Original Research
Neonatal and Infant Outcomes in Twin Gestations With Preterm Premature Rupture of Membranes at 24–31 Weeks of Gestation Hector Mendez-Figueroa, MD, Joshua D. Dahlke, MD, Oscar A. Viteri, MD, Suneet P. Chauhan, Dwight J. Rouse, MD, MSPH, Baha M. Sibai, MD, and Sean C. Blackwell, MD OBJECTIVE: To describe the perinatal and infant and early childhood morbidity associated with preterm premature rupture of membranes (PROM) in a cohort of twin pregnancies evaluated prospectively with neonatal follow-up to 2 years of age. METHODS: This was a secondary analysis of a randomized controlled trial of magnesium sulfate for prevention of cerebral palsy. Inclusion criteria were twin gestation with preterm PROM diagnosed between 24 0/7 and 31 6/7 weeks of gestation and planned expectant management. Latency (time from membrane rupture to delivery) and perinatal outcomes were evaluated by gestational age at membrane rupture. Long-term neonatal outcomes were also analyzed. RESULTS: Among 151 women who met inclusion criteria, the median gestational age at preterm PROM was 28.1 weeks (range 24.1–31.6 weeks). Approximately onethird of women achieved a latency of at least 1 week. Gestational age at preterm PROM (odds ratio [OR] 0.75, 95% confidence interval [CI] 0.63–0.90 for each week after 24 weeks of gestation) and cervical dilation at admission (OR 0.66, 95% CI 0.49–0.90 for each centimeter of dilation) were inversely associated with a latency
From the Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Texas Health Science Center at Houston, Houston, Texas; and the Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Women and Infants’ Hospital, Warren Alpert Medical School of Brown University, Providence, Rhode Island. Dr. Rouse, Associate Editor of Obstetrics & Gynecology, was not involved in the review or decision to publish this article. Corresponding author: Hector Mendez-Figueroa, MD, Department of Obstetrics, Gynecology and Reproductive Sciences, Division of Maternal Fetal Medicine, University of Texas Health Science Center Houston, 6431 Fannin, MSB 3.286, Houston, TX 77030; e-mail: [email protected]. Financial Disclosure The authors did not report any potential conflicts of interest. © 2014 by The American College of Obstetricians and Gynecologists. Published by Lippincott Williams & Wilkins. ISSN: 0029-7844/14
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period of at least 1 week. There were no stillbirths (95% CI 0–1%), but the rate of neonatal mortality was 90 per 1,000 newborns (95% CI 57–112) with a 7.3% cerebral palsy rate among survivors (95% CI 4.4–10.3%). CONCLUSION: In twin pregnancies, preterm PROM from 24 to 31 weeks of gestation is associated with a neonatal mortality rate of 9.0% and an overall cerebral palsy rate of 7.3%. A longer latency period is associated with less advanced cervical dilation and later gestational age at PROM. (Obstet Gynecol 2014;124:323–31) DOI: 10.1097/AOG.0000000000000369
LEVEL OF EVIEDENCE: II
P
reterm premature rupture of membranes (PROM) is a major contributing factor to the risk of preterm birth in multiple gestations.1 Although the risk of preterm PROM with singletons is 2–4%, it occurs in 7–8% of twins.2 Using data from the National Center of Health Statistics, Kristensen et al3 estimated that approximately 6% of stillbirths, 15% of neonatal mortality, and 14% of infant mortality among twins are attributable to preterm PROM. Prior studies of twins with preterm PROM have mostly reported results from one center, had small sample sizes, included different gestational age ranges, administered antenatal corticosteroid variably, or included patient with twin–twin transfusion syndrome or after fetal interventions.2,4–10 The natural history of preterm PROM in twin pregnancies has not been extensively described. Since expectant management of early preterm PROM has become a common clinical practice in modern obstetrics, knowledge of the risks, benefits, and longterm outcomes is therefore required to appropriately counsel patients. Based on a PubMed search from 1950 to 2014 of the English language using the terms
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Table 1. Publications on Twins With Premature Rupture of Membranes No. of Centers
Study Period (y)
n
Included Gestational Age (wk)
Gestational Age at PROM (wk)
Mercer et al, 1993
1
11
90
19–36
30.1*
Hsieh et al, 1999
1
10
48
20–36
29.7*
Bianco et al, 1996
1
116
24–36
32.4*
Myles et al, 1997 Jacquemyn et al, 2003
1 1
3 5
28 33
Less than 36 20–36
29.5 NR
Von Dadelszen et al, 2003
3
2
246
24–36
31.3*
Trentacoste et al, 2008 Ehsanipoor et al, 2012
1 1
3 9
49 41
24–34 24–32
31.0† 27.7*
Study
PROM, premature rupture of membranes; NR, not reported; NICU, neonatal intensive care unit; PVL, periventricular leukomalacia; PDA, patent ductus arteriosus; TTN, transient tachypnea of the newborn. * Mean. † Median.
“PPROM,” “twins,” “multiple gestation,” and “rupture membranes,” eight studies of twin pregnancy complicated by preterm PROM have been published to date, all of them retrospective, which do not report on longterm neonatal or infant outcomes (Table 1).2,4–10 The purposes of this secondary analysis of a randomized controlled trial of magnesium sulfate for the prevention of cerebral palsy are 1) to describe the peripartum and neonatal outcomes with preterm PROM at 24 0/7 to 31 6/7 weeks of gestation stratified by gestational age at membrane rupture; 2) report both the long-term neonatal and infant outcomes for up to 2 years of age within this cohort; and 3) identify factors associated with a latency period greater than 7 days.
MATERIALS AND METHODS This study is a secondary analysis of a multicenter randomized trial that evaluated the use of magnesium sulfate for the prevention of moderate to severe cerebral palsy or death among infants born prematurely. Full
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details of this study have been reported.11 In brief, gravid women between 24 0/7 and 31 6/7 weeks of gestation at high risk for preterm birth were randomized to receive magnesium sulfate (a loading dose of 6 g infused for 20–30 minutes followed by a maintenance infusion of 2 g per hour) or placebo. Excluded from the parent trial were all higher order multiples, multiple gestations managed by fetal reduction, patients with rupture of membranes before 22 0/7 weeks, and known fetal anomalies.11 For this trial, the diagnosis of preterm PROM was made when any two of the following were documented: 1) pooling of fluid in the vaginal vault; 2) a positive Nitrazine test; or 3) ferning of vaginal fluid or by any one of the following: indigo carmine pooling in the vagina after amnioinfusion or visible leakage of amniotic fluid from the cervix. Cervical dilation and effacement were assessed either by visual or digital examination. Chorioamnionitis was diagnosed when the maternal temperature was at least 100°F (37.8°C) in the presence of at least one of the
Neonatal Outcomes in Twin Preterm PROM
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Corticosteroids Latency (%) Period
Latency Related to
Chorioamnionitis (%)
Fetal or Neonatal Death
Reported Neonatal Morbidity Intraventricular hemorrhage, respiratory distress syndrome, hyaline membrane disease, pneumonia, necrotizing enterocolitis, meningitis, sepsis, mechanical ventilation, neonatal death Intraventricular hemorrhage, respiratory distress syndrome, hyaline membrane disease, pneumonia, necrotizing enterocolitis, NICU admission, death Intraventricular hemorrhage, pneumonia, necrotizing enterocolitis, NICU admission NR Intraventricular hemorrhage, PVL, respiratory distress syndrome, PDA, retinopathy of prematurity, necrotizing enterocolitis, death Intraventricular hemorrhage, TTN, sepsis, meconium aspiration, neonatal death Neonatal death Intraventricular hemorrhage, necrotizing enterocolitis, pneumonia, respiratory distress syndrome, sepsis, neonatal death
25.3
86.1 h*
Gestational age
30.4
2.5%/19%
NR
3.4 d*
Gestational age
17.6
NR/8.3%
11
11.4 h†
Gestational age
25
73.9 81.8
3.0 d† 19 h†
NR Gestational age
8.7 15.2
3.6%/NR 0%/9.1%
38.7
22.5 h†
Gestational age, chorioamnionitis
13.8
0%/4.1%
NR 95.0
0 d† 3.6 d†
Gestational age NR
16.3 9.8
0%/8.2% 0%/4.9%
following: malodorous fluid, persistent fetal tachycardia, persistent maternal tachycardia, uterine tenderness, or maternal leukocytosis greater than 20,000 cells per millimeters cubed. The use of tocolytics drugs was proscribed by the study design; the use of steroids and antibiotics was left to the discretion of the managing physicians. Neonatal outcomes including neonatal intensive care admission, days spent in the hospital, respiratory distress syndrome, need for mechanical ventilation, culture-proven sepsis, intraventricular hemorrhage grades 3 or 4, bronchopulmonary dysplasia, retinopathy of prematurity, periventricular leukomalacia, necrotizing enterocolitis, stillbirth, and neonatal death were analyzed and reported for the entire study population as well as by the gestational age at which preterm PROM occurred. After delivery, live-born infants were evaluated with up to three follow-up visits (until the corrected age of 2 years) in which detailed developmental assessments were performed by trained examiners.
