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Early-onset severe preeclampsia: induction of labor vs elective cesarean delivery and neonatal outcomes
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Early-onset severe preeclampsia: induction of labor vs elective cesarean delivery and neonatal outcomes Mark C. Alanis, MD; Christopher J. Robinson, MD; Thomas C. Hulsey, ScD, MSPH; Myla Ebeling, RA; Donna D. Johnson, MD OBJECTIVE: The purpose of this study was to describe the success rate of and analyze differences in neonatal outcomes with labor induction, compared with elective cesarean delivery in women with earlyonset severe preeclampsia. STUDY DESIGN: We conducted a cross-sectional study of women with
and 68.8% of women who underwent labor induction between 24 and 28, 28 and 32, and 32 and 34 weeks of gestation, respectively. Induction of labor was not associated with an increase in neonatal morbidity or mortality rate after we controlled for gestational age and other confounders.
severe preeclampsia who required delivery between 24 and 34 weeks of gestation. Bivariate and multivariable regression analyses were used to determine factors that were associated with assignment to, success of, and odds of neonatal outcomes after induction of labor.
CONCLUSION: Neonatal outcomes are not worsened by induction of labor in women with early-onset severe preeclampsia, although it is rarely successful at ⬍28 weeks of gestation.
RESULTS: Fifty-seven and four-tenths percent of 491 women under-
went induction of labor. Vaginal delivery occurred in 6.7%, 47.5%,
Key words: cesarean delivery, induction of labor, neonatal morbidity, preeclampsia
Cite this article as: Alanis MC, Robinson CJ, Hulsey TC, Ebeling M, Johnson DD. Early-onset severe preeclampsia: induction of labor vs elective cesarean delivery and neonatal outcomes. Am J Obstet Gynecol 2008;199:262.e1-262.e6.
P
reeclampsia is the leading cause of medically indicated preterm birth and accounts for 25-43% of all such births.1,2 Most patients with preeclampsia whose condition requires preterm delivery will not be in spontaneous labor. The obstetrician then faces a dilemma regarding the optimal mode of delivery after the absolute obstetric indications for cesarean delivery have been excluded. Even with reassuring fetal status, many obstetricians favor elective cesarean delivery over an induction of labor (IOL) in such patients. In a survey of severe preeclampsia practice patterns among members of the Society of Peri-
From the Departments of Obstetrics and Gynecology (Drs Alanis, Robinson, and Johnson) and Pediatrics (Dr Hulsey and Ms Ebeling), Medical University of South Carolina, Charleston, SC. This study was presented at the 28th annual meeting of the Society for Maternal–Fetal Medicine, Dallas, TX, Jan. 28-Feb. 2, 2008. Received March 1, 2008; accepted June 24, 2008 Reprints not available from the authors. 0002-9378/$34.00 © 2008 Mosby, Inc. All rights reserved. doi: 10.1016/j.ajog.2008.06.076
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natal Obstetricians, the estimated overall cesarean delivery rate was 73% (range, 10-100%) for infants ⬍32 weeks of gestation in pregnancies that were complicated by preeclampsia.3 Cesarean delivery, however, may not improve neonatal outcomes, despite the avoidance of the stress of labor.4 Reviews of primary elective cesarean delivery demonstrate that the balance of short- and longterm neonatal morbidity favors vaginal delivery for preterm fetuses.5 In addition, elective cesarean delivery has not reduced the rate of cerebral palsy, which contrasts with the belief that prelabor cesarean delivery may be neuroprotective.6 However, the patient with early-onset (⬍34 weeks of gestation) severe preeclampsia often faces unique challenges. Increased attention has focused on the optimal management of delivery in such women, given the prevalence of low parity, unfavorable cervical examinations, and pathologic cardiovascular and renal manifestations that can result in increased maternal or fetal compromise.7 The objectives of this study were (1) to describe the success rate of IOL, (2) to identify factors that are associated with the decision to proceed with an IOL vs elective cesarean delivery, and (3) to analyze the relationship of IOL vs elective
American Journal of Obstetrics & Gynecology SEPTEMBER 2008
cesarean delivery on neonatal outcomes in women with early-onset severe preeclampsia.
M ATERIALS AND M ETHODS Patients This was a cross-sectional study of women who delivered at the Medical University of South Carolina (the region’s tertiary referral center) between January 1, 1996, and December 31, 2006, was approved by the Institutional Review Board. Early-onset severe preeclampsia was defined as new onset hypertension (systolic blood pressure ⱖ140 mm Hg or diastolic blood pressure ⱖ90 mm Hg at least twice ⱖ6 hours apart) and proteinuria (ⱖ300 mg per 24hour period or ⱖ1⫹ on random urine dipstick in the acute setting) after 20 weeks of gestation with severe criteria according to guidelines published by the American College of Obstetricians and Gynecologists8 in women who required delivery between 24 and 34 weeks of gestation. Patients were excluded if obstetric contraindications to labor were present, such as noncephalic presentation, placenta previa, or active genital herpes. Other exclusion criteria included patients with spontaneous preterm labor
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www.AJOG.org or ruptured membranes, any evidence of fetal distress before assignment to an IOL or elective cesarean delivery, multiple gestation, HIV-positive status, or a known fetal anomaly. In addition, patients with intrapartum eclampsia were excluded because of low frequency and a very high rate of emergent cesarean delivery in this group. Standard practice at our institution during the study period included an attempt to provide 48 hours of intramuscular corticosteroids for fetal lung maturation; intrapartum intravenous magnesium sulfate was provided during the intrapartum period and continued for at least 24 hours after delivery for seizure prophylaxis in all patients. Methods of labor induction, determined on an individual basis by an attending physician, included oxytocin, prostaglandin E2, vaginal misoprostol, and transcervical balloon catheter with or without oxytocin.
