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Delivery After Previous Cesarean: Long-Term Outcomes in the Child
Delivery After Previous Cesarean: Long-Term Outcomes in the Child T. Michael O’Shea, MD, MPH,* Mark A. Klebanoff, MD, MPH,† and Caroline Signore, MD, MPH† In subsequent pregnancies after a cesarean delivery, women must choose between attempting to deliver vaginally or undergoing another cesarean delivery. Information relevant to this choice includes the long-term benefits and harms to the baby. In this article we discuss the relationship of mode of delivery (planned trial of labor, either with or without vaginal delivery, or elective repeat cesarean delivery) and long-term outcomes, including brachial plexus palsy, neurodevelopmental impairment, and asthma. No randomized trials are available that relate directly to the choice of delivery method after previous cesarean. Observational studies suggest that cesarean delivery might be associated with a greater risk of asthma, caused perhaps by altered gut colonization, increased risk of neonatal respiratory disease, decreased gestational age at birth or decreased likelihood of breastfeeding. By contrast, vaginal delivery after a previous cesarean delivery is associated with greater risks of neurodevelopmental impairment and upper-extremity motor impairment, caused, respectively, by greater risks of perinatal hypoxic-ischemic encephalopathy and brachial plexus injury. Available information does not provide a precise estimate of the relative risks for infants delivered after a trial of labor versus elective cesarean delivery. Semin Perinatol 34:281-292 © 2010 Elsevier Inc. All rights reserved. KEYWORDS asthma, brachial plexus injury, cesarean delivery, neonatal encephalopathy, shoulder dystocia, uterine rupture, vaginal delivery
M
ost attempts to deliver vaginally after a previous cesarean delivery (CD) are successful. Nonetheless, in the past decade, an increasing proportion of women chose not to attempt vaginal birth after cesarean (VBAC); among their concerns was that harm would come to the fetus from complications of VBAC.1 Randomized comparisons of planned VBAC versus planned CD would provide the most valid conclusions about the effects of these modes of delivery on maternal and child outcomes. We are aware of no completed trials of mode of delivery after previous cesarean,2 although at least 1 such trial is underway.3 Information pertinent to the risks and benefits
*Department of Pediatrics (Neonatology), Wake Forest University, Health Sciences, Winston-Salem, NC. †Eunice Kennedy Shriver National Institute of Human Development, National Institutes of Health, Department of Health and Human Services, Bethesda, MD. Source of financial support: Dr Klebanoff was supported by Intramural Funds from the NIH, NICHD. Address reprint requests to T. Michael O’Shea, MD, MPH, Department of Pediatrics, Wake Forest University, Health Sciences, Medical Center Blvd, Winston-Salem, NC 27157. E-mail: [email protected]
0146-0005/10/$-see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1053/j.semperi.2010.03.008
of VBAC versus planned repeat CD includes observational studies of elective CD,4,5 particularly those studies that include women with a previous cesarean birth.3,6-9 Extant studies, in addition to being nonrandomized, provide data only about short-term outcomes for the child (eg, low Apgar score, neonatal encephalopathy, brachial plexus injury, and respiratory dysfunction) and the maternal-child dyad (eg, initiation of breastfeeding). We will review these studies and discuss how short-term outcomes might relate to health and development in later childhood. The absence of data from randomized trials presents a serious methodological problem when estimating the relative risks for VBAC versus elective repeat CD. Absent such data, the least-biased estimates would derive from observational studies of cohorts of women who have previously undergone CD and have, at study inception, planned to have either a VBAC or repeat CD, on the basis of factors that do not influence the likelihood of successful VBAC or any of the outcomes associated with VBAC. An “inception cohort,” as just described, would allow the researcher to observe the rate at which the cohort members who plan to have a CD actually go into labor before the date of their elective scheduled CD, and 281
T.M. O’Shea, M.A. Klebanoff, and C. Signore
282
Figure 1 Causal pathways that might link delivery plan after prior cesarean delivery with long-term health outcomes in the child. CD, cesarean delivery; TOL, trial of labor.
the rate at which such women deliver vaginally, as opposed to having an “emergency” CD. Such a study would also provide an estimate of the frequency at which women who plan to deliver by VBAC (ie, those choosing a trial of labor) develop an indication (maternal or fetal) for nonelective CD. Finally, it would enable estimation of the frequency with which women change their mind regarding their intended mode of delivery as pregnancy progresses. All of these complexities are lost when one compares women on the basis of only what happened at the very end of pregnancy because the mode of delivery, even for women who deliver vaginally, is not always the planned mode of delivery. Given the 2 serious limitations of available information, conclusions about how mode of delivery after previous CD affects long-term child outcomes can only be determined on the basis of evidence that is too weak to be definitive. Therefore, we will avoid drawing conclusions about the relative benefits and risk of VBAC. However we will suggest areas of focus to be considered in future research.
Mechanisms Linking Mode of Delivery and Long-Term Health in the Child Pathways by which mode of delivery might affect health and development in the offspring are illustrated in Figure 1 and summarized in Table 1. The 2 most important complications of a trial of labor after previous CD are uterine rupture6 and brachial plexus injury,10 the risks of which are greater among neonates delivered vaginally compared with those delivered by cesarean. Uterine rupture can result in hypoxic-ischemic injury to the fetal heart, gastrointestinal tract, kidneys, and brain. Hypoxic-ischemic injury to the fetal heart, manifesting as papillary muscle dysfunction and tricuspid regurgitation in the neonate, typically resolves in a few days and almost never leads to chronic cardiac dysfunction. Hypoxic-ischemic injury to the kidney most often manifests as acute tubular ne-
Table 1 Mechanisms by Which Mode of Delivery Might Influence Health and Development in the Offspring Obstetrical Event
Mechanism
Uterine rupture during trial of labor Shoulder dystocia during vaginal delivery Cesarean delivery
Perinatal asphyxia causing brain damage Nerve injury
Neonatal encephalopathy
Neonatal Manifestation
Retained fetal lung fluid; surfactant deficiency
Cesarean delivery
Altered gut flora
Cesarean delivery
Lower rate of initiation of breastfeeding
Respiratory distress; hypoxic respiratory failure in severe cases Altered immune function maturation Altered immune function maturation
Upper extremity palsy
Childhood Outcome Neurodevelopmental impairments, such as cerebral palsy Upper extremity motor impairment Neurodevelopmental impairments after extracorporeal membrane oxygenation; asthma Asthma Asthma
Outcomes of child after previous cesarean crosis and typically resolves during the neonatal period. Much less frequently, hypoxic-ischemic renal damage manifests as cortical necrosis, which can lead to persisting renal insufficiency. Intestinal hypoxic-ischemic injury typically resolves in several days, but in a small proportion of cases leads to necrotizing enterocolitis, which is associated with a high mortality rate.11 Neonatal hypoxic-ischemic encephalopathy (HIE) refers to the acute manifestation of hypoxic-ischemic brain injury. Permanent dysfunction is not unusual after moderate or severe neonatal HIE. The most consistently observed dysfunction after neonatal encephalopathy is cerebral palsy, a persisting abnormality of movement and posture, with impaired motor function.12 Brachial plexus palsy is strongly associated with shoulder dystocia and is rarely observed in neonates delivered by cesarean.10,13 Estimates of the incidence of brachial plexus palsy after shoulder dystocia range from 4% to 40%,10 and permanent upper extremity neurological impairment occurs in about 25% of cases of brachial plexus palsy.13 The mechanisms linking elective CD to long-term outcomes are not as well understood as those linking these outcomes to complications of VBAC. However, CD is associated with an increased risk of neonatal respiratory dysfunction, altered bacterial colonization of the gut, and lower rates of breastfeeding, which could explain the observation that asthma is more prevalent among children delivered by cesarean. We will discuss in more detail each of these mechanisms that might link mode of delivery and long-term outcomes in the child.
Brain Damage and Birth After a Previous CD Perinatal brain damage after a previous CD is related primarily to uterine rupture, which can lead to HIE. In 2004, Guise et al9 reported a systematic review of the incidence and consequences of uterine rupture in women with a previous CD. The estimated rate of symptomatic uterine rupture (uterine separation diagnosed at laparotomy performed for maternal or fetal signs or symptoms), on the basis of pooled data from 10 observational studies, was 3.8 (95% confidence interval 1.3-6.2) per 1000 trials of labor. Guise et al estimated, on the basis of 1 retrospective and 1 prospective study (including 3411 women with a trial of labor and 3444 with elective repeat CD), that the incremental risk associated with a trial of labor versus elective repeat CD is 2.7 (0.7 to 4.73) symptomatic ruptures per 1000 trials of labor and that there is no incremental risk for asymptomatic uterine rupture. The National Institutes of Health Maternal Fetal Medicine Units (MFMU) Network reported the incidence of uterine rupture among 17,898 women who attempted a vaginal delivery and 15,801 women who underwent elective repeat CD without a trial of labor.6 This study excluded women who presented in early labor and subsequently underwent CD and women who underwent indicated repeat CD. Symptomatic uterine rupture occurred in 124 trials of labor (7 per 1000), almost twice the rate reported in the meta-analysis by Guise