3%/NR
Infants with a normal neurologic examination at 1 year of age were deemed not to have developed cerebral palsy and thus did not require any further neurologic evaluation. The diagnosis of cerebral palsy was made if two or more of the following three features were present: a delay of 30% or more in gross motor developmental milestones (eg, inability to sit without arm support by 9.5 months or walk by 17 months of corrected age); abnormality in muscle tone (eg, scissoring), 4+ or absent deep tendon reflexes, or movement abnormality (eg, posturing or gait asymmetry); or persistence of primitive reflexes or absence of protective reflexes.11 The STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) guidelines for reporting observational studies were followed. This analysis is limited to women with twin gestation complicated by preterm PROM enrolled in this trial irrespective of whether they were allocated to magnesium sulfate. To assess the effects of gestational age at preterm PROM on
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neonatal outcomes, we created four mutually exclusive categories: 24 0/7–26 0/7 weeks of gestation, 26 1/7–28 0/7 weeks of gestation, 28 1/7–30 0/7 weeks of gestation, and 30 1/7–31 6/7 weeks of gestation. A comparison was performed stratified by administration of magnesium sulfate, presenting compared with nonpresenting twin, route of delivery, newborn gender, and birth weight discordance to assess their effect on neonatal outcomes. To identify factors associated with latency period of at least 7 days or more, nine variables of interest (gestational age at membrane rupture, maternal age, African American race, Hispanic ethnicity, prepregnancy body mass index (calculated as weight (kg)/ [height (m)]2), nulliparity, cervical dilation at admission, administration of antenatal steroids, and allocation to intravenous magnesium sulfate administration) were included in the regression analysis using backward elimination. All analyses were performed using SPSS 22. Descriptive statistics were used to report all variables of interest. Continuous variables were compared using Student’s t test, whereas categorical variables were compared using x2 or Fisher’s exact test as appropriate. We calculated odds ratios (ORs) with 95% confidence intervals (CIs) for variables of interest. Confidence intervals excluding integer 1.0 were considered significant. Logistic regression analysis was used to identify independent variables that were associated with a latency period of less than compared with 7 or more days. All tests were two-tailed with P,.05 considered significant. This analysis qualified for exempt status from the institutional review board at the University of Texas Health Science Center at Houston because it involved the study of publically available data.
Table 2. Demographic and Clinical Characteristics of Twins With Preterm Premature Rupture of Membranes
RESULTS
BMI, body mass index; UTI, urinary tract infection; PROM, premature rupture of membranes. Data are median (range) or n (%).
From the original patient population of 2,241 included in the trial, 203 were twin gestations (9.1%). Of these, 164 patients were admitted to the trial with the diagnosis of preterm PROM. One patient did not meet the study criteria for PROM and 13 were diagnosed with preterm PROM before 24 weeks of gestation, leaving a total of 151 (74.4%) eligible for this secondary analysis. Neonatal and infant data were available for 300 out of the 302 live-borns (99.3%). Table 2 shows the baseline demographic characteristics of the participants. Almost all the cohort received antenatal steroids and close to half were allocated to magnesium sulfate. Latency antibiotics were administered in 92% of the participants. The rates of
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Variable
Value
Age (y) Prepregnancy BMI (kg/m2) Less than 30 30 or more Race or ethnicity African American Caucasian Hispanic Other Nulliparous Pregestational or gestational diabetes Preeclampsia Years of education Corticosteroid administration Antibiotics administered Latency Treatment for chorioamnionitis Treatment for UTI Magnesium therapy administration Gestational age at preterm PROM (wk) 24 0/7–26 0/7 26 1/7–28 0/7 28 1/7–30 0/7 30 1/7–31 6/7 Cervical dilation at admission (cm) 0–1 2–3 4–5 6 or greater Average latency period (d) Latency period greater than 48 h Latency period 7 d or greater Latency period 14 d or greater Latency period 30 d or greater Birth weight (g)—median (range)
27.0 (22–31) 26.0 (22.4–31.4) 99 (70.7) 41 (39.3) 50 (33.1) 75 (49.7) 22 (14.6) 4 (2.6) 74 (49.0) 12 (7.9) 2 (0.7) 12.0 (12–15) 147 (97.4) 143 (94.7) 131 (91.6) 11 (7.7) 1 (0.7) 72 (47.7) 28.1 (24.1–31.6) 37 (24.5) 37 (24.5) 36 (23.8) 41 (27.2) 1.0 (0–2) 89 (58.9) 39 (25.8) 15 (9.9) 8 (5.3) 3.9 (1.3–9.9) 101 (68.7) 50 (34.0) 24 (16.3) 8 (5.4) 1,201.0 (937.5–1,516)
corticosteroid administration and latency antibiotic use remained fairly consistent across all gestational ages (P..05 among all comparisons), whereas the rate of neonatal death significantly decreased with advancing gestational age. The average gestational age at membrane rupture was 28.1 weeks. The median latency period was 3.9 days (interquartile range 1.3– 9.9 days); this is shorter than the median latency period of 7.7 days seen in singleton preterm PROM gestations included in the parent trial (P,.01). Only 50 (34.0%) of the study cohort remained pregnant 7 days after preterm PROM.
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Logistic regression indicated that two variables, gestational age at membrane rupture (OR 0.75, 95% CI 0.63–0.90 for each week above 24 weeks of gestation) and cervical dilation at admission (OR 0.66, 95% CI 0.49–0.90 for each centimeter of dilation) were inversely associated with a latency period 7 days or greater. Maternal age, race, parity, and body mass index and allocation to magnesium sulfate were not associated with latency. Table 3 depicts the clinical outcomes by gestational age at which preterm PROM occurred. Maternal morbidity as well as both short-term and long-term neonatal and infant outcomes are reported in Table 4. The combined rate of chorioamnionitis and endometritis was 20% and of cesarean delivery 60%. Of the cases delivered by cesarean, 21 (23.3%) were delivered secondary to fetal indications. The median length of stay in the neonatal intensive care unit was 41.5 days (interquartile range 25.8–63) with a median neonatal hospital stay of 55.0 days (interquartile range 30–70). The rate of Bell’s stage 2 or 3 necrotizing enterocolitis was 5.7%; grade III or IV intraventricular hemorrhage was diagnosed in 5.6%. Neonatal morbidity did not differ between the presenting compared with nonpresenting twin and twins who received magnesium sulfate as opposed to placebo or among twins with discordant birth weight, defined as a birth weight difference 18% or
greater. Route of delivery was not associated with neonatal morbidity. Need for mechanical ventilation (P,.01) and retinopathy of prematurity (P5.03) occurred significantly more frequently with growthrestricted newborns than those with appropriate for gestational age. Male newborns were more like to have retinopathy of prematurity than female (22% compared with 34%; P5.02). The diagnosis of cerebral palsy was made in 7.3% of the neonates (95% CI 4.4–10.3%) of which 3.3% was moderate or severe. Neonatal mortality was 90 per 1,000 live newborns (95% CI 57–112 per 1,000). No stillbirths or deaths at 1 year of age after neonatal intensive care unit discharge were noted (95% CI 0–1%). Neonatal and infant complications were inversely related to gestational age and are depicted in Figure 1A–B.