Data A research-quality perinatal database, which links maternal and neonatal records for all deliveries at the Medical University of South Carolina, was used to obtain maternal, obstetric, and neonatal data. The database is populated according to an active surveillance system whereby information is abstracted specifically for the purpose of this database. The inter- and intrarater reliability both exceed 97%, and logical error checks are performed routinely on all data that are entered by trained personnel. Assignment of delivery mode was described as IOL or elective cesarean delivery, and the ultimate mode of delivery was described as vaginal or cesarean delivery. A failed IOL was defined as a cesarean delivery after an unsuccessful labor induction with or without fetal distress. An elective cesarean delivery was defined as a cesarean delivery in the absence of an IOL. The decision to induce a patient to delivery, proceed with cesarean delivery for failed IOL, or perform an elective cesarean delivery was made by the attending physician. Success rates of IOL were reported within clinically relevant gestational age categories: 24-28, 28-32, and 32-34 weeks of gestation. Maternal variables that were analyzed were age at de-
livery, parity, cervical dilation before assignment of delivery mode, previous cesarean delivery, prepregnancy body mass index (kg/m2), and race (black or non-black). Neonatal outcomes included birthweight, Apgar score at 5 minutes ⬍7, neonatal death, hyaline membrane disease, bronchopulmonary dysplasia, transient tachypnea of the newborn infant, retinopathy of prematurity, intracranial hemorrhage (grade III or IV intraventricular hemorrhage or periventricular hemorrhage), necrotizing enterocolitis, neonatal seizures, neonatal sepsis, birth injury (cephalhematoma, any fracture, or nerve palsy), and neonatal intensive care unit (NICU) admission and duration of stay. In addition, a composite neonatal index was defined as ⱖ1 of any adverse neonatal outcome, except 5-minute Apgar score ⬍7 and NICU admission, because only discrete neonatal pathologic conditions were considered. Small for gestational age was defined as a birthweight ⬍10th percentile for gestational age calculated with the use of population birthweight tables.9
Statistical analysis Data were reported in medians (interquartile range), and percents for continuous and categoric variables, respectively. All analyses were performed according to the intention-to-treat principle (IOL or elective cesarean delivery) rather than by delivery outcomes (vaginal vs cesarean delivery). Bivariate analyses were performed with Wilcoxon rank sum and chisquare tests to assess the relationship between IOL and continuous and categoric variables, respectively. The Cochran-Armitage test for trend was used to compare 2-level categoric variables across the 3-levels of gestational age categories. Multivariable logistic regression analyses were performed to determine whether specific maternal or fetal variables were significant predictors of assignment to and success of IOL. Both models included gestational age, nulliparity, previous cesarean delivery, cervical dilation ⬎1 cm, small for gestational age, black race, maternal age, and hemolysis, elevated liver
enzymes and low platelets (HELLP) syndrome.10 In addition, fetal distress in labor was also included as a predictor in the model for successful IOL. Multivariable logistic regression was performed to determine whether the odds of receiving corticosteroids were affected by IOL after we controlled for HELLP syndrome (as a marker of maternal condition severity), gestational age, and fetal distress. Finally, multivariable linear and logistic regression analyses were performed for continuous and dichotomous variables, respectively, to determine whether the odds of neonatal outcomes were increased or decreased by IOL, after we controlled for the following clinically significant variables: gestational age, maternal age, maternal body mass index, black race, intramuscular corticosteroids for fetal lung maturity, and small for gestational age. Adjusted odds ratios with 95% CIs were reported, and 2-tailed probability values of ⬍.05 were considered statistically significant for all tests. Statistical analysis was performed with SAS software (version 9.1; SAS Institute, Inc, Cary, NC).
R ESULTS Figure 1 describes how patients were selected and analyzed. Four hundred ninety-one eligible women were identified. Overall, vaginal delivery was successful in 53.5% (n ⫽ 151) of women who underwent IOL. Mode of delivery outcomes by gestational age are listed in Table 1. Success rates for IOL were 6.7%, 47.5%, and 68.8% for women delivering at 24-28, 28-32, and 32-34 weeks of gestation, respectively. Maternal characteristics and percent small for gestational age are listed in Table 2 in relation to assignment to IOL or elective cesarean delivery. Both assignment to and success of IOL were significantly and negatively associated with decreasing gestational age, nulliparity, and previous cesarean delivery (Table 3). In addition, fetal distress in labor was associated significantly with a reduction in successful IOL but did not differ by gestational age category (P ⫽
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.32). There was a 58% decrease in the odds of a patient being assigned to IOL if the HELLP syndrome was present (P ⫽ .01), but this did not affect the success of IOL if the patient was assigned already (P ⫽ .4). Overall, 84.9% of mothers received a course of intramuscular corticosteroids before delivery. After we controlled for distress and HELLP syndrome, intramuscular corticosteroid use was significantly lower with advancing gestational age (odds ratio [OR], 0.29; 95% CI, 0.17-0.49 per 4 weeks) and significantly higher with IOL (OR, 2.5; 95% CI, 1.4-4.5; Figure 2). The median birthweights among women who underwent IOL and elective cesarean delivery were 1467.5 g (range, 1220.0-1805.0 g) and 1160.0 g (range, 835.0-1560.0 g), respectively (P ⬍ .001). This reflects the higher number of patients who undergo elective cesarean delivery at earlier gestational ages. There were no differences in individual or composite neonatal outcomes for women who underwent IOL vs women who underwent elective cesarean delivery, except for bronchopulmonary dysplasia (Table 4). IOL was associated with a 52% decrease in the odds for bronchopulmonary dysplasia after being controlled for gestational age, corticosteroids, and other confounders. The duration for which neonates required mechanical ventilation was greater in the elective cesarean delivery group (6.0, range, 2-23 days) compared with the IOL group (3.0, range 2-28 days, P ⱕ .001). However, this difference disappeared after adjustment for gestational age (data not shown). Newborn infants who were delivered by elective cesarean delivery required 7 more days in the NICU, although this was not significant after ad-
FIGURE 1
Patient selection flow diagram
Alanis. Early-onset severe preeclampsia. Am J Obstet Gynecol 2008.
justment for gestational age, corticosteroids, and other confounders (P ⫽ .07).