283 et al. In a subsequent analysis from the MFMU Network, 5 groups were studied: women delivering (vaginally or by CD) after a trial of labor, elective repeat CD with no labor, elective repeat CD with labor, indicated repeat CD with no labor, and indicated repeat CD with labor. Rates of uterine rupture, in descending order were trial of labor (7.4 per 1000), indicated repeat CD with labor (2.8 per 1000), elective repeat CD with labor (1.5 per 1000), indicated repeat CD without labor (0.8 per 1000), and elective repeat CD without labor (none). On the basis of these studies just reviewed, the risk difference for uterine rupture when comparing a trial of labor and elective CD is probably in the range of 2.79 to 5.98 per 1000 deliveries. Symptomatic uterine rupture, with resultant fetal hypoxiaischemia, can lead to fetal or neonatal death or HIE. In the meta-analysis by Guise et al, among the total of 74 symptomatic uterine ruptures, there were 6 fetal/neonatal deaths, corresponding to an additional 1.4 (0 to 9.8) additional deaths per 10,000 trials of labor. However, in the MFMU Network study, a trial of labor was not associated with higher mortality rate. Neonatal mortality rates, in descending order, were 2 per 1000 for indicated repeat CD without labor, 1.1 per 1000 for elective repeat CD with labor, 0.9 per 1000 for indicated repeat CD with labor, 0.8 per 1000 for trial of labor, and 0.4 per 1000 for elective repeat CD without labor. A trial of labor appears to be associated with a greater rate of HIE. In the MFMU Network studies, HIE was observed only among those delivered after a trial of labor (0.08% of neonates) and indicated repeat CD without labor (0.06%).8 Of the 12 infants with HIE delivered after a trial of labor, 7 occurred after symptomatic uterine rupture (7/114 or 6.1% of trials of labor with uterine rupture), and 5 occurred in women without uterine rupture (5/15209 or 0.03% of trials of labor without uterine rupture). Thus, hypoxic-ischemic injury to the fetal brain occurs more frequently with labor and vaginal delivery than with elective CD, even when labor is not complicated by uterine rupture. Rates reported by Spong et al8 of HIE among neonates delivered by elective repeat CD versus a trial of labor (excluding those born after indicated repeat CD) suggest that for every 10,000 elective repeat CD performed after a previous cesarean, 8 cases of HIE would be prevented. This presumed benefit should be considered in light of the long-term consequences of HIE, which are not described in either the metaanalysis by Guise et al or the MFMU Network studies. In the population-based Western Australian study of 276 newborns born at term with moderate or severe neonatal encephalopathy, 25 (9.1%) died and 32 (12.7% of survivors) developed cerebral palsy.14 The rate of cerebral palsy was 8% among infants with moderate encephalopathy and 23% among those with severe encephalopathy. Of those with cerebral palsy, 47% had severe cerebral palsy, 75% had an intelligence quotient ⬍ 70%, and 53% had epilepsy. This prognostic information applies to neonates with encephalopathy, some of which is not attributable to HIE. For example, in 1 population-based study of neonatal encephalopathy, only 29% of affected infants experienced events thought to
T.M. O’Shea, M.A. Klebanoff, and C. Signore
284 indicate birth asphyxia,15 and 10% of cases were attributed to birth defects.16 Probably more pertinent to the outcome of neonates with HIE after uterine rupture are estimates of rates of mortality and morbidity among neonates with HIE who participated in trials of therapeutic hypothermia versus standard care.17 For infants diagnosed with moderate or severe HIE who were randomized to hypothermia, the mortality rates in 3 trials have been 16% for those with moderate HIE (n ⫽ 141) and 51% for those with severe HIE (n ⫽ 75). Rates of major disability among survivors have been 26% for moderate HIE (n ⫽ 118) and 41% for severe HIE (n ⫽ 37). Among infants with either moderate or severe HIE, the rate of cerebral palsy has been 30%, several-fold greater than the rate reported from the population-based study by Badawi et al,14 suggesting that the prognosis is worse for HIE than for other causes of neonatal encephalopathy. The prevalence of HIE reported from the MFMU Network (0.8 per 1000 trials of labor) is less than one-quarter of that described in population-based studies, suggesting that cases identified in the latter studies might be less severely affected than those identified in the former. (For instance, popula-
tion-based studies might have used less stringent criteria to identify cases.) The prevalence reported in 3 studies in North America, 5 studies in the United Kingdom, and 1 study in Sweden, of births that occurred 1959-1997, range from a low of 1.2 per 1000 live births to a high of 7.7 per 1000 live births.18 In the Western Australian study alluded to previously, the birth prevalence of moderate or severe newborn encephalopathy was 3.8/1000 term live births,15 very similar to the incidence of umbilical arterial pH ⬍ 7.0 (3.7 per 1000 live births) in 6 North American studies and 1 study from the Netherlands of babies born 1986-2002.18
Brachial Plexus Injury in Births After Previous CD Studies that provide estimates of the rates of shoulder dystocia, perinatal brachial plexus palsy, and permanent neuromotor impairment after brachial plexus palsy are summarized in Table 2. Shoulder dystocia is a strong risk factor for brachial plexus palsy, perhaps because greater traction forces are needed to deliver the fetal shoulders, resulting in over-
Table 2 Studies of Shoulder Dystocia and Perinatal Brachial Plexus Palsy
Authors
Sample
Alexander et al (2006)26
37,110 Cesarean deliveries USA NIH Maternal Fetal Medicine Units Network 89,978 Deliveries (vaginal and CD) at University of Mississippi Hospital; 1980-2002 University of Oxford, UK, 1991-2005 University Hospital, Detroit, Michigan, 1996-2001 537,316 singleton cephalic deliveries whose first and second babies were delivered vaginally 19672005 in Norway 26,722 normal birth weight births in Saudi Arabia Teaching Hospital 19902005 4126 nulliparous women who reached the second stage of labor in the USA NIH Maternal Fetal Medicine Units Network
Chauhan et al (2005)64
Mackenzie et al (2007)20 Mehta et al (2006)21 Overland et al (2009)65
Rahman et al (2009)19
Rouse et al (2009)25
Rate of Shoulder Dystocia
Rate of Perinatal Brachial Plexus Palsy
Rate of Permanent Motor Impairment
9/37,110 (0.2 per 1000 CD) 46/89,978 (0.5 per 1000 deliveries)
514/79,781 (6 per 1000 vaginal deliveries) 206/25,995 (8 per 1000 vaginal deliveries) 2344/537,316 (4 per 1000 first vaginal deliveries); 4466/537,316 (8 per 1000 vaginal deliveries)
44/514 (9% of cases of shoulder dystocia) 19/206 (9% of cases of shoulder dystocia)
104/26,722 (3.9 per 1000 vaginal deliveries)
21/104 (25% of cases of shoulder dystocia)
11/3819 (2.9 per 1000 pregnancies that reached the second stage of labor and were delivered vaginally); 0/307 pregnancies that reached the second stage of labor and were delivered by Cesarean
8/46 (17%)
3/21 (14%)
Outcomes of child after previous cesarean stretching and injury to the plexus. Estimates of the incidence of shoulder dystocia range between 4 and 8 per 1000 vaginal deliveries.19-22 The rate of perinatal brachial plexus injury in vaginal deliveries complicated by shoulder dystocia is 9% to 25%.19-22 The risk of permanent neurological impairment among neonates with perinatal brachial plexus injury has been estimated to be 9% to 17%,19,22,23 leading to an estimate of about 1 case of permanent upper-extremity impairment caused by perinatal brachial plexus injury per 10,000 vaginal deliveries. Prognosis for recovery of function after perinatal brachial plexus palsy depends on the severity at 3 weeks. When only cervical roots 5, 6, and 7 are involved, 65% of infants demonstrate complete recovery at 6 months, compared with only 14% for infants with involvement of cervical root 8 and thoracic root 1.24 Although brachial plexus injury after CD is rare,10 CD does not eliminate the risk of brachial plexus injury. In a study from the National Institutes of Health Maternal Fetal Medicine Network, of women who reached the second stage of labor at or beyond 36-week gestation, brachial plexus injury was observed in 11 (0.29%) of 3819 infants born vaginally and none of 307 infants born by CD.25 In another study of 37,110 CD deliveries in this network, the incidence of perinatal brachial plexus injury was 0.2 per 1000 infants born by CD, and 0.3 per 1000 among babies born by elective repeat CD.26
Respiratory Dysfunction in Births After Previous CD Method of Delivery and Perinatal Respiratory Dysfunction Infants delivered by elective CD have an increased risk of transient tachypnea of the newborn (odds ratios 2.4-2.8),27,28 persistent pulmonary hypertension (odds ratio 4.6 [1.9, 11]),27 respiratory morbidity (odds ratios 2.1 to 2.6),28-31 and respiratory distress syndrome (odds ratio 8.6).28 Most studies of the association of CD and neonatal respiratory dysfunction have not been restricted to infants born after a previous CD. In 1 study that was limited to women with a previous CD, infants delivered by elective CD were more likely to have a respiratory problem (odds ratio 2.3) and to develop transient tachypnea (odds ratio 2.6).31 In another such study, infants born after intended CD were more than twice as likely to receive oxygen during delivery room resuscitation (odds ratio 2.35) and in the neonatal intensive care unit (odds ratio 2.5).32 The mechanism(s) that underlie the associations between CD and respiratory dysfunction might include the both the failure of the normal preparation of the lung for extrauterine life33 as well as the leftward shift in gestational age at birth that might occur when pregnancy is truncated by elective CD.5 We are aware of no direct evidence relating the excess respiratory morbidity after CD to long-term sequelae. Longitudinal studies of neonates with respiratory morbidity have focused on the most severely ill, such as those with hypoxic
285 respiratory failure and persistent pulmonary hypertension. In 9 studies of inhaled nitric oxide for hypoxic respiratory failure, the mortality rate was 9% for infants randomized to inhaled nitric oxide. Neurodevelopmental impairment occurred in 28% of survivors (2 trials) and cerebral palsy in 10% of survivors.34 Greater rates of death (28%; meta-analysis of 4 trials) and neurodevelopmental impairment (20%; 1 trial) have been observed in neonates with persistent pulmonary hypertension who were randomized to extracorporeal membrane oxygenation.35 The frequency at which infants with CD-related respiratory morbidity have hypoxic respiratory failure and persistent pulmonary hypertension is not well characterized. In a study from the only center offering extracorporeal membrane oxygenation in western Missouri and the state of Kansas in the years 2000 through 2005, Truog et al36 described the severity of respiratory illness among 315 infants who were born at or beyond 36-week gestation, had hypoxic respiratory failure requiring mechanical ventilation for at least 24 hours, and had no major anomaly to which their respiratory dysfunction was attributable. In this sample of infants, 56% had an oxygenation index greater than 15% and 21% had an oxygenation index greater than 25; thus 21% to 56% of infants would have been eligible for most of the randomized trials of nitric oxide for infants at or near term gestation with hypoxic respiratory failure.34 These frequencies almost certainly overstate the frequency at which infants with CD-related respiratory morbidity have hypoxic respiratory failure, and the true frequency could be considerably lower.