DISCUSSION This report describes the maternal, neonatal, and infant characteristics of twin pregnancies evaluated prospectively complicated by preterm PROM. We noted that when twin gestations are complicated by preterm PROM at 24 0/7 to 31 6/7 weeks of gestation, a 7-day latency period is seen in approximately onethird of the cases, and one in five cases will be undelivered for 14 days or more. Neonatal outcomes were reported by gestational age at membrane rupture; this allows counseling to be individualized at the
Table 3. Clinical Outcomes by Gestational Age at Time of Rupture of Membranes for Twin Gestations Gestational Age at Time of Rupture of Membranes (wk) Outcome Latency period (d) Latency 48 h or greater 7 d or greater 14 d or greater 30 d or greater Pregnancies delivered at 34 wk of gestation or greater Gestational age at delivery (wk) Chorioamnionitis Endometritis Abruption Cesarean delivery Admission to NICU NICU length of stay (d) Total neonatal hospital stay (d) Stillbirth Neonatal death
24 0/7–26 0/7 (n537)
26 1/7–28 0/7 (n537)
28 1/7–30 0/7 (n536)
30 1/7–31 6/7 (n541)
6.5 (1–15) 29 (78.4) 19 (51.4) 10 (27.0) 4 (10.8) 29 (78.4) 1 (2.7)
4.8 (2–10) 32 (86.5) 17 (45.9) 5 (13.5) 1 (2.7) 32 (86.5) 0
2.5 (1–10) 24 (64.9) 11 (29.7) 8 (21.6) 2 (5.4) 24 (64.9) 2 (5.6)
2.7 (1–5) 26 (70.3) 10 (27.0) 4 (10.8) 2 (5.4) 26 (70.3) 3 (7.3)
26.1 (24.1–27.4) 8 (21.6) 4 (10.8) 0 22 (59.5) 36 (100) 81 (37–105) 84 (63–107.8) 0 17 (23.3)
28.0 (26.3–28.6) 3 (8.1) 6 (16.2) 5 (13.5) 28 (75.7) 37 (100) 57.5 (39–77.8) 61 (48–83) 0 9 (12.3)
29.6 (29.2–30.2) 1 (2.8) 2 (7.7) 1 (2.8) 17 (47.2) 35 (97.2) 39 (28.3–51) 42.5 (33.8–51) 0 0
31.6 (31.1–32.0) 0 5 (12.2) 3 (7.3) 24 (58.5) 38 (92.7) 26 (16.5–36) 28 (21–36) 0 1 (1.2)
NICU, neonatal intensive care unit. Data are median (range) or n (%).
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Table 4. Neonatal and Infant Morbidity and Mortality Associated With Preterm Premature Rupture of Membranes in Twin Pregnancies by Gestational Age at Rupture Variable (Weeks of Gestation)
Per Pregnancy
Per Neonate
Need for mechanical ventilation 24 0/7–26 0/7 26 1/7–28 0/7 28 1/7–30 0/7 30 1/7–32 0/7 Respiratory distress syndrome 24 0/7–26 0/7 26 1/7–28 0/7 28 1/7–30 0/7 30 1/7–32 0/7 Bronchopulmonary dysplasia 24 0/7–26 0/7 26 1/7–28 0/7 28 1/7–30 0/7 30 1/7–32 0/7 Sepsis 24 0/7–26 0/7 26 1/7–28 0/7 28 1/7–30 0/7 30 1/7–32 0/7 Retinopathy of prematurity 24 0/7–26 0/7 26 1/7–28 0/7 28 1/7–30 0/7 30 1/7–32 0/7 Stage 2–3 necrotizing enterocolitis 24 0/7–26 0/7 26 1/7–28 0/7 28 1/7–30 0/7 30 1/7–32 0/7 Intraventricular hemorrhage grades III–IV 24 0/7–26 0/7 26 1/7–28 0/7 28 1/7–30 0/7 30 1/7–32 0/7 Periventricular leukomalacia 24 0/7–26 0/7 26 1/7–28 0/7 28 1/7–30 0/7 30 1/7–32 0/7 Seizures 24 0/7–26 0/7 26 1/7–28 0/7 28 1/7–30 0/7 30 1/7–32 0/7 Cerebral palsy 24 0/7–26 0/7 26 1/7–28 0/7 28 1/7–30 0/7 30 1/7–32 0/7 Moderate to severe cerebral palsy 24 0/7–26 0/7 26 1/7–28 0/7 28 1/7–30 0/7 30 1/7–32 0/7
68.8 (61.0–76.6) 89.9 (80.1–94.9) 91.9 (79.5–100) 69.4 (53.3–85.5) 34.2 (22.3–47.8) 72.0 (63.8–79.3) 91.7 (80.7–100) 86.5 (78.0–100) 61.1 (44.7–77.5) 51.2 (37.9–67.1) 29.3 (22.5–35.7) 63.9 (47.4–80.2) 48.7 (33.3–63.9) 5.6 (0–12.1) 4.9 (0.3–9.8) 31.3 (24.6–37.6) 52.8 (36.5–68.9) 37.8 (24.2–51.5) 19.4 (9.1–29.7) 14.6 (6.4–23.6) 37.3 (29.9–44.3) 66.7 (50.2–83.0) 51.4 (35.7–66.9) 25.0 (11.6–38.6) 7.3 (1.7–13.3) 8.0 (4.2–11.6) 22.2 (11.3–33.0) 13.5 (3.4–23.6) 0 0 10.4 (6.2–13.7) 25.7 (13.8–36.2) 13.9 (4.4–22.6) 2.9 (0–6.7) 0 4.6 (2.1–7.1) 5.7 (0–11.0) 2.8 (0–6.5) 5.8 (0–11.1) 5.2 (0–10.1) 3.3 (1.3–5.4) 2.8 (0–6.5) 8.1 (1.7–14.5) 2.8 (0–6.6) 0 9.8 (5.7–14.1) 21.9 (12.0–32.4) 16.4 (6.7–25.8) 2.8 (0–8.1) 9.8 (2.6–17.4) 6.7 (3.7–9.5) 16.4 (7.7–25.7) 5.5 (0.1–10.7) 0 4.9 (0.3–9.8)
61.7 (56.2–67.2) 87.5 (77.9–99.7) 82.4 (73.7–91.2) 59.7 (71.1–48.3) 22.0 (12.9–30.9) 62.0 (56.5–67.5) 87.5 (80.1–94.9) 77.0 (67.4–86.7) 52.8 (41.2–64.4) 34.2 (23.8–44.5) 21.7 (17.0–26.3) 48.6 (37.4–59.8) 33.8 (22.9–44.6) 4.2 (0–8.8) 2.4 (0–5.8) 20.7 (16.1–25.3) 41.7 (30.7–52.7) 23.0 (13.3–32.6) 11.1 (3.8–18.4) 8.5 (2.5–14.6) 28.0 (22.9–33.1) 54.2 (43.0–65.3) 36.5 (25.4–47.5) 20.8 (11.4–30.3) 3.7 (0–7.8) 5.7 (3.1–8.3) 12.5 (5.1–19.9) 10.8 (3.7–17.9) 0 0 5.6 (2.9–8.2) 12.9 (5.3–20.4) 8.3 (1.9–14.8) 1.5 (0–4.3) 0 2.4 (0.7–4.2) 2.9 (0–6.6) 1.4 (0–4.1) 2.9 (0–6.9) 2.6 (0–6.2) 1.7 (0.2–3.1) 1.4 (0–4.0) 4.1 (0–8.6) 1.4 (0–4.1) 0 7.3 (4.4–10.3) 11.0 (4.0–17.9) 9.6 (2.8–16.4) 2.8 (0–6.6) 6.1 (0.9–11.3) 3.3 (1.3–5.4) 8.2 (2.1–14.3) 2.7 (0–6.5) 0 2.4 (0–5.8) (continued )
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Table 4. Neonatal and Infant Morbidity and Mortality Associated With Preterm Premature Rupture of Membranes in Twin Pregnancies by Gestational Age at Rupture (continued ) Variable (Weeks of Gestation)
Per Pregnancy
Per Neonate
Stillbirth 24 0/7–26 0/7 26 1/7–28 0/7 28 1/7–30 0/7 30 1/7–32 0/7 Neonatal death 24 0/7–26 0/7 26 1/7–28 0/7 28 1/7–30 0/7 30 1/7–32 0/7
0 (0–1.1) 0 (0–1.1) 0 (0–1.1) 0 (0–1.0) 0 (0–1.1) 13.3 (8.6–17.8) 35.6 (22.3–49.9) 19.2 (8.2–12.6) 0 (0–10) 2.4 (0–5.9)
0 (0–0.5) 0 (0–0.8) 0 (0–0.8) 0 (0–0.8) 0 (0–0.7) 9.0 (5.8–12.2) 23.3 (13.9–32.7) 12.3 (4.7–19.9) 0 (0–10) 1.2 (0–3.6)
Data are % (95% CI).