C OMMENT This study shows that labor induction should be considered strongly in eligible women with early-onset severe preeclampsia between 28 and 34 weeks of gestation, regardless of suspected intrauterine growth restriction, preripening cervical dilation, or parity. Before 28 weeks of gestation, however, labor induction is rarely successful. Although fetal distress often leads to cesarean deliv-
ery in laboring patients with early-onset severe preeclampsia, the rate of neonatal morbidity is not increased in patients who have at least attempted a vaginal delivery. When labor induction is not successful, fetal distress is present in approximately one-half of the cases, regardless of the gestational age. Several studies have attempted to address the role of labor induction in women with early-onset severe preeclampsia. However, conclusions from many of these studies are limited by several problems that include comparison
TABLE 1
Delivery outcomes among 3 clinically relevant groups of gestational age Gestational age (wk)
Vaginal delivery (n)
Failed IOL with fetal distress (n)
Failed IOL without fetal distress (n)
Elective cesarean delivery (n)
24-28 (n ⫽ 56)
1 (1.8%)
7 (12.5%)
7 (12.5%)
41 (73.2%)
28-32 (n ⫽ 286)
75 (26.2%)
44 (15.4%)
39 (13.6%)
128 (44.8%)
32-34 (n ⫽ 149)
75 (50.3%)
17 (11.4%)
17 (11.4%)
40 (26.9%)
................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................
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TABLE 2
FIGURE 2
Maternal and fetal factors that were associated with assignment of delivery mode
Frequency of corticosteroid administration in women with early-onset severe preeclampsia
IOL (n ⴝ 282)
Variable b
Elective cesarean delivery (n ⴝ 209)
P valuea
Maternal age (y)
25.0 (21-31)
27.0 (23-32)
.003c
Body mass index (kg/m )
31.0 (27-36)
32.0 (27-38)
.33
99 (47.4%)
.005
.............................................................................................................................................................................................................................................. 2b c ..............................................................................................................................................................................................................................................
Nulliparity (n)
170 (60.3%)
..............................................................................................................................................................................................................................................
11 (3.9%)
87 (41.6%)
⬍.001
180 (63.8%)
120 (57.4%)
.15
Small for gestational age (n)
76 (27.0%)
56 (26.8%)
.97
HELLP syndrome (n)
24 (8.5%)
34 (16.3%)
.009
Previous cesarean delivery (n)
..............................................................................................................................................................................................................................................
Black race (n)
.............................................................................................................................................................................................................................................. .............................................................................................................................................................................................................................................. .............................................................................................................................................................................................................................................. a
Chi-square test unless otherwise noted.
b
Data are presented as medians (IQR).
c
Wilcoxon rank sum test
CS, cesarean section. Alanis. Early-onset severe preeclampsia. Am J Obstet Gynecol 2008.
Alanis. Early-onset severe preeclampsia. Am J Obstet Gynecol 2008.
of vaginal delivery with cesarean delivery with or without labor,11 comparison of cases of IOL with cases of emergent cesarean delivery,12 and analysis of outcomes by birthweight rather than by gestational age.13-15 Strengths of this study include a relatively large study population, categorization of women into clinically relevant gestational age categories, and analysis of neonatal outcomes according to the intention-to-treat principle by a comparison of IOL with elective cesarean delivery, instead of by the ultimate mode of delivery.
Our finding that IOL is not associated with adverse neonatal outcomes agrees with several previous studies15-17 and disagrees with others.13,18 The study by Mashiloane and Moodley18 demonstrated increased perinatal mortality rates in women who underwent IOL at ⬍27 weeks of gestation. However, this study was conducted in a developing country, where significant differences in newborn care are likely. In the study by Alexander et al,13 a 5-minute Apgar score of ⬍3 was more common in women who underwent IOL, although
no differences in survival or other neonatal outcomes were reported. Our finding of reduced bronchopulmonary dysplasia with IOL compared with elective cesarean delivery must be interpreted with caution. However, labor has been shown to decrease the occurrence and severity of neonatal respiratory distress syndrome,19 which may reduce the length of time that mechanical ventilator assistance is required for premature neonates. Bronchopulmonary dysplasia is primarily a chronic pulmonary disease that is related directly to the use of mechanical ventilation and other antenatal
TABLE 3
Factors that were associated with assignment to and success of IOL Factor
Assignment to IOL Adjusted ORa
95% CI
Successful IOL Adjusted ORb
95% CI
Increasing gestational age
1.54
1.38-1.72
1.43
1.24-1.66
Nulliparity
0.29
0.15-0.55
0.21
0.11-0.42
Previous cesarean delivery
0.01
0.01-0.03
0.09
0.02-0.40
Fetal distress
—
—
0.32
0.18-0.57
HELLP syndrome
0.42
0.22-0.82
0.65
0.24-1.79
Cervical dilation ⬎1 cm
1.19
0.32-4.37
1.95
0.52-7.38
Small for gestational age
0.81
0.48-1.36
0.74
0.39-1.38
Black race
1.31
0.79-2.16
1.78
0.97-3.26
Increasing maternal age
0.97
0.94-1.01
0.94
0.90-0.99
................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ a
Multivariable analysis was adjusted for gestational age, nulliparity, HELLP syndrome, previous cesarean delivery, cervical dilation ⬎1 cm, small for gestational age, black race, and maternal age.
b
Multivariable analysis was adjusted for gestational age, nulliparity, HELLP syndrome, previous cesarean delivery, fetal distress, cervical dilation ⬎1 cm, small for gestational age, black race, and maternal age.
Alanis. Early-onset severe preeclampsia. Am J Obstet Gynecol 2008.
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TABLE 4
Effects of IOL on neonatal outcomes in women with early-onset severe preeclampsiaa Outcome (n)
IOL (n ⴝ 282)
Elective cesarean delivery Adjusted (n ⴝ 209) OR 95% CI
Apgar score at 1 minute ⬍7
153 (54.3%)
126 (60.3%)
1.20
0.77-1.86
Apgar score at 5 minutes ⬍7
60 (21.3%)
51 (24.4%)
1.51
0.90-2.00
7 (2.5%)
18 (8.6%)
1.12
0.38-3.34
.............................................................................................................................................................................................................................................. ..............................................................................................................................................................................................................................................