Method of Delivery and Asthma Table 3 summarizes findings from 32 studies of the association between CD and childhood asthma. In a meta-analysis that included 21 of these studies the estimated odds ratio for asthma after CD was 1.2 (95% confidence limits 1.141.26).37 A second meta-analysis, determined on the basis of 20 of the studies listed in Table 3, yielded a summary odds ratios of 1.18 (95% confidence limits 1.05-1.32) for asthma and 1.23 (95% confidence limits 1.12-1.31) for hospitalization caused by asthma.38 Given the modest strength of association found in both meta-analyses, perhaps the observed CD⫺asthma association is explained entirely by unaccounted for confounders. Nonetheless, in 5 of the 6 studies published since the 2 existing meta-analyses, somewhat greater odds ratios were observed: 1.52 (1.42-1.62),39 1.2 (1.02-1.42),40 1.79 (1.27- 2.51),41 1.1 (0.75, 3.86),42 and 1.1 (0.6, 2.3).43 The largest of these studies included 1,756,700 singleton births that occurred between 1967 and 1998, followed up to 18 years or the year 2002, and adjustment was made for maternal age, maternal history of asthma, maternal education, child’s gender, and year of birth.39 In this study, delivery by emergency cesarean was associated with a 59% increased risk of asthma and delivery by planned CD with a 42% increased risk. The biological mechanism(s) that explains the putative association of CD and asthma is not known. One possibility is that neonatal respiratory dysfunction or treatment for respi-
286
Table 3 Studies of Cesarean Delivery and Asthma in the Child First Author Al-Kubaisy et al*66 Annesi-Maesano*67 Aspberg39
Number Delivered by CD/Vaginal
Year of Birth of Cohort
OR (95% Confidence Limits) for Asthma
Benn†69
504/3000 (17%)
1992-94
0.92 (0.64-1.34) 1.47 (1.02-2.1) 1.44 (1. 37-1.50); 1.08 (1.01-1.17) For instrumented vaginal vs noninstrumented OR CD vs spontaneous vaginal: 1.22 (0.87-1.73) current asthma; 1.33 (1.02-1.74) asthma ever; OR CD vs vaginal: 1.31 (1.01-1.71) asthma ever; 1.24 (0.85-1.79) for vacuum vs spontaneous vaginal 1.1 (0.6-1.9)
Bernsen*,† Calvani†70
85/1712 (5%) Cases: 97/322 (30%); controls: 160/450 (36%) Cases: 385/2028 (19%); controls: 1246/8299 (15%) 3525/24,633 (14%)
1988-90 NA
1.03 (0.51-2.08) 0.78 (0.57-1.06)
1987-94 1994-2002
Asthma hospitalization: 1.2 (1.04-1.39) overall; 1.15 (0.97-1.34) among term infants; 1.90 (1.09-3.02) among premature 1.3 (1.1-1.5)
88/788 (11%)
1997-2002
1.31 (0.80-2.13)‡
Hakansson*,†74
44,869/577,252 (8%)
1984-96
Juhn*,†75 Kero*,†76 Kurukulaaratchy*77
714/7106 (10%) 2050/59,865 (3%) 81/844 (10%)
1976-82 1987 1989
All CD vs spontaneous vaginal; 1.31 (1. 23-1.40); Emergency CD vs spontaenous vaginal: 1.26 (1.16-1.37); 1.38 (1.26-1.52) elective CD vs spontaneous vaginal; 1.10 (1.01-1.19) instrument vaginal vs spontaneous vaginal 0.93 (0.6-1.4) 1.21 (1.08-1.36) 1.82 (1.01-3.28)‡
Maitra*,†78 Mallen42 Mckeever*,†79 Metsala80
1387/12,367 (11%) 44/567 (9%) 4073/24,690 (16%) Cases: 2919/13,568 (22%); controls: 2241/13,470 (17%)
1991-92 1977-84 NA 1996-2004
Nafstad*,†81
279/2472 (11%)
1992-93
1.1 (0.9-1.4) 1.71 (0.75-3.02) 1.06 (0.99-1.14) 1.19 (1.06, 1.07, 1.31) Planned CD vs spontaneous Vaginal; 1.39 (1.27-1.58) emergency CD vs spontaneous Vaginal; 1.19 (1.06-1.34) assisted vaginal vs spontaneous vaginal 1.1 (0.7-1.8)
Negele*,†82
435/2500 (17%)
1997-99
1.41 (1.02-1.96)
Oliveti*,†83
Cases: 33/131 (25%); controls: 31/131 (24%) 102/433 (24%)
1983-89
1.09 (0.62-1.91)
1994-96
1.1 (0.6-2.3)
Debley*,†71 Gessner and Chimonas†72 Hagendorens*73
Pistiner43
1973-77
Discussion
Outcome of interest: asthma requiring hospitalization Women only; 20-28 years old
OR 1.3 (0.7-2.4) if adjusted for breastfeeding “Nonatopic asthma” Outcome of interest: asthma hospitalization Multivariate odds ratio not provided Outcome of interest: Parent report of wheezing
Outcome of interest: wheezing
Outcome of interest: asthma at 4 years Outcome of interest: recurrent wheezing
Subjects: children with parent history of atopy
T.M. O’Shea, M.A. Klebanoff, and C. Signore
2000-02 1958 1987-99
Bager*,†68
603/2110 (29%) 288/4065 (7%) 15,409 with asthma; 1,386,029 without 493/9722 (5%)
First Author
Number Delivered by CD/ Vaginal
Year of Birth of Cohort
Renz-Polser*,†55
1286/7872 (16%)
1990-92
Roduit41
247/2670
1996-97
Rusconi*84
4163/15,609 (27%)
1987-89
Salam*,†54 Smith*,†
717/3464 (21%) 25,369/173,139 (15%)
1975-87 1992-95
Tollanes39
1055/137,790 (8%)
1967-98
Vonk*,†85 Werner†86
39/434 (9%) 841/7119 (12%)
1975-78 1984-87
Xu (2001)*87 Xu (2000)*,†88
96/2951 (3%) NA
1966 NA
OR (95% Confidence Limits) for Asthma 1.24 (1.01-1.52); 1.08 (0.81-1.69) for boys; 1.23 (1.06-1.43) for girls; 1.17 (0.91-1.69) for CD without PROM vs others 1.79 (1.27-2.51); 2.91 (1.2-7.05) If 2 allergic parents; 1.86 (1.12-3.09) if 1; 1.36 (0.77-2.42) if 0 1.12 (0.93-1.36)
Discussion
Outcomes of child after previous cesarean
Table 3 Continued
Outcome of interest: persistent wheezing
1.33 (1.01-1.75) Rates of asthma were 2.2% (vaginal); 2.5% (all CD); 2.5% (emergency CD); 2.6% (elective CD) 1.52 (1.42-1.62); 1.14 (1.01-1.28) Instrument vaginal vs spontaneous vaginal; 1.42 (1.25-1.61) planned CD vs spontaneous vaginal; 1.59 (1.44-1.75) emergency CD vs spontaneous vaginal 1.77 (0.89-3.51)‡ 1.11 (0.88-1.39) CD vs vaginal; 1.20 (0.9-1.58) emergency CD vs vaginal; 0.98 (0.69-1.39) elective CD vs vaginal 3.23 (1.53-6.8) CD vs spontaneous vaginal: 1.38 (1.0-1.92); vacuum extraction vs spontaneous vaginal: 1.32 (0.8-2.19); other instrumental delivery: 2.14 (1.06-4.33)
Abbreviations: CD, cesarean delivery; NA, not applicable; OR, odds ratio. *Included in the meta-analysis by Thavagnanam et al.39 †Included in the meta-analysis by Bager et al.40 ‡Odds ratios not available in publication; these odds ratios are presented in the meta-analysis reported by Thavagnanam et al.37
287
T.M. O’Shea, M.A. Klebanoff, and C. Signore
288 ratory dysfunction (eg, supplemental oxygen) could predispose to asthma. In a study of 2137 newborns subsequently diagnosed with asthma and 2094 controls, those with transient tachypnea of the newborn had a 50% greater risk of asthma (odds ratio 1.5; 95% confidence limits 1.13-1.99).44 Another hypothesis is that method of delivery influences immune system ontogeny by either a direct effect of labor on immune regulatory cells45 or by reducing exposure to specific microbes which are acquired when infants swallow vaginal fluid containing microorganisms from the mother’s gastrointestinal tract.46 CD is associated with increased neonatal secretion of interleukin-13 (IL-13) and interferon-␥,45 and decreased secretion of interleukin-10 (IL-10) in cord blood mononuclear cells. IL-13 is a cytokine produced by Th2 cells and has been linked to bronchial hyperresponsiveness, goblet cell hyperplasia with excessive mucus production, and asthma.47 Further, polymorphisms in this gene are associated with susceptibility to asthma.48,49 IL-10 is antiinflammatory.50 A third possible explanation for the association of elective CD and asthma is a decreased rate of initiation, or duration, of breastfeeding.51-53 Table 4 summarizes 7 studies of this
association on the basis of recently born cohorts. In 6 of these studies, women who delivered by CD were less likely to initiate breastfeeding, with multivariate odds ratios ranging from 0.24 to 0.79. In the largest of these studies, women who experienced a spontaneous vaginal delivery were more likely to initiate breastfeeding, and this association was stronger when considering women delivered without labor (OR 0.64, 95% confidence limits 0.6-0.67).52 Table 5 summarizes 17 studies of the association of CD and allergic disorders other than asthma. Five of these studies reported statistically significant associations with either parent-reported food allergy or a composite of any allergic disorder or allergic sensitization.41,43,54-56 A meta-analysis that included 6 of these studies yielded an odds ratio of 1.32 (1.12-1.55) for food allergy/food atopy, and a meta-analysis of 7 of these studies yielded an odds ratio of 1.23 (1.12-1.35) for allergic rhinitis. Significant associations were not found from meta-analyses of eczema/atopic dermatitis (odds ratio: 1.03 from 6 studies) or inhalant atopy (odds ratio: 1.06 from 4 studies). In addition to possible effects on the risk of asthma or allergy, altered, or delayed, colonization of the gut with com-
Table 4 Studies of CD and Subsequent Breastfeeding
Authors
Sample
CD Rate, %
Breastfeeding Rate, %
OR
Chien, et al (2007)53
2064 Births in Taiwan 2003
33.9
65
1.19
Chung et al (2008)89
865 Birth in South Korea 2003
39.8
81.3
0.51
Kohlhuber et al (2008)90
3822 birth in Bavaria, Germany 2005
27
Leung et al (2002)51
7825 births in Hong Kong 1997
27.1
Liston et al (2008)52
142, 929 Births in Nova Scotia 1988-2002
19
Perez-Rios et al (2008)91 Theofilogiannakou et al (2006)92
1695 Births in Puerto Rico 1990-96 312 Births in Athens, Greece 2003-04
36
90% Initiated; 70% at 2 mo; 61% at 4 mo; 52% at 6 mo
0.59
34
0.66
Spontaneous vaginal, 59.1 assisted vaginal, 60.1 CD in labor, 59.5 CD without labor, 54.5 61.5
38%
Abbreviations: CD, cesarean delivery; OR, odds ratio; NA, not available.
57
1 NA 0.79 0.64
Confounding Factors for Which Adjustment Made Maternal age, education, and work status, spousal support for breastfeeding Maternal education, maternal employment status, prematurity, amount of prenatal care Maternal age, maternal education, maternal smoking, number of siblings, partner’s and maternal and paternal grandmothers’ attitudes towards breastfeeding, preterm birth Gestational age, birth weight, maternal and paternal smoking, mother’s age, maternal and paternal education, paternal employment status, birth order of infant, gender Year of delivery, maternal age, parity, smoking, maternal weight at delivery, hypertensive disease, diabetes, previous CD, regional anesthesia, induction of labor, gestational age, large and small for gestational age
0.64 0.24
Season of birth, socioeconomic level, mother’s and father’s age, mother’s and father’s educational level, mother’s body mass index, smoking habits, miscarriage, in vitro fertilization
Outcomes of child after previous cesarean
289
Table 5 Studies of Cesarean Delivery and Allergy in the Child
First Author Bager*68 Bernsen*93 Eggesbo*56
Number Delivered by CD/Vaginal 493/9722 (5%) 85/1712 (5%) 328/2803 (12%)
Hagendorens*73 Kero*76 Maitra*78 Mallen42
88/788 (11%) 42/131 (32%) 1387/12,367 (11%) 44/567 (9%)
McKeever*79
4073/24,690 (16%)
Montgomery*94 Nafstad*81 Negele*82
Year of Birth of Cohort 1973-77 1988-90 1992-93
1.16 (0.9, 1.49) 1.12 (0.56, 2.24) 3.2 (1.4, 7.3); 9.3 (3.1, 28) If mother herself had allergy 1997-2002 OR <1 (not statistically significant) 1990 1.31 (0.65, 2.65) 1991-92 1.18 (0.9, 1.5) 1977-84 1.49 (0.78, 2.84) NA
169/5519 (3%) 279/2472 (11%) 435/2500 (17%)
1970 1992-93 1997-99
102/433 (24%)
1994-96
1286/7872 (16%)
1990-92
Roduit41
247/2917 (8%)
1996-97
Salam*54
717/3464 (21%)
1975-87
29/213 (14%)
2002-03
Pistiner43 Renz-Polser*55
Sugiyama*95 Xu*87
96/2951 (3%)
OR for Allergy
1966
Hay fever: 1.01 (0.85, 1.21); eczema: 1.04 (0.98, 1.10) 1.21 (0.84, 1.74) 1.2 (0.7, 2.1) Atopic dermatitis: 1.21 (0.92, 1.59); allergic rhinoconjunctivitis: 1.4 (0.8, 2.44); physiciandiagnosed atopic dermatitis: 1.04 (0.79, 1.39) 2.1 (1.1, 3.9) Any allergic disorder: 1.23 (1.06, 1.80); 1.41 (1.1, 1.8) for CD without PROM vs others Sensitization to any allergen: 2.14 (1.16, 3.98) 1.26 (1.03, 1.53) Any allergy