tively. Our results can be used to counsel women and inform neonatologists about the likelihood of complications and inform decision-making about maternal transfer to facilities with appropriate neonatal care expertise.12,13 Several previous studies have also addressed the issue of preterm PROM in twin gestations.2,4–10 These studies are all retrospective and typically compare latency periods between twin and singleton pregnancies.
moment of admission. The two variables—gestational age at preterm PROM and cervical dilation at admission—that are inversely related to latency period are nonmodifiable. The identification of these two variables is consistent with previously published studies.2,4–8 Furthermore, we report both short-term and long-term neonatal and infant outcomes up to 2 years corrected age and found that the overall rate of cerebral palsy and mortality within this cohort was 7.3% and 9.0%, respec-
100
Mechanical ventilation
90 Bronchopulmonary dysplasia
80 Percentage
70
Retinopathy of prematurity
60
Sepsis
50 40
Periventricular leukomalacia
30
Seizures
20
Necrotizing enterocolitis stage 2, 3
10 0 24 0/7–26 0/7
A
26 1/7–28 0/7
28 1/7–30 0/7
30 1/7–32 0/7
Grade 3, 4 intraventricular hemorrhage
Gestational age (weeks) 30 Cerebral palsy
Percentage
25 20
Moderate/severe cerebral palsy
15 10
Neonatal mortality 5 0 24 0/7–26 0/7
B
26 1/7–28 0/7
28 1/7–30 0/7
30 1/7–32 0/7
Gestational age (weeks)
Fig. 1. A. Short-term neonatal complications with twins and premature rupture of membranes by gestational age at rupture. B. Long-term neonatal and infant complications with twins and premature rupture of membranes by gestational age at rupture. Mendez-Figueroa. Neonatal Outcomes in Twin Preterm PROM. Obstet Gynecol 2014.
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The difference in study design and primary endpoints makes comparison among the studies challenging as does differing use rates of antenatal strategies known to improve neonatal outcomes are not consistently reported throughout the literature. For example, the use of corticosteroids in our cohort was almost universal, whereas it ranged from 11% to 95% in prior publications.6,10 The variable rate of steroid administration must be considered when comparing neonatal outcomes in published reports. The median latency period from diagnosis of rupture of membranes to delivery in our cohort was 3.9 days. In other studies, this period has been reported to be between 11 hours and 3.6 days. The increased length of the latency in our study could be explained by the almost universal use of latency antibiotics and by the fact that this analysis focused on patients at an earlier gestational age, a factor linked with increased latency periods. A major advantage of the present trial is prospective evaluation of well-defined neonatal and infant outcomes up to 2 years corrected age. Because moderate or severe cerebral palsy was systematically and rigorously diagnosed in this cohort, this is perhaps the first study to reliably report the rate of cerebral palsy among twins with preterm PROM. The results of our study allow the clinician to effectively counsel patients on the risk of this longterm outcome. Specifically, the overall likelihood of cerebral palsy with twin preterm PROM at 24 0/7 and 31 6/7 weeks of gestation is 7.3% (95% CI 4.4– 10.3%) compared with 4.3% for preterm PROM singletons enrolled in the parent trial.11 Our finding of a differential rate of cerebral palsy among singletons compared with twins is consistent with previous publications.14–16 This secondary analysis has some limitations. The chorionicity of the twins was unknown and it may influence the outcomes.17,18 Of the available reports in the literature, only two focused specifically on dichorionic twin pregnancies.4,7 Because ours was not a prespecified secondary analysis, the sample size limited our statistical power to evaluate differences in the occurrence of low-frequency outcomes. Our current report encompasses data from 20 different sites that were either academic centers or affiliated to one; thus, our results may not be generalizable to other settings. In conclusion, twins with preterm PROM at 24 0/7 and 31 6/7 weeks of gestation are at risk for neonatal and infant morbidity, including cerebral palsy, which is knowable and quantifiable. Evaluation of interventions to decrease the rate of preterm
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PROM among twins as well as identification of modifiable factors that could prolong the latency period is warranted. Meanwhile, the results of this study can be used to counsel women, inform clinicians, encourage maternal transport, and design studies to mitigate morbidity and optimize outcomes. REFERENCES 1. Pakrashi T, Defranco EA. The relative proportion of preterm births complicated by premature rupture of membranes in multifetal gestations: a population-based study. Am J Perinatol 2013;30:69–74. 2. Mercer BM, Crocker LG, Pierce WF, Sibai BM. Clinical characteristics and outcome of twin gestation complicated by preterm premature rupture of the membranes. Am J Obstet Gynecol 1993;168:1467–73. 3. Kristensen S, Salihu HM, Ding H, Alexander GR. Early mortality in twin pregnancies complicated by premature rupture of membranes in the United States. J Obstet Gynaecol 2004;24:233–8. 4. Jacquemyn Y, Noelmans L, Mahieu L, Buytaert P. Twin versus singleton pregnancy and preterm prelabour rupture of the membranes. Clin Exp Obstet Gynecol 2003;30:99–102. 5. Hsieh YY, Chang CC, Tsai HD, Yang TC, Lee CC, Tsai CH. Twin vs. singleton pregnancy. Clinical characteristics and latency periods in preterm premature rupture of membranes. J Reprod Med 1999;44:616–20. 6. Bianco AT, Stone J, Lapinski R, Lockwood C, Lynch L, Berkowitz RL. The clinical outcome of preterm premature rupture of membranes in twin versus singleton pregnancies. Am J Perinatol 1996;13:135–8. 7. Trentacoste SV, Jean-Pierre C, Baergen R, Chasen ST. Outcomes of preterm premature rupture of membranes in twin pregnancies. J Matern Fetal Neonatal Med 2008;21:555–7. 8. von Dadelszen P, Kives S, Delisle MF, Wilson RD, Joy R, Ainsworth L, et al. The association between early membrane rupture, latency, clinical chorioamnionitis, neonatal infection, and adverse perinatal outcomes in twin pregnancies complicated by preterm prelabour rupture of membranes. Twin Res 2003;6:257–62. 9. Myles TD, Espinoza R, Meyer W, Bieniarz A. Preterm premature rupture of membranes: comparison between twin and singleton gestations. J Matern Fetal Med 1997;6:159–63. 10. Ehsanipoor RM, Arora N, Lagrew DC, Wing DA, Chung JH. Twin versus singleton pregnancies complicated by preterm premature rupture of membranes. J Matern Fetal Neonatal Med 2012;25:658–61. 11. Rouse DJ, Hirtz DG, Thom E, Varner MW, Spong CY, Mercer BM, et al. A randomized, controlled trial of magnesium sulfate for the prevention of cerebral palsy. N Engl J Med 2008; 359:895–905. 12. Menard MK, Liu Q, Holgren EA, Sappenfield WM. Neonatal mortality for very low birth weight deliveries in South Carolina by level of hospital perinatal service. Am J Obstet Gynecol 1998;179:374–81. 13. Sanderson M, Sappenfield WM, Jespersen KM, Liu Q, Baker SL. Association between level of delivery hospital and neonatal outcomes among South Carolina Medicaid recipients. Am J Obstet Gynecol 2000;183:1504–11. 14. Scher AI, Petterson B, Blair E, Ellenberg JH, Grether JK, Haan E, et al. The risk of mortality or cerebral palsy in twins:
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a collaborative population-based study. Pediatr Res 2002;52: 671–81. 15. Petterson B, Nelson KB, Watson L, Stanley F. Twins, triplets, and cerebral palsy in births in Western Australia in the 1980s. BMJ 1993;307:1239–43. 16. Sutcliffe AG, Derom C. Follow-up of twins: health, behaviour, speech, language outcomes and implications for parents. Early Hum Dev 2006;82:379–86.
17. Gezer A, Rashidova M, Güralp O, Ocer F. Perinatal mortality and morbidity in twin pregnancies: the relation between chorionicity and gestational age at birth. Arch Gynecol Obstet 2012;285:353–60. 18. Hack KE, Derks JB, Elias SG, Franx A, Roos EJ, Voerman SK, et al. Increased perinatal mortality and morbidity in monochorionic versus dichorionic twin pregnancies: clinical implications of a large Dutch cohort study. BJOG 2008;115:58–67.