Neonatal death
..............................................................................................................................................................................................................................................
Hyaline membrane disease
118 (41.8%)
142 (68.0%)
0.68
0.41-1.13
Bronchopulmonary dysplasia
26 (9.2%)
69 (33.0%)
0.48
0.24-0.97
Transient tachypnea newborn infant
8 (2.8%)
9 (4.3%)
0.32
0.10-1.04
Intracranial hemorrhage
9 (3.2%)
8 (3.8%)
1.91
0.56-6.41
Periventricular leukomalacia
2 (0.7%)
6 (2.9%)
0.73
0.11-4.70
Neonatal seizures
3 (1.1%)
1 (0.5%)
2.32
0.19-27.95
Retinopathy of prematurity
3 (1.1%)
4 (1.9%)
2.72
0.38-19.60
Necrotizing enterocolitis
9 (3.2%)
10 (4.8%)
1.95
0.61-6.27
44 (15.6%)
66 (31.6%)
0.83
0.48-1.43
7 (2.5%)
1 (0.5%)
5.74
0.62-52.91
.............................................................................................................................................................................................................................................. ..............................................................................................................................................................................................................................................
.............................................................................................................................................................................................................................................. ..............................................................................................................................................................................................................................................
trial of labor, highlights the need for better predictors of safe and successful labor induction practices in women with early-onset severe preeclampsia. Such research strategies include the assessment of various cervical ripening methods and the role of umbilical cord and fetal Doppler studies before the decision to induce labor in such women is made. A randomized clinical trial of IOL vs elective cesarean delivery for stable patients with early-onset severe preeclampsia and reassuring fetal status would be the gold standard clinical design, although this would be very difficult to conduct, given the low rate of eligible candidates at ⬍28 f weeks of gestation.
.............................................................................................................................................................................................................................................. .............................................................................................................................................................................................................................................. .............................................................................................................................................................................................................................................. ..............................................................................................................................................................................................................................................
Neonatal sepsis
..............................................................................................................................................................................................................................................
Birth injury
..............................................................................................................................................................................................................................................
Neonatal composite morbidity 145 (51.4%)
159 (76.1%)
0.69
0.41-1.16
Neonatal intensive care unit admission
171 (81.8%)
0.84
0.46-1.51
..............................................................................................................................................................................................................................................
177 (62.8%)
.............................................................................................................................................................................................................................................. a
Multivariable analysis controlled for gestational age, maternal age, black race, corticosteroids, body mass index, and small for gestational age.
Alanis. Early-onset severe preeclampsia. Am J Obstet Gynecol 2008.
and postnatal exposures.20 Although the number of days on mechanical ventilation was greater in the elective cesarean delivery group compared with the IOL group, this difference was not statistically significant after adjustment for confounders. Overall, success rates after IOL in women with early-onset severe preeclampsia have ranged from 3265%13-18; our rate of 53.5% is in line with these other studies. Similar to Blackwell et al,17 we found a very low rate of success in women who underwent IOL at ⬍28 weeks of gestation. Given the increased cost21 and morbidity22 of cesarean delivery after a failed trial of labor and the very low rate of success in this group, it is prudent to consider elective cesarean delivery at ⬍28 weeks of gestation in women with early-onset severe preeclampsia. Limitations to this study include a retrospective design and lack of infor262.e5
mation on confounders, other than those reported, that might have influenced assignment of delivery mode and neonatal outcomes, such as umbilical cord Doppler ultrasound and the amniotic fluid index. In addition, small for gestational age as determined by birthweight was used as a surrogate for suspected intrauterine growth restriction in the regression models, because information on antepartum estimated fetal weight was not available. However, this study demonstrated that neither assignment of delivery mode nor successful vaginal delivery were associated with the finding of small for gestational age. In summary, our study demonstrates an acceptably high rate of successful labor induction in women with severe preeclampsia at ⱖ28 weeks of gestation and the safety of labor induction in regards to neonatal outcomes. The high rate of elective cesarean delivery, despite the lack of absolute contraindications to a
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ACKNOWLEDGMENTS We thank William Goodnight, MD, for his thoughtful comments and general advice regarding the statistical methods that were used in the original and revised versions of the article.
REFERENCES 1. Ananth CV, Vintzileos AM. Maternal-fetal conditions necessitating a medical intervention resulting in preterm birth. Am J Obstet Gynecol 2006;195:1557-63. 2. Meis PJ, Goldenberg RL, Mercer BM, et al. The term prediction study: risk factors for indicated preterm births. Am J Obstet Gynecol 1998;178:562-7. 3. Catanzarite V, Quirk JG, Aisenbrey G. How do perinatologists manage preeclampsia? Am J Perinatol 1991;8:7-10. 4. Wax JR, Cartin A, Pinette MG, Blackstone J. Patient choice cesarean: an evidence-based review. Obstet Gynecol Surv 2004;59:601-16. 5. Drife J. Mode of delivery in the early preterm infant (⬍28 weeks). BJOG 2006;113(suppl): 81-5. 6. Clark SL, Hankins GDV. Temporal and demographic trends in cerebral palsy: fact and fiction. Am J Obstet Gynecol 2003;188:628-33. 7. von Dadelszen P, Phil D, Magee LA, Roberts JM. Subclassification of preeclampsia. Hypertens Pregnancy 2003;22:143-8. 8. American College of Obstetricians and Gynecologists. Diagnosis and management of preeclampsia and eclampsia. Obstet Gynecol 2002;99:159-68. 9. Brenner WE, Edelman DA, Hendricks CH. A standard of fetal growth for the United States of America. Am J Obstet Gynecol 1976;126: 555-64. 10. Weinstein L. Syndrome of hemolysis, elevated liver enzymes, and low platelet count: severe consequence of hypertension in pregnancy. Am J Obstet Gynecol 1982;142: 159-67.