Notes on Study Participants or Outcomes of Interest Allergic rhinitis Any atopic disorder Parent reported reaction to egg, fish, or nuts Atopic dermatitis Skin prick tests Atopy at 7 years ⴝ 3 mm Atopy refers to Number of allergic conditions Hay fever and eczema Hay fever Allergic rhinitis Atopic dermatitis, rhinoconjunctivitis, and physician-diagnosed atopic dermatitis Children with parent history of atopy Any allergic disorder
Risk of sensitization to any allergen at 8 years Any allergy ⴝ food or drug, inhalant, dermal allergy
Atopic dermatitis: 0.77 (0.22, 2.74); eczema: 1.88 (0.64, 5.52) Atopy: 0.96 (0.59, 1.56); hay fever: 1.28 (0.73, 2.24); atopic eczema: 1.19 (0.62, 2.28)
*Included in the meta-analysis by Bager et al.38
mensal flora might also increase the risk of type 1 diabetes. In a meta-analysis of 20 studies, including 9938 cases, the odds ratio for the association of CD and type 1 diabetes was 1.19 (1.04-1.36), adjusted for gestational age, birth weight, maternal age, birth order, breastfeeding, and maternal diabetes.57 Despite some evidence that breastfeeding initiation is less likely after CD, it is not clear that a lower frequency of breastfeeding among women who deliver by CD increases the risk of asthma. In largest randomized trial of an intervention to promote breastfeeding, no effect was found on either asthma risk or the risk of allergic symptoms.58,59 Nonetheless, if CD does decrease the rate of breastfeeding initiation, multiple long-term outcomes might be altered. The authors of meta-analyses suggest that breastfeeding is associated with a lower risk of gastrointestinal infections, a lower risk of overweight, and greater intelligence. In the aforementioned randomized trial to increase breastfeeding, the intervention resulted in a decreased risk of gastrointestinal tract infection and atopic eczema in the first year of life,58 and increased intelligence at 6.5 years.60 However, no bene-
ficial effects were found on anthropometrics or blood pressure.59,61,62
Conclusions Estimates of risk differences between neonatal outcomes after a trial of labor versus a planned CD are presented in Table 6. On the basis of an estimated risk difference for symptomatic uterine rupture of 2.79-5.98 per 1000 trials of labor (vs repeat CD), and a mortality risk of 8% among infants born after symptomatic uterine rupture,9 the risk difference in mortality caused by symptomatic uterine rupture would be 2-4.7 per 10,000 trials of labor. On the basis of an estimated risk difference for HIE of 8 per 10,000 trials of labor,8 a 28% mortality rate for infants with HIE,17 and a 30% risk of major disability among survivors of HIE,17 the risk difference for mortality would be 2.2 per 10,000 trials of labor, and the risk difference for major disability would be 1.7 per 10,000 trials of labor. Assuming that 90% of cases of perinatal brachial plexus injuries occur among infants delivered vaginally, then
T.M. O’Shea, M.A. Klebanoff, and C. Signore
290 Table 6 Risk differences for Child Outcomes Comparing a Trial of Labor and Planned Cesarean Delivery
Outcome Death caused by uterine rupture* Neurodevelopmental impairment after uterine rupture and HIE† Upper extremity neuromotor impairment after brachial plexus palsy‡ Neurodevelopmental impairment after hypoxic respiratory failure§ Death due to hypoxic respiratory failure§ Asthma¶
Estimated Risk Difference per 10,000 Deliveries 2 to 4.7 1.7 1.1 to 2.3
2.8 to ⴚ6.3 ⴙ0.9 to ⴚ2 ⴚ200
Positive numbers indicate higher rate of occurrence following a trial of labor, whereas negative numbers indicate a higher rate of occurrence with planned cesarean delivery. *On the basis of data from Guise et al9 and Spong et al8 (see text). †On the basis of risk difference for HIE from Spong et al8 and meta-analysis of outcomes after HIE by Jacobs et al.17 ‡On the basis of multiplying incidence of shoulder dystocia in vaginal births19-22 times risk of perinatal brachial plexus injury associated with shoulder dystocia19-22 times risk of permanent neurological impairment among infants with perinatal brachial plexus injury.19,22,23 §Assumes risk difference for hypoxic respiratory failure (aspiration pneumonitis or respiratory distress syndrome) of ⴙ9 to ⴚ20 per 100027,31,32 that 10% of those with hypoxic respiratory failure are severe enough to require nitric oxide,36 and rates of death and impairment similar to those observed among participants in randomized trials of nitric oxide.34 ¶Assumes a relative riskCD:vaginal of 1.2 and a prevalence of asthma of 10%.63
based on the incidence of shoulder dystocia among infants delivered vaginally,19-21 the risk of perinatal brachial plexus injury with shoulder dystocia,19-21 and the risk of permanent impairment after perinatal brachial plexus injury,19,22,23 the risk difference for permanent brachial plexus injury is about 0.2-2.7 per 10,000 trials of labor. The frequency at which infants with CD-related respiratory morbidity have hypoxic respiratory failure and persistent pulmonary hypertension is not well characterized, but based on an assumption that 5% to 10% of infants with hypoxic respiratory failure require treatment with nitric oxide (on the basis of the assumption that the estimate from the study by Truog et al [21%-56%]36 could be 5-10 times the true frequency), the estimated risk difference for hypoxic respiratory failure (aspiration pneumonitis or respiratory distress syndrome) of 4.8 per 1000,52 and the rates of mortality and impairment among participants in trials of nitric oxide, an estimated risk difference for mortality is 0.2 to 0.4 per 10,000 repeat CD, and an estimated risk difference for neurodevelopmental impairment caused by hypoxic respiratory failure is 0.6 to 0.12 per 10,000 repeated CD. Finally, the relative risk of asthma among infants delivered by CD versus
those delivered vaginally,37,38 combined with an estimated prevalence of asthma of 10%,(65) leads to an estimated risk difference for asthma of 200 per 10,000 repeat CD. Thus, estimated risk differences for all the outcomes except death attributable to uterine rupture and asthma are small. The estimated risk difference for mortality attributable to uterine rupture (2-4.7 neonatal deaths per 10,000 trials of labor) implies that at least several thousand elective CD must be performed to prevent 1 death associated with a trial of labor. However, this presumed benefit might be offset by an increase rate of death or neurodevelopmental impairment associated with hypoxic respiratory failure. For example, if an estimate that is only one half of that reported by Truog et al36 is assumed for the rate of hypoxic respiratory failure among infants with aspiration pneumonitis or respiratory distress syndrome, the estimated risk difference for the composite outcome of death or neurodevelopmental impairment caused by hypoxic respiratory failure after CD could be as high as 4.5. This result is very similar to the estimated risk difference for that composite outcome caused by uterine rupture during an trial of labor. Further, our estimate is that an additional 200 cases of asthma might result from each 10,000 elective CDs performed. Additional observational studies are needed to provide more precise estimates of the risk differences that are pertinent to the decision of whether to attempt a trial of labor after previous CD. Awaiting these data, there is no clear advantage to either a trial of labor or a planned CD. Randomized trials comparing these 2 approaches would provide the most valid basis for obstetrical care.
References 1. Harer WB: Vaginal birth after Cesarean delivery—Current status. JAMA 287:2627-2630, 2002 2. Dodd JM, Crowther CA: Elective repeat Caesarean section versus induction of labour for women with a previous Caesarean birth. Cochrane Database Syst Rev Oct 18;(4):CD004906, 2006 3. Dodd JM, Crowther CA, Hiller JE, et al: Birth after Caesarean study— Planned vaginal birth or planned elective repeat Caesarean for women at term with a single previous Caesarean birth: Protocol for a patient preference study and randomised trial. BMC Pregnancy Childbirth, 2007. Available at: http://www.biomedcentral.com/1471-2393/7/17. Accessed April 8, 2010 4. Signore C, Klebanoff M: Neonatal morbidity and mortality after elective Cesarean delivery. Clin Perinatol 35:361, 2008 5. Tita ATN, Landon MB, Spong CY, et al: Timing of elective repeat Cesarean delivery at term and neonatal outcomes. N Engl J Med 360: 111U29, 2009 6. Landon MB, Hauth JC, Leveno KJ, et al: Maternal and perinatal outcomes associated with a trial of labor after prior Cesarean delivery. N Engl J Med 351:2581-2589, 2004 7. Chauhan SP, Martin JN, Henrichs CE, et al: Maternal and perinatal complications with uterine rupture in 142,075 patients who attempted vaginal birth after Cesarean delivery: A review of the literature. Am J Obstet Gynecol 189:408-417, 2003 8. Spong CY, Landon MB, Gilbert S, et al: Risk of uterine rupture and adverse perinatal outcome at term after Cesarean delivery. Obstet Gynecol 110:801-807, 2007 9. Guise JM, McDonagh MS, Osterweil P, et al: Systematic review of the incidence and consequences of uterine rupture in women with previous Caesarian section. BMJ 329:19-23, 2004 10. Doumouchtsis SK, Arullkumaran S: Are all brachial plexus injuries caused by shoulder dystocia? Obstet Gynecol Surv 64:615-623, 2009
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291 36. Truog WE, Kurth G, Haney B, et al: Hypoxic respiratory failure: Etiology and outcomes at one referral center 2000 through 2005. J Perinatol 27:371-374, 2007 37. Thavagnanam S, Fleming J, Bromley A, et al: A meta-analysis of the association between Caesarian section and childhood asthma. Clin Exp Allergy 38:629-633, 2008 38. Bager P, Wohlfahrt J, Westergaard T: Caesarean delivery and risk of atopy and allergic disesase: Meta-analyses. Clin Exp Allergy 38:634642, 2008 39. Tollanes MC, Moster D, Daltveit AK, et al: Cesarian section and risk of severe childhood asthma: A population-based cohort study. J Pediatr 153:112-116, 2008 40. Aspberg S, Dahlquist G, Kahan T, et al: Is neonatal phototherapy associated with an increased risk for hospitalized childhood bronchial asthma? Pediatr Allergy Immunol 18:313-319, 2007 41. Roduit C, Scholtens S, de Jongste JC, et al: Asthma at 8 years of age in children born by caesarean section. Thorax 64:107-113, 2009 42. Mallen CD, Mottram S, Wynne-Jones G, et al: Birth-related exposures and asthma and allergy in adulthood: A population-based cross-sectional study of young adults in North Staffordshire. J Asthma 45:309312, 2008 43. Pistiner M, Gold DR, Abdulkerim H, et al: Birth by Cesarian section, allergic rhinitis, and allergic sensitization among children with a parental history of atopy. J Allergy Clin Immunol 122:274-279, 2008 44. Birnkrant DJ, Picone C, Markowitz W, et al: Association of transient tachypnea of the newborn and childhood asthma. Pediatr Pulmonol 41:978-984, 2006 45. Ly NP, Ruiz-Perez B, Onderdonk AB, et al: Mode of delivery and cord blood cytokines: A birth cohort study. Clin Mol Allergy 4:13, 2006 46. Gronlund MM, Lehtonen OP, Eerola E, et al: Fecal microflora in healthy infants born by different methods of delivery: Permanent changes in intestinal flora after Cesarean delivery. J Pediatr Gastroenterol Nutr 28:19-25, 1999 47. Zhang J, Paré PD, Sandford AJ: Recent advances in asthma genetics. Respir Res 9:4, 2008 48. Sadeghnejad A, Karmaus W, Arshad SH, et al: IL13 gene polymorphisms modify the effect of exposure to tobacco smoke on persistent wheeze and asthma in childhood, a longitudinal study. Respir Res 9:2, 2008 49. Beghé B, Hall IP, Parker SG, et al: Polymorphisms in IL13 pathway genes in asthma and chronic obstructive pulmonary disease. Allergy 65:474-481, 2010 50. Urry Z, Xystrakis E, Hawrylowicz CM: Interleukin-10-secreting regulatory T cells in allergy and asthma. Curr Allergy Asthma Rep 6:363371, 2006 51. Leung GM, Lam TH, Ho LM: Breast-feeding and its relation to smoking and mode of delivery. Obstet Gynecol 99:785-794, 2002 52. Liston FA, Allen VM, O’Connell CM, et al: Neonatal outcomes with Caesarean delivery at term. Arch Dis Child Fetal Neonatal Ed 93:F176F182, 2008 53. Chien LY, Tai CJ: Effect of delivery method and timing of breastfeeding initiation on breastfeeding outcomes in Taiwan. Birth Issues Perinat Care 34:123-130, 2007 54. Salam MT, Margolis HG, McConnell R, et al: Mode of delivery is associated with asthma and allergy occurrences in children. Ann Epidemiol 16:341-346, 2006 55. Renz-Polster H, David MR, Buist AS, et al: Caesarian section delivery and the risk of allergic disorders in childhood. Clin Exp Allergy 35: 1466-1472, 2005 56. Eggesbo M, Botten G, Stigum H, et al: Is delivery by Cesarian section a risk factor for food allergy? J Allergy Clin Immunol 112:420-426, 2003 57. Cardwell CR, Stene LC, Joner G, et al: Caesarian section is associated with an increased risk of childhood-onset type 1 diabetes mellitus: A meta-analysis of observational studies. Diabetologia 51:726-735, 2008 58. Kramer MS, Chalmers B, Hodnett ED, et al: Promotion of breastfeeding intervention trial (PROBIT)—A randomized trial in the Republic of Belarus. JAMA 285:413-420, 2001
