Background
The Management of Myelomeningocele Study was a multicenter randomized trial to compare prenatal and standard postnatal closure of myelomeningocele. The trial was stopped early at recommendation of the data and safety monitoring committee and outcome data for 158 of the 183 randomized women published.
Objective
In this report, pregnancy outcomes for the complete trial cohort are presented. We also sought to analyze risk factors for adverse pregnancy outcome among those women who underwent prenatal myelomeningocele repair.
Study Design
Pregnancy outcomes were compared between the 2 surgery groups. For women who underwent prenatal surgery, antecedent demographic, surgical, and pregnancy complication risk factors were evaluated for the following outcomes: premature spontaneous membrane rupture ≤34 weeks 0 days (preterm premature rupture of membranes), spontaneous membrane rupture at any gestational age, preterm delivery at ≤34 weeks 0 days, nonintact hysterotomy (minimal uterine wall tissue between fetal membranes and uterine serosa, or partial or complete dehiscence at delivery), and chorioamniotic membrane separation. Risk factors were evaluated using χ 2 and Wilcoxon tests and multivariable logistic regression.
Results
A total of 183 women were randomized: 91 to prenatal and 92 to postnatal surgery groups. Analysis of the complete cohort confirmed initial findings: that prenatal surgery was associated with an increased risk for membrane separation, oligohydramnios, spontaneous membrane rupture, spontaneous onset of labor, and earlier gestational age at birth. In multivariable logistic regression of the prenatal surgery group adjusting for clinical center, earlier gestational age at surgery and chorioamniotic membrane separation were associated with increased risk of spontaneous membrane rupture (odds ratio, 1.49; 95% confidence interval, 1.01–2.22; and odds ratio, 2.96, 95% confidence interval, 1.05–8.35, respectively). Oligohydramnios was associated with an increased risk of subsequent preterm delivery (odds ratio, 9.21; 95% confidence interval, 2.19–38.78). Nulliparity was a risk factor for nonintact hysterotomy (odds ratio, 3.68; 95% confidence interval, 1.35–10.05).
Conclusion
Despite the confirmed benefits of prenatal surgery, considerable maternal and fetal risk exists compared with postnatal repair. Early gestational age at surgery and development of chorioamniotic membrane separation are risk factors for ruptured membranes. Oligohydramnios is a risk factor for preterm delivery and nulliparity is a risk factor for nonintact hysterotomy at delivery.
Introduction
The National Institutes of Health-sponsored Management of Myelomeningocele Study (MOMS) was initiated in 2003 to compare the safety and efficacy of prenatal repair of myelomeningocele with that of standard postnatal repair. The trial was stopped in 2010 before reaching the target sample size, at the recommendation of its data and safety monitoring committee according to prespecified stopping rules for the efficacy of prenatal surgery. Results of the trial were reported based on 158 women who had undergone randomization before July 1, 2009, as this was the cohort analyzed for the data and safety monitoring committee. Findings in that report demonstrated a significant improvement in the primary outcomes at 12 and 30 months of age, and in multiple secondary outcomes, including reversal of hindbrain herniation and ambulation by 30 months, in the prenatal repair group. However, prenatal surgical intervention was associated with significantly higher rates of oligohydramnios and chorioamniotic separation, as well as spontaneous membrane rupture (SROM) and preterm delivery (PTD) ( P < .001). Moreover, of those in the prenatal surgery group, only 64% had an intact, well-healed hysterotomy site from the prenatal repair surgery observed at cesarean delivery.
The initial MOMS report summarized the pregnancy outcomes of 86% of the 183 randomized women. The primary objective of the current report is to update the final pregnancy outcome results from the MOMS trial, as well as to analyze risk factors for preterm premature rupture of membranes (PPROM), SROM at any gestation, early preterm delivery (PTD), and uterine dehiscence among those women who underwent prenatal repair. It is the authors’ view that these additional components are anticipated to enhance the knowledge of benefits, risk assessment, and informed consent process for future families considering fetal myelomeningocele repair, where maternal and fetal characteristics match those set forth in the inclusion and exclusion criteria of the trial.