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www.AJOG.org 11. Coppage KH, Polzin WJ. Severe preeclampsia and delivery outcomes: is immediate cesarean delivery beneficial? Am J Obstet Gynecol 2002;186:921-3. 12. Hall DR, Odendaal HJ, Steyn DW. Delivery of patients with early onset, severe pre-eclampsia. Int J Gynecol Obstet 2001;74:143-50. 13. Alexander JM, Bloom SL, McIntire DD, Leveno KJ. Severe preeclampsia and the very low birth weight infant: is induction of labor harmful? Obstet Gynecol 1999;93:485-8. 14. Regenstein AC, Laros RK Jr, Wakeley A, Kitterman JA, Tooley WH. Mode of delivery in pregnancies complicated by preeclampsia with very low birth weight infants. J Perinatol 1995;15:2-6.
15. Chibber RM. Severe preeclampsia and the very-low-birth-weight infant: the controversy over delivery mode continues. J Reprod Med 2002;47:925-30. 16. Nassar AH, Adra AM, Chakhtoura N, GomezMarin O, Beydoun S. Severe preeclampsia remote from term: labor induction or elective cesarean delivery? Am J Obstet Gynecol 1998;179:1210-3. 17. Blackwell SC, Redman ME, Tomlinson M, et al. Labor induction for the preterm severe pre-eclamptic patient: is it worth the effort? J Matern Fetal Med 2001;10:305-11. 18. Mashiloane CD, Moodley J. Induction or caesarean section for preterm pre-eclampsia? J Obstet Gynaecol 2002;22:353-6.
19. Hook B, Kiwi R, Amini SB. Fanaroff A, Hack M. Neonatal morbidity after elective repeat cesarean section and trial of labor. Pediatrics 1997;100:348-53. 20. Baraldi E, Filippone M. Chronic lung disease after premature birth. N Engl J Med 2007; 357:1946-55. 21. Allen VM, O’Connell CM, Farrell SA, Baskett TF. Economic implications of method of delivery. Am J Obstet Gynecol 2005;193:192-7. 22. Allen VM, O’Connell CM, Liston RM, Baskett TF. Maternal morbidity associated with cesarean delivery without labor compared with spontaneous onset of labor at term. Obstet Gynecol 2003;102:477-82.
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Early-onset severe preeclampsia: induction of labor vs elective cesarean delivery and neonatal outcomes Mark C. Alanis, MD; Christopher J. Robinson, MD; Thomas C. Hulsey, ScD, MSPH; Myla Ebeling, RA; Donna D. Johnson, MD OBJECTIVE: The purpose of this study was to describe the success rate of and analyze differences in neonatal outcomes with labor induction, compared with elective cesarean delivery in women with earlyonset severe preeclampsia. STUDY DESIGN: We conducted a cross-sectional study of women with
and 68.8% of women who underwent labor induction between 24 and 28, 28 and 32, and 32 and 34 weeks of gestation, respectively. Induction of labor was not associated with an increase in neonatal morbidity or mortality rate after we controlled for gestational age and other confounders.
severe preeclampsia who required delivery between 24 and 34 weeks of gestation. Bivariate and multivariable regression analyses were used to determine factors that were associated with assignment to, success of, and odds of neonatal outcomes after induction of labor.
CONCLUSION: Neonatal outcomes are not worsened by induction of labor in women with early-onset severe preeclampsia, although it is rarely successful at ⬍28 weeks of gestation.
RESULTS: Fifty-seven and four-tenths percent of 491 women under-
went induction of labor. Vaginal delivery occurred in 6.7%, 47.5%,
Key words: cesarean delivery, induction of labor, neonatal morbidity, preeclampsia
Cite this article as: Alanis MC, Robinson CJ, Hulsey TC, Ebeling M, Johnson DD. Early-onset severe preeclampsia: induction of labor vs elective cesarean delivery and neonatal outcomes. Am J Obstet Gynecol 2008;199:262.e1-262.e6.
P
reeclampsia is the leading cause of medically indicated preterm birth and accounts for 25-43% of all such births.1,2 Most patients with preeclampsia whose condition requires preterm delivery will not be in spontaneous labor. The obstetrician then faces a dilemma regarding the optimal mode of delivery after the absolute obstetric indications for cesarean delivery have been excluded. Even with reassuring fetal status, many obstetricians favor elective cesarean delivery over an induction of labor (IOL) in such patients. In a survey of severe preeclampsia practice patterns among members of the Society of Peri-
From the Departments of Obstetrics and Gynecology (Drs Alanis, Robinson, and Johnson) and Pediatrics (Dr Hulsey and Ms Ebeling), Medical University of South Carolina, Charleston, SC. This study was presented at the 28th annual meeting of the Society for Maternal–Fetal Medicine, Dallas, TX, Jan. 28-Feb. 2, 2008. Received March 1, 2008; accepted June 24, 2008 Reprints not available from the authors. 0002-9378/$34.00 © 2008 Mosby, Inc. All rights reserved. doi: 10.1016/j.ajog.2008.06.076
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natal Obstetricians, the estimated overall cesarean delivery rate was 73% (range, 10-100%) for infants ⬍32 weeks of gestation in pregnancies that were complicated by preeclampsia.3 Cesarean delivery, however, may not improve neonatal outcomes, despite the avoidance of the stress of labor.4 Reviews of primary elective cesarean delivery demonstrate that the balance of short- and longterm neonatal morbidity favors vaginal delivery for preterm fetuses.5 In addition, elective cesarean delivery has not reduced the rate of cerebral palsy, which contrasts with the belief that prelabor cesarean delivery may be neuroprotective.6 However, the patient with early-onset (⬍34 weeks of gestation) severe preeclampsia often faces unique challenges. Increased attention has focused on the optimal management of delivery in such women, given the prevalence of low parity, unfavorable cervical examinations, and pathologic cardiovascular and renal manifestations that can result in increased maternal or fetal compromise.7 The objectives of this study were (1) to describe the success rate of IOL, (2) to identify factors that are associated with the decision to proceed with an IOL vs elective cesarean delivery, and (3) to analyze the relationship of IOL vs elective
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cesarean delivery on neonatal outcomes in women with early-onset severe preeclampsia.