292 59. Kramer MS, Matush L, Vanilovich I, et al: Effects of prolonged and exclusive breastfeeding on child height, weight, adiposity, and blood pressure at age 6.5 y: Evidence from a large randomized trial. Am J Clin Nutr 86:1717-1721, 2007 60. Kramer MS, Aboud F, Mironova E, et al: Breastfeeding and child cognitive development—New evidence from a large randomized trial. Arch Gen Psychiatry 65:578-584, 2008 61. Kramer MS, Matush L, Bogdanovich N, et al: Health and development outcomes in 6.5-y-old children breastfed exclusively for 3 or 6 mo. Am J Clin Nutr 90:1070-1074, 2009 62. Kramer MS, Matush L, Vanilovich I, et al: A randomized breast-feeding promotion intervention did not reduce child obesity in Belarus. J Nutr 139:417S-421S, 2009 63. Pearce N, Ait-Khaled N, Beasley R, et al: Worldwide trends in the prevalence of asthma symptoms: Phase III of the International study of asthma and allergies in childhood (Isaac). Thorax 62:758-766, 2007 64. Chauhan SP, Rose CH, Gherman RB, et al: Brachial plexus injury: A 23-year experience from a tertiary center. Am J Obstet Gynecol 192: 1795-1800, 2005 65. Overland EA, Spydslaug A, Nielsen CS, et al: Risk of shoulder dystocia in second delivery: Does a history of shoulder dystocia matter? Am J Obstet Gynecol 506:e1-e6, 2009 66. Al Kubaisy W, Ali SH, Al Thamiri D: Risk factors for asthma among primary schoolchildren in Baghdad, Iraq. Saudi Med J 26:460-466, 2005 67. Annesi-Maesano I, Moreau D, Strachan D: In utero and perinatal complications preceding asthma. Allergy 56:491-497, 2001 68. Bager P, Melbye M, Rostgaard K, et al: Mode of delivery and risk of allergic rhinitis and asthma. J Allergy Clin Immunol 111:51-56, 2003 69. Benn CS, Thorsen P, Jensen JS, et al: Maternal vaginal microflora during pregnancy and the risk of asthma hospitalization and use of antiasthma medication in early childhood. J Allergy Clin Immunol 110:72-77, 2002 70. Calvani M, Alessandri C, Sopo SM, et al: Infectious and uterus related complications during pregnancy and development of atopic and nonatopic asthma in children. Allergy 59:99-106, 2004 71. Debley JS, Smith JM, Redding GJ, et al: Childhood asthma hospitalization risk after Cesarean delivery in former term and premature infants. Ann Allergy Asthma Immunol 94:228-233, 2005 72. Gessner BD, Chimonas MAR: Asthma is associated with preterm birth but not with small for gestational age status among a population-based cohort of Medicaid-enrolled children ⬍ 10 years of age. Thorax 62: 231-236, 2007 73. Hagendorens MM, Bridts CH, Lauwers K, et al: Perinatal risk factors for sensitization, atopic dermatitis and wheezing during the first year of life (PIPO study). Clin Exp Allergy 35:733-740, 2005 74. Hakansson S, Kallen K: Caesarian section increases the risk of hospital care in childhood for asthma and gastroenteritis. Clin Exp Allergy 33: 757-764, 2003 75. Juhn YJ, Weaver A, Katusic S, et al: Mode of delivery at birth and development of asthma: A population-based cohort study. J Allergy Clin Immunol 116:510-516, 2005 76. Kero J, Gissler M, Gronlund MM, et al: Mode of delivery and asthma—Is there a connection? Pediatr Res 52:6-11, 2002
T.M. O’Shea, M.A. Klebanoff, and C. Signore 77. Kurukulaaratchy RJ, Waterhouse L, Matthews SM, et al: Are influences during pregnancy associated with wheezing phenotypes during the first decade of life? Acta Paediatr 94:553-558, 2005 78. Maitra A, Sherriff A, Strachan D, et al: Mode of delivery is not associated with asthma or atopy in childhood. Clin Exp Allergy 34:1349-1355, 2004 79. Mckeever TM, Lewis SA, Smith C, et al: Mode of delivery and risk of developing allergic disease. J Allergy Clin Immunol 109:800-802, 2002 80. Metsala J, Kilkkinen A, Kaila M, et al: Perinatal factors and the risk of asthma in childhood—A population-based register study in Finland. Am J Epidemiol 168:170-178, 2008 81. Nafstad P, Magnus P, Jaakkola JJK: Risk of childhood asthma and allergic rhinitis in relation to pregnancy complications. J Allergy Clin Immunol 106:867-873, 2000 82. Negele K, Heinrich J, Borte M, et al: Mode of delivery and development of atopic disease during the first 2 years of life. Pediatr Allergy Immunol 15:48-54, 2004 83. Oliveti JF, Kercsmar CM, Redline S: Pre- and perinatal risk factors for asthma in inner city African-American children. Am J Epidemiol 143: 570-577, 1996 84. Rusconi F, Galassi C, Forastiere F, et al: Maternal complications and procedures in pregnancy and at birth and wheezing phenotypes in children. Am J Respir Crit Care Med 175:16-21, 2007 85. Vonk JM, Boezen HM, Postma DS, et al: Perinatal risk factors for bronchial hyperresponsiveness and atopy after a follow-up of 20 years. J Allergy Clin Immunol 114:270-276, 2004 86. Werner A, Ramlau-Hansen CH, Jeppesen SK, et al: Caesarean delivery and risk of developing asthma in the offspring. Acta Paediatr 96:595596, 2007 87. Xu B, Pekkanen J, Hartikainen AL, et al: Caesarian section and risk of asthma and allergy in adulthood. J Allergy Clin Immunol 107:732-733, 2001 88. Xu B, Pekkanen J, Jarvelin MR: Obstetric complications and asthma in childhood. J Asthma 37:589-594, 2000 89. Chung W, Kim H, Nam CM: Breast-feeding in South Korea: Factors influencing its initiation and duration. Public Health Nutr 11:225-229, 2008 90. Kohlhuber M, Rebhan B, Schwegler U, et al: Breastfeeding rates and duration in Germany: A Bavarian cohort study. Br J Nutr 99:11271132, 2008 91. Perez-Rios N, Ramos-Valencia G, Ortiz AP: Cesarean delivery as a barrier for breastfeeding initiation: The Puerto Rican experience. J Hum Lact 24:293-302, 2008 92. Theofilogiannakou M, Skouroliakou M, Gounaris A, et al: Breast-feeding in Athens, Greece: Factors associated with its initiation and duration. J Pediatr Gastroenterol Nutr 43:379-384, 2006 93. Bernsen RMD, de Jongste JC, Koes BW, et al: Perinatal characteristics and obstetric complications as risk factors for asthma, allergy and eczema at the age of 6 years. Clin Exp Allergy 35:1135-1140, 2005 94. Montgomery SM, Wakefield AJ, Morris DL, et al: The initial care of newborn infants and subsequent hay fever. Allergy 55:916-922, 2000 95. Sugiyama M, Arakawa H, Ozawa K, et al: Early-life risk factors for occurrence of atopic dermatitis during the first year. Pediatrics 119: E716-E723, 2007
M
ost attempts to deliver vaginally after a previous cesarean delivery (CD) are successful. Nonetheless, in the past decade, an increasing proportion of women chose not to attempt vaginal birth after cesarean (VBAC); among their concerns was that harm would come to the fetus from complications of VBAC.1 Randomized comparisons of planned VBAC versus planned CD would provide the most valid conclusions about the effects of these modes of delivery on maternal and child outcomes. We are aware of no completed trials of mode of delivery after previous cesarean,2 although at least 1 such trial is underway.3 Information pertinent to the risks and benefits
*Department of Pediatrics (Neonatology), Wake Forest University, Health Sciences, Winston-Salem, NC. †Eunice Kennedy Shriver National Institute of Human Development, National Institutes of Health, Department of Health and Human Services, Bethesda, MD. Source of financial support: Dr Klebanoff was supported by Intramural Funds from the NIH, NICHD. Address reprint requests to T. Michael O’Shea, MD, MPH, Department of Pediatrics, Wake Forest University, Health Sciences, Medical Center Blvd, Winston-Salem, NC 27157. E-mail: [email protected]
0146-0005/10/$-see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1053/j.semperi.2010.03.008
of VBAC versus planned repeat CD includes observational studies of elective CD,4,5 particularly those studies that include women with a previous cesarean birth.3,6-9 Extant studies, in addition to being nonrandomized, provide data only about short-term outcomes for the child (eg, low Apgar score, neonatal encephalopathy, brachial plexus injury, and respiratory dysfunction) and the maternal-child dyad (eg, initiation of breastfeeding). We will review these studies and discuss how short-term outcomes might relate to health and development in later childhood. The absence of data from randomized trials presents a serious methodological problem when estimating the relative risks for VBAC versus elective repeat CD. Absent such data, the least-biased estimates would derive from observational studies of cohorts of women who have previously undergone CD and have, at study inception, planned to have either a VBAC or repeat CD, on the basis of factors that do not influence the likelihood of successful VBAC or any of the outcomes associated with VBAC. An “inception cohort,” as just described, would allow the researcher to observe the rate at which the cohort members who plan to have a CD actually go into labor before the date of their elective scheduled CD, and 281
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282
Figure 1 Causal pathways that might link delivery plan after prior cesarean delivery with long-term health outcomes in the child. CD, cesarean delivery; TOL, trial of labor.
the rate at which such women deliver vaginally, as opposed to having an “emergency” CD. Such a study would also provide an estimate of the frequency at which women who plan to deliver by VBAC (ie, those choosing a trial of labor) develop an indication (maternal or fetal) for nonelective CD. Finally, it would enable estimation of the frequency with which women change their mind regarding their intended mode of delivery as pregnancy progresses. All of these complexities are lost when one compares women on the basis of only what happened at the very end of pregnancy because the mode of delivery, even for women who deliver vaginally, is not always the planned mode of delivery. Given the 2 serious limitations of available information, conclusions about how mode of delivery after previous CD affects long-term child outcomes can only be determined on the basis of evidence that is too weak to be definitive. Therefore, we will avoid drawing conclusions about the relative benefits and risk of VBAC. However we will suggest areas of focus to be considered in future research.