Standards for Different Types of Articles Guidelines for five different types of articles have been adopted by Obstetrics & Gynecology: 1. CONSORT (Consolidated Standards of Reporting Trials) standards for reporting randomized trials 2. PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines for meta-analyses and systematic reviews of randomized controlled trials 3. MOOSE (Meta-analysis of Observational Studies in Epidemiology) guidelines for meta-analyses and systematic reviews of observational studies 4. STARD (Standards for Reporting of Diagnostic Accuracy) standards for reporting studies of diagnostic accuracy 5. STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) guidelines for the reporting of observational studies Investigators who are planning, conducting, or reporting randomized trials, meta-analyses of randomized trials, meta-analyses of observational studies, studies of diagnostic accuracy, or observational studies should be thoroughly familiar with these sets of standards and follow these guidelines in articles submitted for publication. NOW AVAILABLE ONLINE - http://ong.editorialmanager.com
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Neonatal and Infant Outcomes in Twin Gestations With Preterm Premature Rupture of Membranes at 24–31 Weeks of Gestation Hector Mendez-Figueroa, MD, Joshua D. Dahlke, MD, Oscar A. Viteri, MD, Suneet P. Chauhan, Dwight J. Rouse, MD, MSPH, Baha M. Sibai, MD, and Sean C. Blackwell, MD OBJECTIVE: To describe the perinatal and infant and early childhood morbidity associated with preterm premature rupture of membranes (PROM) in a cohort of twin pregnancies evaluated prospectively with neonatal follow-up to 2 years of age. METHODS: This was a secondary analysis of a randomized controlled trial of magnesium sulfate for prevention of cerebral palsy. Inclusion criteria were twin gestation with preterm PROM diagnosed between 24 0/7 and 31 6/7 weeks of gestation and planned expectant management. Latency (time from membrane rupture to delivery) and perinatal outcomes were evaluated by gestational age at membrane rupture. Long-term neonatal outcomes were also analyzed. RESULTS: Among 151 women who met inclusion criteria, the median gestational age at preterm PROM was 28.1 weeks (range 24.1–31.6 weeks). Approximately onethird of women achieved a latency of at least 1 week. Gestational age at preterm PROM (odds ratio [OR] 0.75, 95% confidence interval [CI] 0.63–0.90 for each week after 24 weeks of gestation) and cervical dilation at admission (OR 0.66, 95% CI 0.49–0.90 for each centimeter of dilation) were inversely associated with a latency
From the Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Texas Health Science Center at Houston, Houston, Texas; and the Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Women and Infants’ Hospital, Warren Alpert Medical School of Brown University, Providence, Rhode Island. Dr. Rouse, Associate Editor of Obstetrics & Gynecology, was not involved in the review or decision to publish this article. Corresponding author: Hector Mendez-Figueroa, MD, Department of Obstetrics, Gynecology and Reproductive Sciences, Division of Maternal Fetal Medicine, University of Texas Health Science Center Houston, 6431 Fannin, MSB 3.286, Houston, TX 77030; e-mail: [email protected]. Financial Disclosure The authors did not report any potential conflicts of interest. © 2014 by The American College of Obstetricians and Gynecologists. Published by Lippincott Williams & Wilkins. ISSN: 0029-7844/14
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period of at least 1 week. There were no stillbirths (95% CI 0–1%), but the rate of neonatal mortality was 90 per 1,000 newborns (95% CI 57–112) with a 7.3% cerebral palsy rate among survivors (95% CI 4.4–10.3%). CONCLUSION: In twin pregnancies, preterm PROM from 24 to 31 weeks of gestation is associated with a neonatal mortality rate of 9.0% and an overall cerebral palsy rate of 7.3%. A longer latency period is associated with less advanced cervical dilation and later gestational age at PROM. (Obstet Gynecol 2014;124:323–31) DOI: 10.1097/AOG.0000000000000369
LEVEL OF EVIEDENCE: II
P
reterm premature rupture of membranes (PROM) is a major contributing factor to the risk of preterm birth in multiple gestations.1 Although the risk of preterm PROM with singletons is 2–4%, it occurs in 7–8% of twins.2 Using data from the National Center of Health Statistics, Kristensen et al3 estimated that approximately 6% of stillbirths, 15% of neonatal mortality, and 14% of infant mortality among twins are attributable to preterm PROM. Prior studies of twins with preterm PROM have mostly reported results from one center, had small sample sizes, included different gestational age ranges, administered antenatal corticosteroid variably, or included patient with twin–twin transfusion syndrome or after fetal interventions.2,4–10 The natural history of preterm PROM in twin pregnancies has not been extensively described. Since expectant management of early preterm PROM has become a common clinical practice in modern obstetrics, knowledge of the risks, benefits, and longterm outcomes is therefore required to appropriately counsel patients. Based on a PubMed search from 1950 to 2014 of the English language using the terms
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Table 1. Publications on Twins With Premature Rupture of Membranes No. of Centers
Study Period (y)
n
Included Gestational Age (wk)
Gestational Age at PROM (wk)
Mercer et al, 1993
1
11
90
19–36
30.1*
Hsieh et al, 1999
1
10
48
20–36
29.7*
Bianco et al, 1996
1
116
24–36
32.4*
Myles et al, 1997 Jacquemyn et al, 2003
1 1
3 5
28 33
Less than 36 20–36
29.5 NR
Von Dadelszen et al, 2003
3
2
246
24–36
31.3*
Trentacoste et al, 2008 Ehsanipoor et al, 2012
1 1
3 9
49 41
24–34 24–32
31.0† 27.7*
Study
PROM, premature rupture of membranes; NR, not reported; NICU, neonatal intensive care unit; PVL, periventricular leukomalacia; PDA, patent ductus arteriosus; TTN, transient tachypnea of the newborn. * Mean. † Median.
“PPROM,” “twins,” “multiple gestation,” and “rupture membranes,” eight studies of twin pregnancy complicated by preterm PROM have been published to date, all of them retrospective, which do not report on longterm neonatal or infant outcomes (Table 1).2,4–10 The purposes of this secondary analysis of a randomized controlled trial of magnesium sulfate for the prevention of cerebral palsy are 1) to describe the peripartum and neonatal outcomes with preterm PROM at 24 0/7 to 31 6/7 weeks of gestation stratified by gestational age at membrane rupture; 2) report both the long-term neonatal and infant outcomes for up to 2 years of age within this cohort; and 3) identify factors associated with a latency period greater than 7 days.
MATERIALS AND METHODS This study is a secondary analysis of a multicenter randomized trial that evaluated the use of magnesium sulfate for the prevention of moderate to severe cerebral palsy or death among infants born prematurely. Full
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details of this study have been reported.11 In brief, gravid women between 24 0/7 and 31 6/7 weeks of gestation at high risk for preterm birth were randomized to receive magnesium sulfate (a loading dose of 6 g infused for 20–30 minutes followed by a maintenance infusion of 2 g per hour) or placebo. Excluded from the parent trial were all higher order multiples, multiple gestations managed by fetal reduction, patients with rupture of membranes before 22 0/7 weeks, and known fetal anomalies.11 For this trial, the diagnosis of preterm PROM was made when any two of the following were documented: 1) pooling of fluid in the vaginal vault; 2) a positive Nitrazine test; or 3) ferning of vaginal fluid or by any one of the following: indigo carmine pooling in the vagina after amnioinfusion or visible leakage of amniotic fluid from the cervix. Cervical dilation and effacement were assessed either by visual or digital examination. Chorioamnionitis was diagnosed when the maternal temperature was at least 100°F (37.8°C) in the presence of at least one of the
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Corticosteroids Latency (%) Period
Latency Related to
Chorioamnionitis (%)
Fetal or Neonatal Death
Reported Neonatal Morbidity Intraventricular hemorrhage, respiratory distress syndrome, hyaline membrane disease, pneumonia, necrotizing enterocolitis, meningitis, sepsis, mechanical ventilation, neonatal death Intraventricular hemorrhage, respiratory distress syndrome, hyaline membrane disease, pneumonia, necrotizing enterocolitis, NICU admission, death Intraventricular hemorrhage, pneumonia, necrotizing enterocolitis, NICU admission NR Intraventricular hemorrhage, PVL, respiratory distress syndrome, PDA, retinopathy of prematurity, necrotizing enterocolitis, death Intraventricular hemorrhage, TTN, sepsis, meconium aspiration, neonatal death Neonatal death Intraventricular hemorrhage, necrotizing enterocolitis, pneumonia, respiratory distress syndrome, sepsis, neonatal death
25.3
86.1 h*
Gestational age
30.4
2.5%/19%
NR
3.4 d*
Gestational age
17.6
NR/8.3%
11
11.4 h†
Gestational age
25
73.9 81.8
3.0 d† 19 h†
NR Gestational age
8.7 15.2
3.6%/NR 0%/9.1%
38.7
22.5 h†
Gestational age, chorioamnionitis
13.8
0%/4.1%
NR 95.0
0 d† 3.6 d†
Gestational age NR
16.3 9.8
0%/8.2% 0%/4.9%
following: malodorous fluid, persistent fetal tachycardia, persistent maternal tachycardia, uterine tenderness, or maternal leukocytosis greater than 20,000 cells per millimeters cubed. The use of tocolytics drugs was proscribed by the study design; the use of steroids and antibiotics was left to the discretion of the managing physicians. Neonatal outcomes including neonatal intensive care admission, days spent in the hospital, respiratory distress syndrome, need for mechanical ventilation, culture-proven sepsis, intraventricular hemorrhage grades 3 or 4, bronchopulmonary dysplasia, retinopathy of prematurity, periventricular leukomalacia, necrotizing enterocolitis, stillbirth, and neonatal death were analyzed and reported for the entire study population as well as by the gestational age at which preterm PROM occurred. After delivery, live-born infants were evaluated with up to three follow-up visits (until the corrected age of 2 years) in which detailed developmental assessments were performed by trained examiners.