Materials and Methods
Study population and design
Patient recruitment, study procedures, details of the primary and secondary outcome parameters, as well as the perioperative management algorithm for prenatal myelomeningocele surgery were described in detail in the previous MOMS trial publication. Briefly, eligible pregnant women with a fetus diagnosed with myelomeningocele and between 19–25 weeks of gestation were randomized at 1 of the 3 MOMS clinical centers to either prenatal or postnatal surgical repair. Women randomized to the postnatal surgery group went home and returned at 37 weeks of gestation to their maternal-fetal surgery center for cesarean delivery and postnatal repair by the center’s neurosurgical team. Given the anticipated increased risk of preterm labor, patients randomized to prenatal myelomeningocele surgery remained close to the MOMS center to permit standardized management after the surgery, including tocolysis therapy, weekly ultrasound evaluations, and delivery at 37 weeks of gestation if still undelivered. In addition to the usual content of a prenatal care visit and assessment of postsurgery maternal well-being, a targeted ultrasound was performed to evaluate amniotic fluid volume and the status of the hysterotomy and membranes, to assess for potential oligohydramnios, dehiscence, or chorioamniotic membrane separation (CMS), during the weekly outpatient visits.
When CMS was seen by ultrasound, patients were placed initially on outpatient bed rest. If the membrane separation progressed and extended to the placental cord insertion site, patients were admitted and placed on bed rest, with fetal heart rate testing obtained every shift or if decreased fetal movement was reported by the patient. Diagnosis of oligohydramnios was managed by hospital admission with assessment of fetal heart rate or nonstress tests every shift when the amniotic fluid index was <5 cm. Tocolytic therapy using indomethacin <32 weeks’ gestation and/or magnesium sulfate was initiated for palpable contractions with documented cervical change. Preterm labor unresponsive to tocolytics or due to chorioamnionitis, suspected uterine rupture, placental abruption, or a nonreassuring fetal status was treated by cesarean delivery. If the patient experienced rupture of membranes at <34 weeks of gestation, she was managed expectantly until 34 weeks of gestation at which time she was delivered by cesarean delivery. If preterm labor was diagnosed and the likelihood of delivery was high <32 weeks (eg, PPROM, vaginal spotting, or nonreassuring antepartum fetal surveillance), a single course of betamethasone therapy was given to minimize complications of prematurity.
At 37 weeks’ gestation, delivery took place by elective cesarean delivery because of the presence of the hysterotomy scar. Although the same abdominal laparotomy incision was used for the cesarean delivery as for the prenatal surgery, the fetus was preferably delivered via a lower uterine segment incision.
Statistical analysis
The updated analysis comparing the prenatal vs postnatal repair groups was performed according to the intention-to-treat principle. Relative risks and 95% confidence intervals were calculated.
For the analysis within the prenatal repair group of risk factors for adverse pregnancy outcome, only women who actually underwent prenatal surgical repair were included. We evaluated risk factors for 5 outcomes: CMS defined as separation from the uterine wall that did not spontaneously resolve ≤34 weeks 0 days; PPROM, defined as any spontaneous rupture ≤34 weeks 0 days; SROM at any gestational age; preterm delivery ≤34 weeks 0 days; and nonintact hysterotomy defined as very thin uterine wall with minimal tissue present between the fetal membranes and uterine serosa, or partial or complete dehiscence of the hysterotomy site at delivery.
A core of 10 risk factors was evaluated for every outcome. Obstetrical and demographic risk factors were maternal age, body mass index at the time of randomization, nulliparity, previous cesarean delivery, preoperative cervical length, and gestational age at surgery. Risk factors associated with the prenatal surgery included posterior vs anterior fundal hysterotomy, duration of uterine surgery (hysterotomy incision to closure) and total duration of surgery (maternal skin incision to closure), and time on magnesium sulfate tocolysis postsurgery. Additionally, oligohydramnios (amniotic fluid index <5 cm) and any CMS were included for all outcomes except CMS. For all outcomes, oligohydramnios and CMS had to occur prior to the outcome to be considered as a risk factor. In addition to the 12 risk factors listed above, we included spontaneous labor and SROM as risk factors for nonintact hysterotomy. In univariable analysis, continuous variables were compared with the Wilcoxon test; categorical variables were compared with the χ 2 or Fisher exact test as appropriate.