Mechanisms Linking Mode of Delivery and Long-Term Health in the Child Pathways by which mode of delivery might affect health and development in the offspring are illustrated in Figure 1 and summarized in Table 1. The 2 most important complications of a trial of labor after previous CD are uterine rupture6 and brachial plexus injury,10 the risks of which are greater among neonates delivered vaginally compared with those delivered by cesarean. Uterine rupture can result in hypoxic-ischemic injury to the fetal heart, gastrointestinal tract, kidneys, and brain. Hypoxic-ischemic injury to the fetal heart, manifesting as papillary muscle dysfunction and tricuspid regurgitation in the neonate, typically resolves in a few days and almost never leads to chronic cardiac dysfunction. Hypoxic-ischemic injury to the kidney most often manifests as acute tubular ne-
Table 1 Mechanisms by Which Mode of Delivery Might Influence Health and Development in the Offspring Obstetrical Event
Mechanism
Uterine rupture during trial of labor Shoulder dystocia during vaginal delivery Cesarean delivery
Perinatal asphyxia causing brain damage Nerve injury
Neonatal encephalopathy
Neonatal Manifestation
Retained fetal lung fluid; surfactant deficiency
Cesarean delivery
Altered gut flora
Cesarean delivery
Lower rate of initiation of breastfeeding
Respiratory distress; hypoxic respiratory failure in severe cases Altered immune function maturation Altered immune function maturation
Upper extremity palsy
Childhood Outcome Neurodevelopmental impairments, such as cerebral palsy Upper extremity motor impairment Neurodevelopmental impairments after extracorporeal membrane oxygenation; asthma Asthma Asthma
Outcomes of child after previous cesarean crosis and typically resolves during the neonatal period. Much less frequently, hypoxic-ischemic renal damage manifests as cortical necrosis, which can lead to persisting renal insufficiency. Intestinal hypoxic-ischemic injury typically resolves in several days, but in a small proportion of cases leads to necrotizing enterocolitis, which is associated with a high mortality rate.11 Neonatal hypoxic-ischemic encephalopathy (HIE) refers to the acute manifestation of hypoxic-ischemic brain injury. Permanent dysfunction is not unusual after moderate or severe neonatal HIE. The most consistently observed dysfunction after neonatal encephalopathy is cerebral palsy, a persisting abnormality of movement and posture, with impaired motor function.12 Brachial plexus palsy is strongly associated with shoulder dystocia and is rarely observed in neonates delivered by cesarean.10,13 Estimates of the incidence of brachial plexus palsy after shoulder dystocia range from 4% to 40%,10 and permanent upper extremity neurological impairment occurs in about 25% of cases of brachial plexus palsy.13 The mechanisms linking elective CD to long-term outcomes are not as well understood as those linking these outcomes to complications of VBAC. However, CD is associated with an increased risk of neonatal respiratory dysfunction, altered bacterial colonization of the gut, and lower rates of breastfeeding, which could explain the observation that asthma is more prevalent among children delivered by cesarean. We will discuss in more detail each of these mechanisms that might link mode of delivery and long-term outcomes in the child.
Brain Damage and Birth After a Previous CD Perinatal brain damage after a previous CD is related primarily to uterine rupture, which can lead to HIE. In 2004, Guise et al9 reported a systematic review of the incidence and consequences of uterine rupture in women with a previous CD. The estimated rate of symptomatic uterine rupture (uterine separation diagnosed at laparotomy performed for maternal or fetal signs or symptoms), on the basis of pooled data from 10 observational studies, was 3.8 (95% confidence interval 1.3-6.2) per 1000 trials of labor. Guise et al estimated, on the basis of 1 retrospective and 1 prospective study (including 3411 women with a trial of labor and 3444 with elective repeat CD), that the incremental risk associated with a trial of labor versus elective repeat CD is 2.7 (0.7 to 4.73) symptomatic ruptures per 1000 trials of labor and that there is no incremental risk for asymptomatic uterine rupture. The National Institutes of Health Maternal Fetal Medicine Units (MFMU) Network reported the incidence of uterine rupture among 17,898 women who attempted a vaginal delivery and 15,801 women who underwent elective repeat CD without a trial of labor.6 This study excluded women who presented in early labor and subsequently underwent CD and women who underwent indicated repeat CD. Symptomatic uterine rupture occurred in 124 trials of labor (7 per 1000), almost twice the rate reported in the meta-analysis by Guise
283 et al. In a subsequent analysis from the MFMU Network, 5 groups were studied: women delivering (vaginally or by CD) after a trial of labor, elective repeat CD with no labor, elective repeat CD with labor, indicated repeat CD with no labor, and indicated repeat CD with labor. Rates of uterine rupture, in descending order were trial of labor (7.4 per 1000), indicated repeat CD with labor (2.8 per 1000), elective repeat CD with labor (1.5 per 1000), indicated repeat CD without labor (0.8 per 1000), and elective repeat CD without labor (none). On the basis of these studies just reviewed, the risk difference for uterine rupture when comparing a trial of labor and elective CD is probably in the range of 2.79 to 5.98 per 1000 deliveries. Symptomatic uterine rupture, with resultant fetal hypoxiaischemia, can lead to fetal or neonatal death or HIE. In the meta-analysis by Guise et al, among the total of 74 symptomatic uterine ruptures, there were 6 fetal/neonatal deaths, corresponding to an additional 1.4 (0 to 9.8) additional deaths per 10,000 trials of labor. However, in the MFMU Network study, a trial of labor was not associated with higher mortality rate. Neonatal mortality rates, in descending order, were 2 per 1000 for indicated repeat CD without labor, 1.1 per 1000 for elective repeat CD with labor, 0.9 per 1000 for indicated repeat CD with labor, 0.8 per 1000 for trial of labor, and 0.4 per 1000 for elective repeat CD without labor. A trial of labor appears to be associated with a greater rate of HIE. In the MFMU Network studies, HIE was observed only among those delivered after a trial of labor (0.08% of neonates) and indicated repeat CD without labor (0.06%).8 Of the 12 infants with HIE delivered after a trial of labor, 7 occurred after symptomatic uterine rupture (7/114 or 6.1% of trials of labor with uterine rupture), and 5 occurred in women without uterine rupture (5/15209 or 0.03% of trials of labor without uterine rupture). Thus, hypoxic-ischemic injury to the fetal brain occurs more frequently with labor and vaginal delivery than with elective CD, even when labor is not complicated by uterine rupture. Rates reported by Spong et al8 of HIE among neonates delivered by elective repeat CD versus a trial of labor (excluding those born after indicated repeat CD) suggest that for every 10,000 elective repeat CD performed after a previous cesarean, 8 cases of HIE would be prevented. This presumed benefit should be considered in light of the long-term consequences of HIE, which are not described in either the metaanalysis by Guise et al or the MFMU Network studies. In the population-based Western Australian study of 276 newborns born at term with moderate or severe neonatal encephalopathy, 25 (9.1%) died and 32 (12.7% of survivors) developed cerebral palsy.14 The rate of cerebral palsy was 8% among infants with moderate encephalopathy and 23% among those with severe encephalopathy. Of those with cerebral palsy, 47% had severe cerebral palsy, 75% had an intelligence quotient ⬍ 70%, and 53% had epilepsy. This prognostic information applies to neonates with encephalopathy, some of which is not attributable to HIE. For example, in 1 population-based study of neonatal encephalopathy, only 29% of affected infants experienced events thought to
T.M. O’Shea, M.A. Klebanoff, and C. Signore
284 indicate birth asphyxia,15 and 10% of cases were attributed to birth defects.16 Probably more pertinent to the outcome of neonates with HIE after uterine rupture are estimates of rates of mortality and morbidity among neonates with HIE who participated in trials of therapeutic hypothermia versus standard care.17 For infants diagnosed with moderate or severe HIE who were randomized to hypothermia, the mortality rates in 3 trials have been 16% for those with moderate HIE (n ⫽ 141) and 51% for those with severe HIE (n ⫽ 75). Rates of major disability among survivors have been 26% for moderate HIE (n ⫽ 118) and 41% for severe HIE (n ⫽ 37). Among infants with either moderate or severe HIE, the rate of cerebral palsy has been 30%, several-fold greater than the rate reported from the population-based study by Badawi et al,14 suggesting that the prognosis is worse for HIE than for other causes of neonatal encephalopathy. The prevalence of HIE reported from the MFMU Network (0.8 per 1000 trials of labor) is less than one-quarter of that described in population-based studies, suggesting that cases identified in the latter studies might be less severely affected than those identified in the former. (For instance, popula-
tion-based studies might have used less stringent criteria to identify cases.) The prevalence reported in 3 studies in North America, 5 studies in the United Kingdom, and 1 study in Sweden, of births that occurred 1959-1997, range from a low of 1.2 per 1000 live births to a high of 7.7 per 1000 live births.18 In the Western Australian study alluded to previously, the birth prevalence of moderate or severe newborn encephalopathy was 3.8/1000 term live births,15 very similar to the incidence of umbilical arterial pH ⬍ 7.0 (3.7 per 1000 live births) in 6 North American studies and 1 study from the Netherlands of babies born 1986-2002.18
Brachial Plexus Injury in Births After Previous CD Studies that provide estimates of the rates of shoulder dystocia, perinatal brachial plexus palsy, and permanent neuromotor impairment after brachial plexus palsy are summarized in Table 2. Shoulder dystocia is a strong risk factor for brachial plexus palsy, perhaps because greater traction forces are needed to deliver the fetal shoulders, resulting in over-
Table 2 Studies of Shoulder Dystocia and Perinatal Brachial Plexus Palsy
Authors
Sample
Alexander et al (2006)26
37,110 Cesarean deliveries USA NIH Maternal Fetal Medicine Units Network 89,978 Deliveries (vaginal and CD) at University of Mississippi Hospital; 1980-2002 University of Oxford, UK, 1991-2005 University Hospital, Detroit, Michigan, 1996-2001 537,316 singleton cephalic deliveries whose first and second babies were delivered vaginally 19672005 in Norway 26,722 normal birth weight births in Saudi Arabia Teaching Hospital 19902005 4126 nulliparous women who reached the second stage of labor in the USA NIH Maternal Fetal Medicine Units Network
Chauhan et al (2005)64
Mackenzie et al (2007)20 Mehta et al (2006)21 Overland et al (2009)65
Rahman et al (2009)19
Rouse et al (2009)25
Rate of Shoulder Dystocia
Rate of Perinatal Brachial Plexus Palsy
Rate of Permanent Motor Impairment
9/37,110 (0.2 per 1000 CD) 46/89,978 (0.5 per 1000 deliveries)
514/79,781 (6 per 1000 vaginal deliveries) 206/25,995 (8 per 1000 vaginal deliveries) 2344/537,316 (4 per 1000 first vaginal deliveries); 4466/537,316 (8 per 1000 vaginal deliveries)
44/514 (9% of cases of shoulder dystocia) 19/206 (9% of cases of shoulder dystocia)
104/26,722 (3.9 per 1000 vaginal deliveries)
21/104 (25% of cases of shoulder dystocia)
11/3819 (2.9 per 1000 pregnancies that reached the second stage of labor and were delivered vaginally); 0/307 pregnancies that reached the second stage of labor and were delivered by Cesarean
8/46 (17%)
3/21 (14%)
Outcomes of child after previous cesarean stretching and injury to the plexus. Estimates of the incidence of shoulder dystocia range between 4 and 8 per 1000 vaginal deliveries.19-22 The rate of perinatal brachial plexus injury in vaginal deliveries complicated by shoulder dystocia is 9% to 25%.19-22 The risk of permanent neurological impairment among neonates with perinatal brachial plexus injury has been estimated to be 9% to 17%,19,22,23 leading to an estimate of about 1 case of permanent upper-extremity impairment caused by perinatal brachial plexus injury per 10,000 vaginal deliveries. Prognosis for recovery of function after perinatal brachial plexus palsy depends on the severity at 3 weeks. When only cervical roots 5, 6, and 7 are involved, 65% of infants demonstrate complete recovery at 6 months, compared with only 14% for infants with involvement of cervical root 8 and thoracic root 1.24 Although brachial plexus injury after CD is rare,10 CD does not eliminate the risk of brachial plexus injury. In a study from the National Institutes of Health Maternal Fetal Medicine Network, of women who reached the second stage of labor at or beyond 36-week gestation, brachial plexus injury was observed in 11 (0.29%) of 3819 infants born vaginally and none of 307 infants born by CD.25 In another study of 37,110 CD deliveries in this network, the incidence of perinatal brachial plexus injury was 0.2 per 1000 infants born by CD, and 0.3 per 1000 among babies born by elective repeat CD.26
Respiratory Dysfunction in Births After Previous CD Method of Delivery and Perinatal Respiratory Dysfunction Infants delivered by elective CD have an increased risk of transient tachypnea of the newborn (odds ratios 2.4-2.8),27,28 persistent pulmonary hypertension (odds ratio 4.6 [1.9, 11]),27 respiratory morbidity (odds ratios 2.1 to 2.6),28-31 and respiratory distress syndrome (odds ratio 8.6).28 Most studies of the association of CD and neonatal respiratory dysfunction have not been restricted to infants born after a previous CD. In 1 study that was limited to women with a previous CD, infants delivered by elective CD were more likely to have a respiratory problem (odds ratio 2.3) and to develop transient tachypnea (odds ratio 2.6).31 In another such study, infants born after intended CD were more than twice as likely to receive oxygen during delivery room resuscitation (odds ratio 2.35) and in the neonatal intensive care unit (odds ratio 2.5).32 The mechanism(s) that underlie the associations between CD and respiratory dysfunction might include the both the failure of the normal preparation of the lung for extrauterine life33 as well as the leftward shift in gestational age at birth that might occur when pregnancy is truncated by elective CD.5 We are aware of no direct evidence relating the excess respiratory morbidity after CD to long-term sequelae. Longitudinal studies of neonates with respiratory morbidity have focused on the most severely ill, such as those with hypoxic
285 respiratory failure and persistent pulmonary hypertension. In 9 studies of inhaled nitric oxide for hypoxic respiratory failure, the mortality rate was 9% for infants randomized to inhaled nitric oxide. Neurodevelopmental impairment occurred in 28% of survivors (2 trials) and cerebral palsy in 10% of survivors.34 Greater rates of death (28%; meta-analysis of 4 trials) and neurodevelopmental impairment (20%; 1 trial) have been observed in neonates with persistent pulmonary hypertension who were randomized to extracorporeal membrane oxygenation.35 The frequency at which infants with CD-related respiratory morbidity have hypoxic respiratory failure and persistent pulmonary hypertension is not well characterized. In a study from the only center offering extracorporeal membrane oxygenation in western Missouri and the state of Kansas in the years 2000 through 2005, Truog et al36 described the severity of respiratory illness among 315 infants who were born at or beyond 36-week gestation, had hypoxic respiratory failure requiring mechanical ventilation for at least 24 hours, and had no major anomaly to which their respiratory dysfunction was attributable. In this sample of infants, 56% had an oxygenation index greater than 15% and 21% had an oxygenation index greater than 25; thus 21% to 56% of infants would have been eligible for most of the randomized trials of nitric oxide for infants at or near term gestation with hypoxic respiratory failure.34 These frequencies almost certainly overstate the frequency at which infants with CD-related respiratory morbidity have hypoxic respiratory failure, and the true frequency could be considerably lower.