3%/NR
Infants with a normal neurologic examination at 1 year of age were deemed not to have developed cerebral palsy and thus did not require any further neurologic evaluation. The diagnosis of cerebral palsy was made if two or more of the following three features were present: a delay of 30% or more in gross motor developmental milestones (eg, inability to sit without arm support by 9.5 months or walk by 17 months of corrected age); abnormality in muscle tone (eg, scissoring), 4+ or absent deep tendon reflexes, or movement abnormality (eg, posturing or gait asymmetry); or persistence of primitive reflexes or absence of protective reflexes.11 The STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) guidelines for reporting observational studies were followed. This analysis is limited to women with twin gestation complicated by preterm PROM enrolled in this trial irrespective of whether they were allocated to magnesium sulfate. To assess the effects of gestational age at preterm PROM on
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neonatal outcomes, we created four mutually exclusive categories: 24 0/7–26 0/7 weeks of gestation, 26 1/7–28 0/7 weeks of gestation, 28 1/7–30 0/7 weeks of gestation, and 30 1/7–31 6/7 weeks of gestation. A comparison was performed stratified by administration of magnesium sulfate, presenting compared with nonpresenting twin, route of delivery, newborn gender, and birth weight discordance to assess their effect on neonatal outcomes. To identify factors associated with latency period of at least 7 days or more, nine variables of interest (gestational age at membrane rupture, maternal age, African American race, Hispanic ethnicity, prepregnancy body mass index (calculated as weight (kg)/ [height (m)]2), nulliparity, cervical dilation at admission, administration of antenatal steroids, and allocation to intravenous magnesium sulfate administration) were included in the regression analysis using backward elimination. All analyses were performed using SPSS 22. Descriptive statistics were used to report all variables of interest. Continuous variables were compared using Student’s t test, whereas categorical variables were compared using x2 or Fisher’s exact test as appropriate. We calculated odds ratios (ORs) with 95% confidence intervals (CIs) for variables of interest. Confidence intervals excluding integer 1.0 were considered significant. Logistic regression analysis was used to identify independent variables that were associated with a latency period of less than compared with 7 or more days. All tests were two-tailed with P,.05 considered significant. This analysis qualified for exempt status from the institutional review board at the University of Texas Health Science Center at Houston because it involved the study of publically available data.
Table 2. Demographic and Clinical Characteristics of Twins With Preterm Premature Rupture of Membranes
RESULTS
BMI, body mass index; UTI, urinary tract infection; PROM, premature rupture of membranes. Data are median (range) or n (%).
From the original patient population of 2,241 included in the trial, 203 were twin gestations (9.1%). Of these, 164 patients were admitted to the trial with the diagnosis of preterm PROM. One patient did not meet the study criteria for PROM and 13 were diagnosed with preterm PROM before 24 weeks of gestation, leaving a total of 151 (74.4%) eligible for this secondary analysis. Neonatal and infant data were available for 300 out of the 302 live-borns (99.3%). Table 2 shows the baseline demographic characteristics of the participants. Almost all the cohort received antenatal steroids and close to half were allocated to magnesium sulfate. Latency antibiotics were administered in 92% of the participants. The rates of
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Variable
Value
Age (y) Prepregnancy BMI (kg/m2) Less than 30 30 or more Race or ethnicity African American Caucasian Hispanic Other Nulliparous Pregestational or gestational diabetes Preeclampsia Years of education Corticosteroid administration Antibiotics administered Latency Treatment for chorioamnionitis Treatment for UTI Magnesium therapy administration Gestational age at preterm PROM (wk) 24 0/7–26 0/7 26 1/7–28 0/7 28 1/7–30 0/7 30 1/7–31 6/7 Cervical dilation at admission (cm) 0–1 2–3 4–5 6 or greater Average latency period (d) Latency period greater than 48 h Latency period 7 d or greater Latency period 14 d or greater Latency period 30 d or greater Birth weight (g)—median (range)
27.0 (22–31) 26.0 (22.4–31.4) 99 (70.7) 41 (39.3) 50 (33.1) 75 (49.7) 22 (14.6) 4 (2.6) 74 (49.0) 12 (7.9) 2 (0.7) 12.0 (12–15) 147 (97.4) 143 (94.7) 131 (91.6) 11 (7.7) 1 (0.7) 72 (47.7) 28.1 (24.1–31.6) 37 (24.5) 37 (24.5) 36 (23.8) 41 (27.2) 1.0 (0–2) 89 (58.9) 39 (25.8) 15 (9.9) 8 (5.3) 3.9 (1.3–9.9) 101 (68.7) 50 (34.0) 24 (16.3) 8 (5.4) 1,201.0 (937.5–1,516)
corticosteroid administration and latency antibiotic use remained fairly consistent across all gestational ages (P..05 among all comparisons), whereas the rate of neonatal death significantly decreased with advancing gestational age. The average gestational age at membrane rupture was 28.1 weeks. The median latency period was 3.9 days (interquartile range 1.3– 9.9 days); this is shorter than the median latency period of 7.7 days seen in singleton preterm PROM gestations included in the parent trial (P,.01). Only 50 (34.0%) of the study cohort remained pregnant 7 days after preterm PROM.
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Logistic regression indicated that two variables, gestational age at membrane rupture (OR 0.75, 95% CI 0.63–0.90 for each week above 24 weeks of gestation) and cervical dilation at admission (OR 0.66, 95% CI 0.49–0.90 for each centimeter of dilation) were inversely associated with a latency period 7 days or greater. Maternal age, race, parity, and body mass index and allocation to magnesium sulfate were not associated with latency. Table 3 depicts the clinical outcomes by gestational age at which preterm PROM occurred. Maternal morbidity as well as both short-term and long-term neonatal and infant outcomes are reported in Table 4. The combined rate of chorioamnionitis and endometritis was 20% and of cesarean delivery 60%. Of the cases delivered by cesarean, 21 (23.3%) were delivered secondary to fetal indications. The median length of stay in the neonatal intensive care unit was 41.5 days (interquartile range 25.8–63) with a median neonatal hospital stay of 55.0 days (interquartile range 30–70). The rate of Bell’s stage 2 or 3 necrotizing enterocolitis was 5.7%; grade III or IV intraventricular hemorrhage was diagnosed in 5.6%. Neonatal morbidity did not differ between the presenting compared with nonpresenting twin and twins who received magnesium sulfate as opposed to placebo or among twins with discordant birth weight, defined as a birth weight difference 18% or
greater. Route of delivery was not associated with neonatal morbidity. Need for mechanical ventilation (P,.01) and retinopathy of prematurity (P5.03) occurred significantly more frequently with growthrestricted newborns than those with appropriate for gestational age. Male newborns were more like to have retinopathy of prematurity than female (22% compared with 34%; P5.02). The diagnosis of cerebral palsy was made in 7.3% of the neonates (95% CI 4.4–10.3%) of which 3.3% was moderate or severe. Neonatal mortality was 90 per 1,000 live newborns (95% CI 57–112 per 1,000). No stillbirths or deaths at 1 year of age after neonatal intensive care unit discharge were noted (95% CI 0–1%). Neonatal and infant complications were inversely related to gestational age and are depicted in Figure 1A–B.