Any risk factor that was found to be associated (with P < .10) with 1 of the 5 outcomes in univariable analysis was included in a multivariable logistic regression for that outcome. However because the total duration of prenatal surgery and the duration of uterine surgery were highly correlated, only total duration of surgery was included in the multivariable logistic regression. To take into consideration potential differences in surgery practice across the MOMS centers, each logistic regression model was adjusted by clinical center. Adjusted odds ratio and 95% confidence interval were calculated.
For all analyses a nominal P value of <.05 was considered to indicate statistical significance. No adjustment was made for multiple comparisons.
Materials and Methods
Study population and design
Patient recruitment, study procedures, details of the primary and secondary outcome parameters, as well as the perioperative management algorithm for prenatal myelomeningocele surgery were described in detail in the previous MOMS trial publication. Briefly, eligible pregnant women with a fetus diagnosed with myelomeningocele and between 19–25 weeks of gestation were randomized at 1 of the 3 MOMS clinical centers to either prenatal or postnatal surgical repair. Women randomized to the postnatal surgery group went home and returned at 37 weeks of gestation to their maternal-fetal surgery center for cesarean delivery and postnatal repair by the center’s neurosurgical team. Given the anticipated increased risk of preterm labor, patients randomized to prenatal myelomeningocele surgery remained close to the MOMS center to permit standardized management after the surgery, including tocolysis therapy, weekly ultrasound evaluations, and delivery at 37 weeks of gestation if still undelivered. In addition to the usual content of a prenatal care visit and assessment of postsurgery maternal well-being, a targeted ultrasound was performed to evaluate amniotic fluid volume and the status of the hysterotomy and membranes, to assess for potential oligohydramnios, dehiscence, or chorioamniotic membrane separation (CMS), during the weekly outpatient visits.
When CMS was seen by ultrasound, patients were placed initially on outpatient bed rest. If the membrane separation progressed and extended to the placental cord insertion site, patients were admitted and placed on bed rest, with fetal heart rate testing obtained every shift or if decreased fetal movement was reported by the patient. Diagnosis of oligohydramnios was managed by hospital admission with assessment of fetal heart rate or nonstress tests every shift when the amniotic fluid index was <5 cm. Tocolytic therapy using indomethacin <32 weeks’ gestation and/or magnesium sulfate was initiated for palpable contractions with documented cervical change. Preterm labor unresponsive to tocolytics or due to chorioamnionitis, suspected uterine rupture, placental abruption, or a nonreassuring fetal status was treated by cesarean delivery. If the patient experienced rupture of membranes at <34 weeks of gestation, she was managed expectantly until 34 weeks of gestation at which time she was delivered by cesarean delivery. If preterm labor was diagnosed and the likelihood of delivery was high <32 weeks (eg, PPROM, vaginal spotting, or nonreassuring antepartum fetal surveillance), a single course of betamethasone therapy was given to minimize complications of prematurity.
At 37 weeks’ gestation, delivery took place by elective cesarean delivery because of the presence of the hysterotomy scar. Although the same abdominal laparotomy incision was used for the cesarean delivery as for the prenatal surgery, the fetus was preferably delivered via a lower uterine segment incision.
Statistical analysis
The updated analysis comparing the prenatal vs postnatal repair groups was performed according to the intention-to-treat principle. Relative risks and 95% confidence intervals were calculated.
For the analysis within the prenatal repair group of risk factors for adverse pregnancy outcome, only women who actually underwent prenatal surgical repair were included. We evaluated risk factors for 5 outcomes: CMS defined as separation from the uterine wall that did not spontaneously resolve ≤34 weeks 0 days; PPROM, defined as any spontaneous rupture ≤34 weeks 0 days; SROM at any gestational age; preterm delivery ≤34 weeks 0 days; and nonintact hysterotomy defined as very thin uterine wall with minimal tissue present between the fetal membranes and uterine serosa, or partial or complete dehiscence of the hysterotomy site at delivery.
