Ehrenkranz, MD,* and Patricia Gettner, RN, Yale University (U10 HD27871, M01 RR 06022); and Waldemar A. Carlo, MD,* Namasivayam Ambalavanan, MD, and Monica V. Collins, RN, University of Alabama at Birmingham (U10 HD34216).
*Principal Investigator.