DISCUSSION This report describes the maternal, neonatal, and infant characteristics of twin pregnancies evaluated prospectively complicated by preterm PROM. We noted that when twin gestations are complicated by preterm PROM at 24 0/7 to 31 6/7 weeks of gestation, a 7-day latency period is seen in approximately onethird of the cases, and one in five cases will be undelivered for 14 days or more. Neonatal outcomes were reported by gestational age at membrane rupture; this allows counseling to be individualized at the
Table 3. Clinical Outcomes by Gestational Age at Time of Rupture of Membranes for Twin Gestations Gestational Age at Time of Rupture of Membranes (wk) Outcome Latency period (d) Latency 48 h or greater 7 d or greater 14 d or greater 30 d or greater Pregnancies delivered at 34 wk of gestation or greater Gestational age at delivery (wk) Chorioamnionitis Endometritis Abruption Cesarean delivery Admission to NICU NICU length of stay (d) Total neonatal hospital stay (d) Stillbirth Neonatal death
24 0/7–26 0/7 (n537)
26 1/7–28 0/7 (n537)
28 1/7–30 0/7 (n536)
30 1/7–31 6/7 (n541)
6.5 (1–15) 29 (78.4) 19 (51.4) 10 (27.0) 4 (10.8) 29 (78.4) 1 (2.7)
4.8 (2–10) 32 (86.5) 17 (45.9) 5 (13.5) 1 (2.7) 32 (86.5) 0
2.5 (1–10) 24 (64.9) 11 (29.7) 8 (21.6) 2 (5.4) 24 (64.9) 2 (5.6)
2.7 (1–5) 26 (70.3) 10 (27.0) 4 (10.8) 2 (5.4) 26 (70.3) 3 (7.3)
26.1 (24.1–27.4) 8 (21.6) 4 (10.8) 0 22 (59.5) 36 (100) 81 (37–105) 84 (63–107.8) 0 17 (23.3)
28.0 (26.3–28.6) 3 (8.1) 6 (16.2) 5 (13.5) 28 (75.7) 37 (100) 57.5 (39–77.8) 61 (48–83) 0 9 (12.3)
29.6 (29.2–30.2) 1 (2.8) 2 (7.7) 1 (2.8) 17 (47.2) 35 (97.2) 39 (28.3–51) 42.5 (33.8–51) 0 0
31.6 (31.1–32.0) 0 5 (12.2) 3 (7.3) 24 (58.5) 38 (92.7) 26 (16.5–36) 28 (21–36) 0 1 (1.2)
NICU, neonatal intensive care unit. Data are median (range) or n (%).
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Table 4. Neonatal and Infant Morbidity and Mortality Associated With Preterm Premature Rupture of Membranes in Twin Pregnancies by Gestational Age at Rupture Variable (Weeks of Gestation)
Per Pregnancy
Per Neonate
Need for mechanical ventilation 24 0/7–26 0/7 26 1/7–28 0/7 28 1/7–30 0/7 30 1/7–32 0/7 Respiratory distress syndrome 24 0/7–26 0/7 26 1/7–28 0/7 28 1/7–30 0/7 30 1/7–32 0/7 Bronchopulmonary dysplasia 24 0/7–26 0/7 26 1/7–28 0/7 28 1/7–30 0/7 30 1/7–32 0/7 Sepsis 24 0/7–26 0/7 26 1/7–28 0/7 28 1/7–30 0/7 30 1/7–32 0/7 Retinopathy of prematurity 24 0/7–26 0/7 26 1/7–28 0/7 28 1/7–30 0/7 30 1/7–32 0/7 Stage 2–3 necrotizing enterocolitis 24 0/7–26 0/7 26 1/7–28 0/7 28 1/7–30 0/7 30 1/7–32 0/7 Intraventricular hemorrhage grades III–IV 24 0/7–26 0/7 26 1/7–28 0/7 28 1/7–30 0/7 30 1/7–32 0/7 Periventricular leukomalacia 24 0/7–26 0/7 26 1/7–28 0/7 28 1/7–30 0/7 30 1/7–32 0/7 Seizures 24 0/7–26 0/7 26 1/7–28 0/7 28 1/7–30 0/7 30 1/7–32 0/7 Cerebral palsy 24 0/7–26 0/7 26 1/7–28 0/7 28 1/7–30 0/7 30 1/7–32 0/7 Moderate to severe cerebral palsy 24 0/7–26 0/7 26 1/7–28 0/7 28 1/7–30 0/7 30 1/7–32 0/7
68.8 (61.0–76.6) 89.9 (80.1–94.9) 91.9 (79.5–100) 69.4 (53.3–85.5) 34.2 (22.3–47.8) 72.0 (63.8–79.3) 91.7 (80.7–100) 86.5 (78.0–100) 61.1 (44.7–77.5) 51.2 (37.9–67.1) 29.3 (22.5–35.7) 63.9 (47.4–80.2) 48.7 (33.3–63.9) 5.6 (0–12.1) 4.9 (0.3–9.8) 31.3 (24.6–37.6) 52.8 (36.5–68.9) 37.8 (24.2–51.5) 19.4 (9.1–29.7) 14.6 (6.4–23.6) 37.3 (29.9–44.3) 66.7 (50.2–83.0) 51.4 (35.7–66.9) 25.0 (11.6–38.6) 7.3 (1.7–13.3) 8.0 (4.2–11.6) 22.2 (11.3–33.0) 13.5 (3.4–23.6) 0 0 10.4 (6.2–13.7) 25.7 (13.8–36.2) 13.9 (4.4–22.6) 2.9 (0–6.7) 0 4.6 (2.1–7.1) 5.7 (0–11.0) 2.8 (0–6.5) 5.8 (0–11.1) 5.2 (0–10.1) 3.3 (1.3–5.4) 2.8 (0–6.5) 8.1 (1.7–14.5) 2.8 (0–6.6) 0 9.8 (5.7–14.1) 21.9 (12.0–32.4) 16.4 (6.7–25.8) 2.8 (0–8.1) 9.8 (2.6–17.4) 6.7 (3.7–9.5) 16.4 (7.7–25.7) 5.5 (0.1–10.7) 0 4.9 (0.3–9.8)
61.7 (56.2–67.2) 87.5 (77.9–99.7) 82.4 (73.7–91.2) 59.7 (71.1–48.3) 22.0 (12.9–30.9) 62.0 (56.5–67.5) 87.5 (80.1–94.9) 77.0 (67.4–86.7) 52.8 (41.2–64.4) 34.2 (23.8–44.5) 21.7 (17.0–26.3) 48.6 (37.4–59.8) 33.8 (22.9–44.6) 4.2 (0–8.8) 2.4 (0–5.8) 20.7 (16.1–25.3) 41.7 (30.7–52.7) 23.0 (13.3–32.6) 11.1 (3.8–18.4) 8.5 (2.5–14.6) 28.0 (22.9–33.1) 54.2 (43.0–65.3) 36.5 (25.4–47.5) 20.8 (11.4–30.3) 3.7 (0–7.8) 5.7 (3.1–8.3) 12.5 (5.1–19.9) 10.8 (3.7–17.9) 0 0 5.6 (2.9–8.2) 12.9 (5.3–20.4) 8.3 (1.9–14.8) 1.5 (0–4.3) 0 2.4 (0.7–4.2) 2.9 (0–6.6) 1.4 (0–4.1) 2.9 (0–6.9) 2.6 (0–6.2) 1.7 (0.2–3.1) 1.4 (0–4.0) 4.1 (0–8.6) 1.4 (0–4.1) 0 7.3 (4.4–10.3) 11.0 (4.0–17.9) 9.6 (2.8–16.4) 2.8 (0–6.6) 6.1 (0.9–11.3) 3.3 (1.3–5.4) 8.2 (2.1–14.3) 2.7 (0–6.5) 0 2.4 (0–5.8) (continued )
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Table 4. Neonatal and Infant Morbidity and Mortality Associated With Preterm Premature Rupture of Membranes in Twin Pregnancies by Gestational Age at Rupture (continued ) Variable (Weeks of Gestation)
Per Pregnancy
Per Neonate
Stillbirth 24 0/7–26 0/7 26 1/7–28 0/7 28 1/7–30 0/7 30 1/7–32 0/7 Neonatal death 24 0/7–26 0/7 26 1/7–28 0/7 28 1/7–30 0/7 30 1/7–32 0/7
0 (0–1.1) 0 (0–1.1) 0 (0–1.1) 0 (0–1.0) 0 (0–1.1) 13.3 (8.6–17.8) 35.6 (22.3–49.9) 19.2 (8.2–12.6) 0 (0–10) 2.4 (0–5.9)
0 (0–0.5) 0 (0–0.8) 0 (0–0.8) 0 (0–0.8) 0 (0–0.7) 9.0 (5.8–12.2) 23.3 (13.9–32.7) 12.3 (4.7–19.9) 0 (0–10) 1.2 (0–3.6)
Data are % (95% CI).