A core of 10 risk factors was evaluated for every outcome. Obstetrical and demographic risk factors were maternal age, body mass index at the time of randomization, nulliparity, previous cesarean delivery, preoperative cervical length, and gestational age at surgery. Risk factors associated with the prenatal surgery included posterior vs anterior fundal hysterotomy, duration of uterine surgery (hysterotomy incision to closure) and total duration of surgery (maternal skin incision to closure), and time on magnesium sulfate tocolysis postsurgery. Additionally, oligohydramnios (amniotic fluid index <5 cm) and any CMS were included for all outcomes except CMS. For all outcomes, oligohydramnios and CMS had to occur prior to the outcome to be considered as a risk factor. In addition to the 12 risk factors listed above, we included spontaneous labor and SROM as risk factors for nonintact hysterotomy. In univariable analysis, continuous variables were compared with the Wilcoxon test; categorical variables were compared with the χ 2 or Fisher exact test as appropriate.
Any risk factor that was found to be associated (with P < .10) with 1 of the 5 outcomes in univariable analysis was included in a multivariable logistic regression for that outcome. However because the total duration of prenatal surgery and the duration of uterine surgery were highly correlated, only total duration of surgery was included in the multivariable logistic regression. To take into consideration potential differences in surgery practice across the MOMS centers, each logistic regression model was adjusted by clinical center. Adjusted odds ratio and 95% confidence interval were calculated.
For all analyses a nominal P value of <.05 was considered to indicate statistical significance. No adjustment was made for multiple comparisons.
Results
A total of 183 women were randomized, including 91 in the prenatal surgery group and 92 in the postnatal surgery group, representing an additional 25 women compared with the previous report. For the full MOMS cohort, baseline characteristics are presented in Table 1 and pregnancy complications and outcomes by surgery group are shown in Table 2 . As previously published, there are no differences between the surgery groups except for spina bifida lesion level L3 or lower and female gender, both of which were more common in the postnatal surgery group. As in the original report, this updated analysis shows that patients who underwent prenatal surgical myelomeningocele repair were at significantly increased risk for CMS, oligohydramnios, SROM, spontaneous onset of labor, and earlier gestational age at birth. Significant prematurity risk was observed in the prenatal surgery group, with 11% of prenatal surgery births occurring <30 weeks, 38% between 30 weeks 0 days and 34 weeks 6 days, 32% from 35 weeks 0 days to 36 weeks 6 days, and only 17% delivering at ≥37 weeks. The hysterotomy site was evaluated in 88 patients; only 65% of women in the prenatal surgery group were described as having an intact, well-healed hysterotomy at time of cesarean delivery. Nonintact hysterotomy was reported in 31 (35%) with complete (N = 2) or partial (N = 8) dehiscence reported in 10 women (11%). There was also a significant increase in placental abruption, pulmonary edema, and need for maternal transfusion in the prenatal repair group.
| Prenatal surgery N = 91 | Postnatal surgery N = 92 | |
|---|---|---|
| Fetal sex female | 42 (46.2) | 57 (62.0) |
| Gestational age at randomization, wk | 23.7 ± 1.4 | 23.9 ± 1.3 |
| Maternal age at screening, y | 29.2 ± 5.2 | 28.7 ± 4.8 |
| Race/ethnicity | ||
| White non-Hispanic | 85 (93.4) | 86 (93.5) |
| Black non-Hispanic | 1 (1.1) | 1 (1.1) |
| Hispanic | 3 (3.3) | 4 (4.3) |
| Other | 2 (2.2) | 1 (1.1) |
| Married or living with partner | 84 (92.3) | 86 (93.5) |
| Education, y | 14.9 ± 1.7 | 14.9 ± 1.7 |
| Body mass index at screening, kg/m 2 | 26.3 ± 3.7 | 26.3 ± 3.9 |
| Currently smoking | 6 (6.6) | 5 (5.4) |
| Either parent with familial history of NTD | 9 (9.9) | 16 (17.4) |
| Nulliparous | 37 (40.7) | 37 (40.2) |
| Previous uterine surgeries, including cesarean | 12 (13.2) | 11 (12.0) |
| Cervical length–transvaginal, mm | 39.5 ± 7.6 | 39.4 ± 5.9 |
| Anterior placenta | 43 (47.3) | 39 (42.4) |
| Lesion level L3 or lower | 62 (68.1) | 76 (82.6) |
| Any clubfoot on ultrasound | 24 (26.4) | 19 (20.7) |
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