M ATERIALS AND M ETHODS Patients This was a cross-sectional study of women who delivered at the Medical University of South Carolina (the region’s tertiary referral center) between January 1, 1996, and December 31, 2006, was approved by the Institutional Review Board. Early-onset severe preeclampsia was defined as new onset hypertension (systolic blood pressure ⱖ140 mm Hg or diastolic blood pressure ⱖ90 mm Hg at least twice ⱖ6 hours apart) and proteinuria (ⱖ300 mg per 24hour period or ⱖ1⫹ on random urine dipstick in the acute setting) after 20 weeks of gestation with severe criteria according to guidelines published by the American College of Obstetricians and Gynecologists8 in women who required delivery between 24 and 34 weeks of gestation. Patients were excluded if obstetric contraindications to labor were present, such as noncephalic presentation, placenta previa, or active genital herpes. Other exclusion criteria included patients with spontaneous preterm labor
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www.AJOG.org or ruptured membranes, any evidence of fetal distress before assignment to an IOL or elective cesarean delivery, multiple gestation, HIV-positive status, or a known fetal anomaly. In addition, patients with intrapartum eclampsia were excluded because of low frequency and a very high rate of emergent cesarean delivery in this group. Standard practice at our institution during the study period included an attempt to provide 48 hours of intramuscular corticosteroids for fetal lung maturation; intrapartum intravenous magnesium sulfate was provided during the intrapartum period and continued for at least 24 hours after delivery for seizure prophylaxis in all patients. Methods of labor induction, determined on an individual basis by an attending physician, included oxytocin, prostaglandin E2, vaginal misoprostol, and transcervical balloon catheter with or without oxytocin.
Data A research-quality perinatal database, which links maternal and neonatal records for all deliveries at the Medical University of South Carolina, was used to obtain maternal, obstetric, and neonatal data. The database is populated according to an active surveillance system whereby information is abstracted specifically for the purpose of this database. The inter- and intrarater reliability both exceed 97%, and logical error checks are performed routinely on all data that are entered by trained personnel. Assignment of delivery mode was described as IOL or elective cesarean delivery, and the ultimate mode of delivery was described as vaginal or cesarean delivery. A failed IOL was defined as a cesarean delivery after an unsuccessful labor induction with or without fetal distress. An elective cesarean delivery was defined as a cesarean delivery in the absence of an IOL. The decision to induce a patient to delivery, proceed with cesarean delivery for failed IOL, or perform an elective cesarean delivery was made by the attending physician. Success rates of IOL were reported within clinically relevant gestational age categories: 24-28, 28-32, and 32-34 weeks of gestation. Maternal variables that were analyzed were age at de-
livery, parity, cervical dilation before assignment of delivery mode, previous cesarean delivery, prepregnancy body mass index (kg/m2), and race (black or non-black). Neonatal outcomes included birthweight, Apgar score at 5 minutes ⬍7, neonatal death, hyaline membrane disease, bronchopulmonary dysplasia, transient tachypnea of the newborn infant, retinopathy of prematurity, intracranial hemorrhage (grade III or IV intraventricular hemorrhage or periventricular hemorrhage), necrotizing enterocolitis, neonatal seizures, neonatal sepsis, birth injury (cephalhematoma, any fracture, or nerve palsy), and neonatal intensive care unit (NICU) admission and duration of stay. In addition, a composite neonatal index was defined as ⱖ1 of any adverse neonatal outcome, except 5-minute Apgar score ⬍7 and NICU admission, because only discrete neonatal pathologic conditions were considered. Small for gestational age was defined as a birthweight ⬍10th percentile for gestational age calculated with the use of population birthweight tables.9
Statistical analysis Data were reported in medians (interquartile range), and percents for continuous and categoric variables, respectively. All analyses were performed according to the intention-to-treat principle (IOL or elective cesarean delivery) rather than by delivery outcomes (vaginal vs cesarean delivery). Bivariate analyses were performed with Wilcoxon rank sum and chisquare tests to assess the relationship between IOL and continuous and categoric variables, respectively. The Cochran-Armitage test for trend was used to compare 2-level categoric variables across the 3-levels of gestational age categories. Multivariable logistic regression analyses were performed to determine whether specific maternal or fetal variables were significant predictors of assignment to and success of IOL. Both models included gestational age, nulliparity, previous cesarean delivery, cervical dilation ⬎1 cm, small for gestational age, black race, maternal age, and hemolysis, elevated liver
enzymes and low platelets (HELLP) syndrome.10 In addition, fetal distress in labor was also included as a predictor in the model for successful IOL. Multivariable logistic regression was performed to determine whether the odds of receiving corticosteroids were affected by IOL after we controlled for HELLP syndrome (as a marker of maternal condition severity), gestational age, and fetal distress. Finally, multivariable linear and logistic regression analyses were performed for continuous and dichotomous variables, respectively, to determine whether the odds of neonatal outcomes were increased or decreased by IOL, after we controlled for the following clinically significant variables: gestational age, maternal age, maternal body mass index, black race, intramuscular corticosteroids for fetal lung maturity, and small for gestational age. Adjusted odds ratios with 95% CIs were reported, and 2-tailed probability values of ⬍.05 were considered statistically significant for all tests. Statistical analysis was performed with SAS software (version 9.1; SAS Institute, Inc, Cary, NC).