Method of Delivery and Asthma Table 3 summarizes findings from 32 studies of the association between CD and childhood asthma. In a meta-analysis that included 21 of these studies the estimated odds ratio for asthma after CD was 1.2 (95% confidence limits 1.141.26).37 A second meta-analysis, determined on the basis of 20 of the studies listed in Table 3, yielded a summary odds ratios of 1.18 (95% confidence limits 1.05-1.32) for asthma and 1.23 (95% confidence limits 1.12-1.31) for hospitalization caused by asthma.38 Given the modest strength of association found in both meta-analyses, perhaps the observed CD⫺asthma association is explained entirely by unaccounted for confounders. Nonetheless, in 5 of the 6 studies published since the 2 existing meta-analyses, somewhat greater odds ratios were observed: 1.52 (1.42-1.62),39 1.2 (1.02-1.42),40 1.79 (1.27- 2.51),41 1.1 (0.75, 3.86),42 and 1.1 (0.6, 2.3).43 The largest of these studies included 1,756,700 singleton births that occurred between 1967 and 1998, followed up to 18 years or the year 2002, and adjustment was made for maternal age, maternal history of asthma, maternal education, child’s gender, and year of birth.39 In this study, delivery by emergency cesarean was associated with a 59% increased risk of asthma and delivery by planned CD with a 42% increased risk. The biological mechanism(s) that explains the putative association of CD and asthma is not known. One possibility is that neonatal respiratory dysfunction or treatment for respi-
286
Table 3 Studies of Cesarean Delivery and Asthma in the Child First Author Al-Kubaisy et al*66 Annesi-Maesano*67 Aspberg39
Number Delivered by CD/Vaginal
Year of Birth of Cohort
OR (95% Confidence Limits) for Asthma
Benn†69
504/3000 (17%)
1992-94
0.92 (0.64-1.34) 1.47 (1.02-2.1) 1.44 (1. 37-1.50); 1.08 (1.01-1.17) For instrumented vaginal vs noninstrumented OR CD vs spontaneous vaginal: 1.22 (0.87-1.73) current asthma; 1.33 (1.02-1.74) asthma ever; OR CD vs vaginal: 1.31 (1.01-1.71) asthma ever; 1.24 (0.85-1.79) for vacuum vs spontaneous vaginal 1.1 (0.6-1.9)
Bernsen*,† Calvani†70
85/1712 (5%) Cases: 97/322 (30%); controls: 160/450 (36%) Cases: 385/2028 (19%); controls: 1246/8299 (15%) 3525/24,633 (14%)
1988-90 NA
1.03 (0.51-2.08) 0.78 (0.57-1.06)
1987-94 1994-2002
Asthma hospitalization: 1.2 (1.04-1.39) overall; 1.15 (0.97-1.34) among term infants; 1.90 (1.09-3.02) among premature 1.3 (1.1-1.5)
88/788 (11%)
1997-2002
1.31 (0.80-2.13)‡
Hakansson*,†74
44,869/577,252 (8%)
1984-96
Juhn*,†75 Kero*,†76 Kurukulaaratchy*77
714/7106 (10%) 2050/59,865 (3%) 81/844 (10%)
1976-82 1987 1989
All CD vs spontaneous vaginal; 1.31 (1. 23-1.40); Emergency CD vs spontaenous vaginal: 1.26 (1.16-1.37); 1.38 (1.26-1.52) elective CD vs spontaneous vaginal; 1.10 (1.01-1.19) instrument vaginal vs spontaneous vaginal 0.93 (0.6-1.4) 1.21 (1.08-1.36) 1.82 (1.01-3.28)‡
Maitra*,†78 Mallen42 Mckeever*,†79 Metsala80
1387/12,367 (11%) 44/567 (9%) 4073/24,690 (16%) Cases: 2919/13,568 (22%); controls: 2241/13,470 (17%)
1991-92 1977-84 NA 1996-2004
Nafstad*,†81
279/2472 (11%)
1992-93
1.1 (0.9-1.4) 1.71 (0.75-3.02) 1.06 (0.99-1.14) 1.19 (1.06, 1.07, 1.31) Planned CD vs spontaneous Vaginal; 1.39 (1.27-1.58) emergency CD vs spontaneous Vaginal; 1.19 (1.06-1.34) assisted vaginal vs spontaneous vaginal 1.1 (0.7-1.8)
Negele*,†82
435/2500 (17%)
1997-99
1.41 (1.02-1.96)
Oliveti*,†83
Cases: 33/131 (25%); controls: 31/131 (24%) 102/433 (24%)
1983-89
1.09 (0.62-1.91)
1994-96
1.1 (0.6-2.3)
Debley*,†71 Gessner and Chimonas†72 Hagendorens*73
Pistiner43
1973-77
Discussion
Outcome of interest: asthma requiring hospitalization Women only; 20-28 years old
OR 1.3 (0.7-2.4) if adjusted for breastfeeding “Nonatopic asthma” Outcome of interest: asthma hospitalization Multivariate odds ratio not provided Outcome of interest: Parent report of wheezing
Outcome of interest: wheezing
Outcome of interest: asthma at 4 years Outcome of interest: recurrent wheezing
Subjects: children with parent history of atopy
T.M. O’Shea, M.A. Klebanoff, and C. Signore
2000-02 1958 1987-99
Bager*,†68
603/2110 (29%) 288/4065 (7%) 15,409 with asthma; 1,386,029 without 493/9722 (5%)
First Author
Number Delivered by CD/ Vaginal
Year of Birth of Cohort
Renz-Polser*,†55
1286/7872 (16%)
1990-92
Roduit41
247/2670
1996-97
Rusconi*84
4163/15,609 (27%)
1987-89
Salam*,†54 Smith*,†
717/3464 (21%) 25,369/173,139 (15%)
1975-87 1992-95
Tollanes39
1055/137,790 (8%)
1967-98
Vonk*,†85 Werner†86
39/434 (9%) 841/7119 (12%)
1975-78 1984-87
Xu (2001)*87 Xu (2000)*,†88
96/2951 (3%) NA
1966 NA
OR (95% Confidence Limits) for Asthma 1.24 (1.01-1.52); 1.08 (0.81-1.69) for boys; 1.23 (1.06-1.43) for girls; 1.17 (0.91-1.69) for CD without PROM vs others 1.79 (1.27-2.51); 2.91 (1.2-7.05) If 2 allergic parents; 1.86 (1.12-3.09) if 1; 1.36 (0.77-2.42) if 0 1.12 (0.93-1.36)
Discussion
Outcomes of child after previous cesarean
Table 3 Continued
Outcome of interest: persistent wheezing
1.33 (1.01-1.75) Rates of asthma were 2.2% (vaginal); 2.5% (all CD); 2.5% (emergency CD); 2.6% (elective CD) 1.52 (1.42-1.62); 1.14 (1.01-1.28) Instrument vaginal vs spontaneous vaginal; 1.42 (1.25-1.61) planned CD vs spontaneous vaginal; 1.59 (1.44-1.75) emergency CD vs spontaneous vaginal 1.77 (0.89-3.51)‡ 1.11 (0.88-1.39) CD vs vaginal; 1.20 (0.9-1.58) emergency CD vs vaginal; 0.98 (0.69-1.39) elective CD vs vaginal 3.23 (1.53-6.8) CD vs spontaneous vaginal: 1.38 (1.0-1.92); vacuum extraction vs spontaneous vaginal: 1.32 (0.8-2.19); other instrumental delivery: 2.14 (1.06-4.33)
Abbreviations: CD, cesarean delivery; NA, not applicable; OR, odds ratio. *Included in the meta-analysis by Thavagnanam et al.39 †Included in the meta-analysis by Bager et al.40 ‡Odds ratios not available in publication; these odds ratios are presented in the meta-analysis reported by Thavagnanam et al.37
287
T.M. O’Shea, M.A. Klebanoff, and C. Signore
288 ratory dysfunction (eg, supplemental oxygen) could predispose to asthma. In a study of 2137 newborns subsequently diagnosed with asthma and 2094 controls, those with transient tachypnea of the newborn had a 50% greater risk of asthma (odds ratio 1.5; 95% confidence limits 1.13-1.99).44 Another hypothesis is that method of delivery influences immune system ontogeny by either a direct effect of labor on immune regulatory cells45 or by reducing exposure to specific microbes which are acquired when infants swallow vaginal fluid containing microorganisms from the mother’s gastrointestinal tract.46 CD is associated with increased neonatal secretion of interleukin-13 (IL-13) and interferon-␥,45 and decreased secretion of interleukin-10 (IL-10) in cord blood mononuclear cells. IL-13 is a cytokine produced by Th2 cells and has been linked to bronchial hyperresponsiveness, goblet cell hyperplasia with excessive mucus production, and asthma.47 Further, polymorphisms in this gene are associated with susceptibility to asthma.48,49 IL-10 is antiinflammatory.50 A third possible explanation for the association of elective CD and asthma is a decreased rate of initiation, or duration, of breastfeeding.51-53 Table 4 summarizes 7 studies of this
association on the basis of recently born cohorts. In 6 of these studies, women who delivered by CD were less likely to initiate breastfeeding, with multivariate odds ratios ranging from 0.24 to 0.79. In the largest of these studies, women who experienced a spontaneous vaginal delivery were more likely to initiate breastfeeding, and this association was stronger when considering women delivered without labor (OR 0.64, 95% confidence limits 0.6-0.67).52 Table 5 summarizes 17 studies of the association of CD and allergic disorders other than asthma. Five of these studies reported statistically significant associations with either parent-reported food allergy or a composite of any allergic disorder or allergic sensitization.41,43,54-56 A meta-analysis that included 6 of these studies yielded an odds ratio of 1.32 (1.12-1.55) for food allergy/food atopy, and a meta-analysis of 7 of these studies yielded an odds ratio of 1.23 (1.12-1.35) for allergic rhinitis. Significant associations were not found from meta-analyses of eczema/atopic dermatitis (odds ratio: 1.03 from 6 studies) or inhalant atopy (odds ratio: 1.06 from 4 studies). In addition to possible effects on the risk of asthma or allergy, altered, or delayed, colonization of the gut with com-
Table 4 Studies of CD and Subsequent Breastfeeding
Authors
Sample
CD Rate, %
Breastfeeding Rate, %
OR
Chien, et al (2007)53
2064 Births in Taiwan 2003
33.9
65
1.19
Chung et al (2008)89
865 Birth in South Korea 2003
39.8
81.3
0.51
Kohlhuber et al (2008)90
3822 birth in Bavaria, Germany 2005
27
Leung et al (2002)51
7825 births in Hong Kong 1997
27.1
Liston et al (2008)52
142, 929 Births in Nova Scotia 1988-2002
19
Perez-Rios et al (2008)91 Theofilogiannakou et al (2006)92
1695 Births in Puerto Rico 1990-96 312 Births in Athens, Greece 2003-04
36
90% Initiated; 70% at 2 mo; 61% at 4 mo; 52% at 6 mo
0.59
34
0.66
Spontaneous vaginal, 59.1 assisted vaginal, 60.1 CD in labor, 59.5 CD without labor, 54.5 61.5
38%
Abbreviations: CD, cesarean delivery; OR, odds ratio; NA, not available.