tively. Our results can be used to counsel women and inform neonatologists about the likelihood of complications and inform decision-making about maternal transfer to facilities with appropriate neonatal care expertise.12,13 Several previous studies have also addressed the issue of preterm PROM in twin gestations.2,4–10 These studies are all retrospective and typically compare latency periods between twin and singleton pregnancies.
moment of admission. The two variables—gestational age at preterm PROM and cervical dilation at admission—that are inversely related to latency period are nonmodifiable. The identification of these two variables is consistent with previously published studies.2,4–8 Furthermore, we report both short-term and long-term neonatal and infant outcomes up to 2 years corrected age and found that the overall rate of cerebral palsy and mortality within this cohort was 7.3% and 9.0%, respec-
100
Mechanical ventilation
90 Bronchopulmonary dysplasia
80 Percentage
70
Retinopathy of prematurity
60
Sepsis
50 40
Periventricular leukomalacia
30
Seizures
20
Necrotizing enterocolitis stage 2, 3
10 0 24 0/7–26 0/7
A
26 1/7–28 0/7
28 1/7–30 0/7
30 1/7–32 0/7
Grade 3, 4 intraventricular hemorrhage
Gestational age (weeks) 30 Cerebral palsy
Percentage
25 20
Moderate/severe cerebral palsy
15 10
Neonatal mortality 5 0 24 0/7–26 0/7
B
26 1/7–28 0/7
28 1/7–30 0/7
30 1/7–32 0/7
Gestational age (weeks)
Fig. 1. A. Short-term neonatal complications with twins and premature rupture of membranes by gestational age at rupture. B. Long-term neonatal and infant complications with twins and premature rupture of membranes by gestational age at rupture. Mendez-Figueroa. Neonatal Outcomes in Twin Preterm PROM. Obstet Gynecol 2014.
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The difference in study design and primary endpoints makes comparison among the studies challenging as does differing use rates of antenatal strategies known to improve neonatal outcomes are not consistently reported throughout the literature. For example, the use of corticosteroids in our cohort was almost universal, whereas it ranged from 11% to 95% in prior publications.6,10 The variable rate of steroid administration must be considered when comparing neonatal outcomes in published reports. The median latency period from diagnosis of rupture of membranes to delivery in our cohort was 3.9 days. In other studies, this period has been reported to be between 11 hours and 3.6 days. The increased length of the latency in our study could be explained by the almost universal use of latency antibiotics and by the fact that this analysis focused on patients at an earlier gestational age, a factor linked with increased latency periods. A major advantage of the present trial is prospective evaluation of well-defined neonatal and infant outcomes up to 2 years corrected age. Because moderate or severe cerebral palsy was systematically and rigorously diagnosed in this cohort, this is perhaps the first study to reliably report the rate of cerebral palsy among twins with preterm PROM. The results of our study allow the clinician to effectively counsel patients on the risk of this longterm outcome. Specifically, the overall likelihood of cerebral palsy with twin preterm PROM at 24 0/7 and 31 6/7 weeks of gestation is 7.3% (95% CI 4.4– 10.3%) compared with 4.3% for preterm PROM singletons enrolled in the parent trial.11 Our finding of a differential rate of cerebral palsy among singletons compared with twins is consistent with previous publications.14–16 This secondary analysis has some limitations. The chorionicity of the twins was unknown and it may influence the outcomes.17,18 Of the available reports in the literature, only two focused specifically on dichorionic twin pregnancies.4,7 Because ours was not a prespecified secondary analysis, the sample size limited our statistical power to evaluate differences in the occurrence of low-frequency outcomes. Our current report encompasses data from 20 different sites that were either academic centers or affiliated to one; thus, our results may not be generalizable to other settings. In conclusion, twins with preterm PROM at 24 0/7 and 31 6/7 weeks of gestation are at risk for neonatal and infant morbidity, including cerebral palsy, which is knowable and quantifiable. Evaluation of interventions to decrease the rate of preterm
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PROM among twins as well as identification of modifiable factors that could prolong the latency period is warranted. Meanwhile, the results of this study can be used to counsel women, inform clinicians, encourage maternal transport, and design studies to mitigate morbidity and optimize outcomes. REFERENCES 1. Pakrashi T, Defranco EA. The relative proportion of preterm births complicated by premature rupture of membranes in multifetal gestations: a population-based study. Am J Perinatol 2013;30:69–74. 2. Mercer BM, Crocker LG, Pierce WF, Sibai BM. Clinical characteristics and outcome of twin gestation complicated by preterm premature rupture of the membranes. Am J Obstet Gynecol 1993;168:1467–73. 3. Kristensen S, Salihu HM, Ding H, Alexander GR. Early mortality in twin pregnancies complicated by premature rupture of membranes in the United States. J Obstet Gynaecol 2004;24:233–8. 4. Jacquemyn Y, Noelmans L, Mahieu L, Buytaert P. Twin versus singleton pregnancy and preterm prelabour rupture of the membranes. Clin Exp Obstet Gynecol 2003;30:99–102. 5. Hsieh YY, Chang CC, Tsai HD, Yang TC, Lee CC, Tsai CH. Twin vs. singleton pregnancy. Clinical characteristics and latency periods in preterm premature rupture of membranes. J Reprod Med 1999;44:616–20. 6. Bianco AT, Stone J, Lapinski R, Lockwood C, Lynch L, Berkowitz RL. The clinical outcome of preterm premature rupture of membranes in twin versus singleton pregnancies. Am J Perinatol 1996;13:135–8. 7. Trentacoste SV, Jean-Pierre C, Baergen R, Chasen ST. Outcomes of preterm premature rupture of membranes in twin pregnancies. J Matern Fetal Neonatal Med 2008;21:555–7. 8. von Dadelszen P, Kives S, Delisle MF, Wilson RD, Joy R, Ainsworth L, et al. The association between early membrane rupture, latency, clinical chorioamnionitis, neonatal infection, and adverse perinatal outcomes in twin pregnancies complicated by preterm prelabour rupture of membranes. Twin Res 2003;6:257–62. 9. Myles TD, Espinoza R, Meyer W, Bieniarz A. Preterm premature rupture of membranes: comparison between twin and singleton gestations. J Matern Fetal Med 1997;6:159–63. 10. Ehsanipoor RM, Arora N, Lagrew DC, Wing DA, Chung JH. Twin versus singleton pregnancies complicated by preterm premature rupture of membranes. J Matern Fetal Neonatal Med 2012;25:658–61. 11. Rouse DJ, Hirtz DG, Thom E, Varner MW, Spong CY, Mercer BM, et al. A randomized, controlled trial of magnesium sulfate for the prevention of cerebral palsy. N Engl J Med 2008; 359:895–905. 12. Menard MK, Liu Q, Holgren EA, Sappenfield WM. Neonatal mortality for very low birth weight deliveries in South Carolina by level of hospital perinatal service. Am J Obstet Gynecol 1998;179:374–81. 13. Sanderson M, Sappenfield WM, Jespersen KM, Liu Q, Baker SL. Association between level of delivery hospital and neonatal outcomes among South Carolina Medicaid recipients. Am J Obstet Gynecol 2000;183:1504–11. 14. Scher AI, Petterson B, Blair E, Ellenberg JH, Grether JK, Haan E, et al. The risk of mortality or cerebral palsy in twins:
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a collaborative population-based study. Pediatr Res 2002;52: 671–81. 15. Petterson B, Nelson KB, Watson L, Stanley F. Twins, triplets, and cerebral palsy in births in Western Australia in the 1980s. BMJ 1993;307:1239–43. 16. Sutcliffe AG, Derom C. Follow-up of twins: health, behaviour, speech, language outcomes and implications for parents. Early Hum Dev 2006;82:379–86.
17. Gezer A, Rashidova M, Güralp O, Ocer F. Perinatal mortality and morbidity in twin pregnancies: the relation between chorionicity and gestational age at birth. Arch Gynecol Obstet 2012;285:353–60. 18. Hack KE, Derks JB, Elias SG, Franx A, Roos EJ, Voerman SK, et al. Increased perinatal mortality and morbidity in monochorionic versus dichorionic twin pregnancies: clinical implications of a large Dutch cohort study. BJOG 2008;115:58–67.
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