R ESULTS Figure 1 describes how patients were selected and analyzed. Four hundred ninety-one eligible women were identified. Overall, vaginal delivery was successful in 53.5% (n ⫽ 151) of women who underwent IOL. Mode of delivery outcomes by gestational age are listed in Table 1. Success rates for IOL were 6.7%, 47.5%, and 68.8% for women delivering at 24-28, 28-32, and 32-34 weeks of gestation, respectively. Maternal characteristics and percent small for gestational age are listed in Table 2 in relation to assignment to IOL or elective cesarean delivery. Both assignment to and success of IOL were significantly and negatively associated with decreasing gestational age, nulliparity, and previous cesarean delivery (Table 3). In addition, fetal distress in labor was associated significantly with a reduction in successful IOL but did not differ by gestational age category (P ⫽
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.32). There was a 58% decrease in the odds of a patient being assigned to IOL if the HELLP syndrome was present (P ⫽ .01), but this did not affect the success of IOL if the patient was assigned already (P ⫽ .4). Overall, 84.9% of mothers received a course of intramuscular corticosteroids before delivery. After we controlled for distress and HELLP syndrome, intramuscular corticosteroid use was significantly lower with advancing gestational age (odds ratio [OR], 0.29; 95% CI, 0.17-0.49 per 4 weeks) and significantly higher with IOL (OR, 2.5; 95% CI, 1.4-4.5; Figure 2). The median birthweights among women who underwent IOL and elective cesarean delivery were 1467.5 g (range, 1220.0-1805.0 g) and 1160.0 g (range, 835.0-1560.0 g), respectively (P ⬍ .001). This reflects the higher number of patients who undergo elective cesarean delivery at earlier gestational ages. There were no differences in individual or composite neonatal outcomes for women who underwent IOL vs women who underwent elective cesarean delivery, except for bronchopulmonary dysplasia (Table 4). IOL was associated with a 52% decrease in the odds for bronchopulmonary dysplasia after being controlled for gestational age, corticosteroids, and other confounders. The duration for which neonates required mechanical ventilation was greater in the elective cesarean delivery group (6.0, range, 2-23 days) compared with the IOL group (3.0, range 2-28 days, P ⱕ .001). However, this difference disappeared after adjustment for gestational age (data not shown). Newborn infants who were delivered by elective cesarean delivery required 7 more days in the NICU, although this was not significant after ad-
FIGURE 1
Patient selection flow diagram
Alanis. Early-onset severe preeclampsia. Am J Obstet Gynecol 2008.
justment for gestational age, corticosteroids, and other confounders (P ⫽ .07).
C OMMENT This study shows that labor induction should be considered strongly in eligible women with early-onset severe preeclampsia between 28 and 34 weeks of gestation, regardless of suspected intrauterine growth restriction, preripening cervical dilation, or parity. Before 28 weeks of gestation, however, labor induction is rarely successful. Although fetal distress often leads to cesarean deliv-
ery in laboring patients with early-onset severe preeclampsia, the rate of neonatal morbidity is not increased in patients who have at least attempted a vaginal delivery. When labor induction is not successful, fetal distress is present in approximately one-half of the cases, regardless of the gestational age. Several studies have attempted to address the role of labor induction in women with early-onset severe preeclampsia. However, conclusions from many of these studies are limited by several problems that include comparison
TABLE 1
Delivery outcomes among 3 clinically relevant groups of gestational age Gestational age (wk)
Vaginal delivery (n)
Failed IOL with fetal distress (n)
Failed IOL without fetal distress (n)
Elective cesarean delivery (n)
24-28 (n ⫽ 56)
1 (1.8%)
7 (12.5%)
7 (12.5%)
41 (73.2%)
28-32 (n ⫽ 286)
75 (26.2%)
44 (15.4%)
39 (13.6%)
128 (44.8%)
32-34 (n ⫽ 149)
75 (50.3%)
17 (11.4%)
17 (11.4%)
40 (26.9%)
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TABLE 2
FIGURE 2
Maternal and fetal factors that were associated with assignment of delivery mode
Frequency of corticosteroid administration in women with early-onset severe preeclampsia
IOL (n ⴝ 282)
Variable b
Elective cesarean delivery (n ⴝ 209)
P valuea
Maternal age (y)
25.0 (21-31)
27.0 (23-32)
.003c
Body mass index (kg/m )
31.0 (27-36)
32.0 (27-38)
.33
99 (47.4%)
.005
.............................................................................................................................................................................................................................................. 2b c ..............................................................................................................................................................................................................................................
Nulliparity (n)
170 (60.3%)
..............................................................................................................................................................................................................................................
11 (3.9%)
87 (41.6%)
⬍.001
180 (63.8%)
120 (57.4%)
.15
Small for gestational age (n)
76 (27.0%)
56 (26.8%)
.97
HELLP syndrome (n)
24 (8.5%)
34 (16.3%)
.009
Previous cesarean delivery (n)
..............................................................................................................................................................................................................................................
Black race (n)
.............................................................................................................................................................................................................................................. .............................................................................................................................................................................................................................................. .............................................................................................................................................................................................................................................. a
Chi-square test unless otherwise noted.
b
Data are presented as medians (IQR).
c
Wilcoxon rank sum test
CS, cesarean section. Alanis. Early-onset severe preeclampsia. Am J Obstet Gynecol 2008.
Alanis. Early-onset severe preeclampsia. Am J Obstet Gynecol 2008.
of vaginal delivery with cesarean delivery with or without labor,11 comparison of cases of IOL with cases of emergent cesarean delivery,12 and analysis of outcomes by birthweight rather than by gestational age.13-15 Strengths of this study include a relatively large study population, categorization of women into clinically relevant gestational age categories, and analysis of neonatal outcomes according to the intention-to-treat principle by a comparison of IOL with elective cesarean delivery, instead of by the ultimate mode of delivery.