57
1 NA 0.79 0.64
Confounding Factors for Which Adjustment Made Maternal age, education, and work status, spousal support for breastfeeding Maternal education, maternal employment status, prematurity, amount of prenatal care Maternal age, maternal education, maternal smoking, number of siblings, partner’s and maternal and paternal grandmothers’ attitudes towards breastfeeding, preterm birth Gestational age, birth weight, maternal and paternal smoking, mother’s age, maternal and paternal education, paternal employment status, birth order of infant, gender Year of delivery, maternal age, parity, smoking, maternal weight at delivery, hypertensive disease, diabetes, previous CD, regional anesthesia, induction of labor, gestational age, large and small for gestational age
0.64 0.24
Season of birth, socioeconomic level, mother’s and father’s age, mother’s and father’s educational level, mother’s body mass index, smoking habits, miscarriage, in vitro fertilization
Outcomes of child after previous cesarean
289
Table 5 Studies of Cesarean Delivery and Allergy in the Child
First Author Bager*68 Bernsen*93 Eggesbo*56
Number Delivered by CD/Vaginal 493/9722 (5%) 85/1712 (5%) 328/2803 (12%)
Hagendorens*73 Kero*76 Maitra*78 Mallen42
88/788 (11%) 42/131 (32%) 1387/12,367 (11%) 44/567 (9%)
McKeever*79
4073/24,690 (16%)
Montgomery*94 Nafstad*81 Negele*82
Year of Birth of Cohort 1973-77 1988-90 1992-93
1.16 (0.9, 1.49) 1.12 (0.56, 2.24) 3.2 (1.4, 7.3); 9.3 (3.1, 28) If mother herself had allergy 1997-2002 OR <1 (not statistically significant) 1990 1.31 (0.65, 2.65) 1991-92 1.18 (0.9, 1.5) 1977-84 1.49 (0.78, 2.84) NA
169/5519 (3%) 279/2472 (11%) 435/2500 (17%)
1970 1992-93 1997-99
102/433 (24%)
1994-96
1286/7872 (16%)
1990-92
Roduit41
247/2917 (8%)
1996-97
Salam*54
717/3464 (21%)
1975-87
29/213 (14%)
2002-03
Pistiner43 Renz-Polser*55
Sugiyama*95 Xu*87
96/2951 (3%)
OR for Allergy
1966
Hay fever: 1.01 (0.85, 1.21); eczema: 1.04 (0.98, 1.10) 1.21 (0.84, 1.74) 1.2 (0.7, 2.1) Atopic dermatitis: 1.21 (0.92, 1.59); allergic rhinoconjunctivitis: 1.4 (0.8, 2.44); physiciandiagnosed atopic dermatitis: 1.04 (0.79, 1.39) 2.1 (1.1, 3.9) Any allergic disorder: 1.23 (1.06, 1.80); 1.41 (1.1, 1.8) for CD without PROM vs others Sensitization to any allergen: 2.14 (1.16, 3.98) 1.26 (1.03, 1.53) Any allergy
Notes on Study Participants or Outcomes of Interest Allergic rhinitis Any atopic disorder Parent reported reaction to egg, fish, or nuts Atopic dermatitis Skin prick tests Atopy at 7 years ⴝ 3 mm Atopy refers to Number of allergic conditions Hay fever and eczema Hay fever Allergic rhinitis Atopic dermatitis, rhinoconjunctivitis, and physician-diagnosed atopic dermatitis Children with parent history of atopy Any allergic disorder
Risk of sensitization to any allergen at 8 years Any allergy ⴝ food or drug, inhalant, dermal allergy
Atopic dermatitis: 0.77 (0.22, 2.74); eczema: 1.88 (0.64, 5.52) Atopy: 0.96 (0.59, 1.56); hay fever: 1.28 (0.73, 2.24); atopic eczema: 1.19 (0.62, 2.28)
*Included in the meta-analysis by Bager et al.38
mensal flora might also increase the risk of type 1 diabetes. In a meta-analysis of 20 studies, including 9938 cases, the odds ratio for the association of CD and type 1 diabetes was 1.19 (1.04-1.36), adjusted for gestational age, birth weight, maternal age, birth order, breastfeeding, and maternal diabetes.57 Despite some evidence that breastfeeding initiation is less likely after CD, it is not clear that a lower frequency of breastfeeding among women who deliver by CD increases the risk of asthma. In largest randomized trial of an intervention to promote breastfeeding, no effect was found on either asthma risk or the risk of allergic symptoms.58,59 Nonetheless, if CD does decrease the rate of breastfeeding initiation, multiple long-term outcomes might be altered. The authors of meta-analyses suggest that breastfeeding is associated with a lower risk of gastrointestinal infections, a lower risk of overweight, and greater intelligence. In the aforementioned randomized trial to increase breastfeeding, the intervention resulted in a decreased risk of gastrointestinal tract infection and atopic eczema in the first year of life,58 and increased intelligence at 6.5 years.60 However, no bene-
ficial effects were found on anthropometrics or blood pressure.59,61,62
Conclusions Estimates of risk differences between neonatal outcomes after a trial of labor versus a planned CD are presented in Table 6. On the basis of an estimated risk difference for symptomatic uterine rupture of 2.79-5.98 per 1000 trials of labor (vs repeat CD), and a mortality risk of 8% among infants born after symptomatic uterine rupture,9 the risk difference in mortality caused by symptomatic uterine rupture would be 2-4.7 per 10,000 trials of labor. On the basis of an estimated risk difference for HIE of 8 per 10,000 trials of labor,8 a 28% mortality rate for infants with HIE,17 and a 30% risk of major disability among survivors of HIE,17 the risk difference for mortality would be 2.2 per 10,000 trials of labor, and the risk difference for major disability would be 1.7 per 10,000 trials of labor. Assuming that 90% of cases of perinatal brachial plexus injuries occur among infants delivered vaginally, then
T.M. O’Shea, M.A. Klebanoff, and C. Signore
290 Table 6 Risk differences for Child Outcomes Comparing a Trial of Labor and Planned Cesarean Delivery
Outcome Death caused by uterine rupture* Neurodevelopmental impairment after uterine rupture and HIE† Upper extremity neuromotor impairment after brachial plexus palsy‡ Neurodevelopmental impairment after hypoxic respiratory failure§ Death due to hypoxic respiratory failure§ Asthma¶
Estimated Risk Difference per 10,000 Deliveries 2 to 4.7 1.7 1.1 to 2.3
2.8 to ⴚ6.3 ⴙ0.9 to ⴚ2 ⴚ200
Positive numbers indicate higher rate of occurrence following a trial of labor, whereas negative numbers indicate a higher rate of occurrence with planned cesarean delivery. *On the basis of data from Guise et al9 and Spong et al8 (see text). †On the basis of risk difference for HIE from Spong et al8 and meta-analysis of outcomes after HIE by Jacobs et al.17 ‡On the basis of multiplying incidence of shoulder dystocia in vaginal births19-22 times risk of perinatal brachial plexus injury associated with shoulder dystocia19-22 times risk of permanent neurological impairment among infants with perinatal brachial plexus injury.19,22,23 §Assumes risk difference for hypoxic respiratory failure (aspiration pneumonitis or respiratory distress syndrome) of ⴙ9 to ⴚ20 per 100027,31,32 that 10% of those with hypoxic respiratory failure are severe enough to require nitric oxide,36 and rates of death and impairment similar to those observed among participants in randomized trials of nitric oxide.34 ¶Assumes a relative riskCD:vaginal of 1.2 and a prevalence of asthma of 10%.63
based on the incidence of shoulder dystocia among infants delivered vaginally,19-21 the risk of perinatal brachial plexus injury with shoulder dystocia,19-21 and the risk of permanent impairment after perinatal brachial plexus injury,19,22,23 the risk difference for permanent brachial plexus injury is about 0.2-2.7 per 10,000 trials of labor. The frequency at which infants with CD-related respiratory morbidity have hypoxic respiratory failure and persistent pulmonary hypertension is not well characterized, but based on an assumption that 5% to 10% of infants with hypoxic respiratory failure require treatment with nitric oxide (on the basis of the assumption that the estimate from the study by Truog et al [21%-56%]36 could be 5-10 times the true frequency), the estimated risk difference for hypoxic respiratory failure (aspiration pneumonitis or respiratory distress syndrome) of 4.8 per 1000,52 and the rates of mortality and impairment among participants in trials of nitric oxide, an estimated risk difference for mortality is 0.2 to 0.4 per 10,000 repeat CD, and an estimated risk difference for neurodevelopmental impairment caused by hypoxic respiratory failure is 0.6 to 0.12 per 10,000 repeated CD. Finally, the relative risk of asthma among infants delivered by CD versus
those delivered vaginally,37,38 combined with an estimated prevalence of asthma of 10%,(65) leads to an estimated risk difference for asthma of 200 per 10,000 repeat CD. Thus, estimated risk differences for all the outcomes except death attributable to uterine rupture and asthma are small. The estimated risk difference for mortality attributable to uterine rupture (2-4.7 neonatal deaths per 10,000 trials of labor) implies that at least several thousand elective CD must be performed to prevent 1 death associated with a trial of labor. However, this presumed benefit might be offset by an increase rate of death or neurodevelopmental impairment associated with hypoxic respiratory failure. For example, if an estimate that is only one half of that reported by Truog et al36 is assumed for the rate of hypoxic respiratory failure among infants with aspiration pneumonitis or respiratory distress syndrome, the estimated risk difference for the composite outcome of death or neurodevelopmental impairment caused by hypoxic respiratory failure after CD could be as high as 4.5. This result is very similar to the estimated risk difference for that composite outcome caused by uterine rupture during an trial of labor. Further, our estimate is that an additional 200 cases of asthma might result from each 10,000 elective CDs performed. Additional observational studies are needed to provide more precise estimates of the risk differences that are pertinent to the decision of whether to attempt a trial of labor after previous CD. Awaiting these data, there is no clear advantage to either a trial of labor or a planned CD. Randomized trials comparing these 2 approaches would provide the most valid basis for obstetrical care.
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