Our finding that IOL is not associated with adverse neonatal outcomes agrees with several previous studies15-17 and disagrees with others.13,18 The study by Mashiloane and Moodley18 demonstrated increased perinatal mortality rates in women who underwent IOL at ⬍27 weeks of gestation. However, this study was conducted in a developing country, where significant differences in newborn care are likely. In the study by Alexander et al,13 a 5-minute Apgar score of ⬍3 was more common in women who underwent IOL, although
no differences in survival or other neonatal outcomes were reported. Our finding of reduced bronchopulmonary dysplasia with IOL compared with elective cesarean delivery must be interpreted with caution. However, labor has been shown to decrease the occurrence and severity of neonatal respiratory distress syndrome,19 which may reduce the length of time that mechanical ventilator assistance is required for premature neonates. Bronchopulmonary dysplasia is primarily a chronic pulmonary disease that is related directly to the use of mechanical ventilation and other antenatal
TABLE 3
Factors that were associated with assignment to and success of IOL Factor
Assignment to IOL Adjusted ORa
95% CI
Successful IOL Adjusted ORb
95% CI
Increasing gestational age
1.54
1.38-1.72
1.43
1.24-1.66
Nulliparity
0.29
0.15-0.55
0.21
0.11-0.42
Previous cesarean delivery
0.01
0.01-0.03
0.09
0.02-0.40
Fetal distress
—
—
0.32
0.18-0.57
HELLP syndrome
0.42
0.22-0.82
0.65
0.24-1.79
Cervical dilation ⬎1 cm
1.19
0.32-4.37
1.95
0.52-7.38
Small for gestational age
0.81
0.48-1.36
0.74
0.39-1.38
Black race
1.31
0.79-2.16
1.78
0.97-3.26
Increasing maternal age
0.97
0.94-1.01
0.94
0.90-0.99
................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ a
Multivariable analysis was adjusted for gestational age, nulliparity, HELLP syndrome, previous cesarean delivery, cervical dilation ⬎1 cm, small for gestational age, black race, and maternal age.
b
Multivariable analysis was adjusted for gestational age, nulliparity, HELLP syndrome, previous cesarean delivery, fetal distress, cervical dilation ⬎1 cm, small for gestational age, black race, and maternal age.
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TABLE 4
Effects of IOL on neonatal outcomes in women with early-onset severe preeclampsiaa Outcome (n)
IOL (n ⴝ 282)
Elective cesarean delivery Adjusted (n ⴝ 209) OR 95% CI
Apgar score at 1 minute ⬍7
153 (54.3%)
126 (60.3%)
1.20
0.77-1.86
Apgar score at 5 minutes ⬍7
60 (21.3%)
51 (24.4%)
1.51
0.90-2.00
7 (2.5%)
18 (8.6%)
1.12
0.38-3.34
.............................................................................................................................................................................................................................................. ..............................................................................................................................................................................................................................................
Neonatal death
..............................................................................................................................................................................................................................................
Hyaline membrane disease
118 (41.8%)
142 (68.0%)
0.68
0.41-1.13
Bronchopulmonary dysplasia
26 (9.2%)
69 (33.0%)
0.48
0.24-0.97
Transient tachypnea newborn infant
8 (2.8%)
9 (4.3%)
0.32
0.10-1.04
Intracranial hemorrhage
9 (3.2%)
8 (3.8%)
1.91
0.56-6.41
Periventricular leukomalacia
2 (0.7%)
6 (2.9%)
0.73
0.11-4.70
Neonatal seizures
3 (1.1%)
1 (0.5%)
2.32
0.19-27.95
Retinopathy of prematurity
3 (1.1%)
4 (1.9%)
2.72
0.38-19.60
Necrotizing enterocolitis
9 (3.2%)
10 (4.8%)
1.95
0.61-6.27
44 (15.6%)
66 (31.6%)
0.83
0.48-1.43
7 (2.5%)
1 (0.5%)
5.74
0.62-52.91
.............................................................................................................................................................................................................................................. ..............................................................................................................................................................................................................................................
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trial of labor, highlights the need for better predictors of safe and successful labor induction practices in women with early-onset severe preeclampsia. Such research strategies include the assessment of various cervical ripening methods and the role of umbilical cord and fetal Doppler studies before the decision to induce labor in such women is made. A randomized clinical trial of IOL vs elective cesarean delivery for stable patients with early-onset severe preeclampsia and reassuring fetal status would be the gold standard clinical design, although this would be very difficult to conduct, given the low rate of eligible candidates at ⬍28 f weeks of gestation.
.............................................................................................................................................................................................................................................. .............................................................................................................................................................................................................................................. .............................................................................................................................................................................................................................................. ..............................................................................................................................................................................................................................................
Neonatal sepsis
..............................................................................................................................................................................................................................................
Birth injury
..............................................................................................................................................................................................................................................
Neonatal composite morbidity 145 (51.4%)
159 (76.1%)
0.69
0.41-1.16
Neonatal intensive care unit admission
171 (81.8%)
0.84
0.46-1.51
..............................................................................................................................................................................................................................................
177 (62.8%)
.............................................................................................................................................................................................................................................. a
Multivariable analysis controlled for gestational age, maternal age, black race, corticosteroids, body mass index, and small for gestational age.
Alanis. Early-onset severe preeclampsia. Am J Obstet Gynecol 2008.
and postnatal exposures.20 Although the number of days on mechanical ventilation was greater in the elective cesarean delivery group compared with the IOL group, this difference was not statistically significant after adjustment for confounders. Overall, success rates after IOL in women with early-onset severe preeclampsia have ranged from 3265%13-18; our rate of 53.5% is in line with these other studies. Similar to Blackwell et al,17 we found a very low rate of success in women who underwent IOL at ⬍28 weeks of gestation. Given the increased cost21 and morbidity22 of cesarean delivery after a failed trial of labor and the very low rate of success in this group, it is prudent to consider elective cesarean delivery at ⬍28 weeks of gestation in women with early-onset severe preeclampsia. Limitations to this study include a retrospective design and lack of infor262.e5
mation on confounders, other than those reported, that might have influenced assignment of delivery mode and neonatal outcomes, such as umbilical cord Doppler ultrasound and the amniotic fluid index. In addition, small for gestational age as determined by birthweight was used as a surrogate for suspected intrauterine growth restriction in the regression models, because information on antepartum estimated fetal weight was not available. However, this study demonstrated that neither assignment of delivery mode nor successful vaginal delivery were associated with the finding of small for gestational age. In summary, our study demonstrates an acceptably high rate of successful labor induction in women with severe preeclampsia at ⱖ28 weeks of gestation and the safety of labor induction in regards to neonatal outcomes. The high rate of elective cesarean delivery, despite the lack of absolute contraindications to a
American Journal of Obstetrics & Gynecology SEPTEMBER 2008
ACKNOWLEDGMENTS We thank William Goodnight, MD, for his thoughtful comments and general advice regarding the statistical methods that were used in the original and revised versions of the article.
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