Pre-labor Cesarean delivery or induction of labor in twin gestation

BACKGROUND: We aimed to compare neonatal and maternal outcomes of twin gestations without spontaneous onset of labor, which underwent induction of labor or pre-labor cesarean section. METHODS: In the Twin Birth Study (TBS), women at 32 0/7 -38 6/7 weeks of gestation, in whom the rst twin was in cephalic presentation, were randomized to planned vaginal delivery or cesarean section. In this secondary analysis of the TBS we focused on the outcomes of the subset of women who did not have a spontaneous onset of labor. We compared those who had an induction of labor with those who had a pre-labor cesarean section. The primary outcome was a composite of fetal or neonatal death or serious neonatal morbidity. Secondary outcome was a composite of maternal morbidity and mortality. RESULTS: Of the 2,804 women included in the TBS, a total of 1,347 (48%) women did not have a spontaneous onset of labor: 568 (42%) in the planned vaginal delivery arm and 779 (58%) in the planned cesarean arm. Induction of labor was attempted in 409 (30%), and 938 (70%) had a pre-labor cesarean section. The rate of intrapartum cesarean section in the induction of labor group was 41.3%. The rate of the primary outcome was comparable between the pre-labor cesarean section and induction of labor groups (1.65% vs. 1.97%; p=0.61; OR 0.83; 95% CI 0.43-1.62). The maternal composite outcome was found to be lower with pre-labor cesarean section compared to induction of labor (7.25% vs. 11.25%; p=0.01; OR 0.61; 95% CI 0.41-0.91). CONCLUSION: In women with twin gestation between 32 0/7 -38 6/7 weeks of gestation with the rst twin in cephalic presentation, induction of labor and pre-labor cesarean section have similar neonatal outcomes. Pre-labor cesarean section is associated with favorable maternal outcomes.


Background
The prevalence of twin gestations is approximately 3% of all pregnancies, and they carry a higher risk pro le compared to singleton gestations 1 . Some of which may necessitate delivery prior to the spontaneous onset of labor, or the pre-scheduled elective cesarean section (CS).
In attempt to limit perinatal mortality and other adverse neonatal outcome, elective delivery at 37 to 39 weeks of gestation has been widely recommended in twin gestations 1-6 . There is a paucity of information concerning the outcomes of pre-labor deliveries using induction of labor (IOL) compared to pre-labor CS in twins. Published studies have compared IOL in twin and singleton gestations (rather than IOL in twins versus CS in twins) or limit their analysis to speci c subgroups, such as monochorionic twin pregnancies [7][8][9] . The Twin Birth Study (TBS) is the largest multicenter, randomized controlled trial, in which women with twin pregnancies between 32 0/7 and 38 6/7 , with the rst twin in cephalic presentation, were randomized to planned vaginal delivery (VD) or planned CS. Results demonstrated that planned VD had similar neonatal and maternal outcomes compared to a planned CS 10 . As the study compared planned modes of delivery, the population included both those who had a Page 3/16 spontaneous onset of labor and those who required delivery by IOL or pre-labor CS (PrlCS). Thus, when facing the need to counsel a patient with twins who requires pre-labor obstetrical intervention, there is still a knowledge gap.
This secondary analysis sought to evaluate and compare fetal, neonatal and maternal outcomes in the subset of women who required IOL or PrlCS.

Methods
A total of 106 centers in 25 countries participated in the original TBS study between December 2003 and April 2011. A full detailed description of the study protocol is available elsewhere 10 , but in brief; Eligibility was limited to women between 32 0/7 and 38 6/7 weeks of gestation, with the rst twin in cephalic presentation, an estimated fetuses weight between 1500g and 4000g, and two viable fetuses. Women with two or more previous low-segment CS, vertical uterine incision, mono-amniotic twins or any contraindication to vaginal birth were excluded. IOL or PrlCS were performed for the indication of "advanced gestational age" in a twin pregnancy (de ned as gestational age between 37 5/7 weeks and 38 6/7 weeks of gestation) or other obstetrical or medical indications (e.g. preeclampsia).
Method of IOL, oxytocin augmentation protocol, mode of analgesia and the management of the second twin were at the discretion of the attending obstetrician. Ability to perform a cesarean section within 30 minutes if necessary was a stipulation of trial participation.
The primary outcome of the TBS and of this secondary analysis was a composite of fetal or neonatal mortality or serious neonatal morbidity. Serious neonatal morbidity included the following: Birth trauma; Apgar score of less than 4 at 5 minutes; seizures before 72 hours of age; coma; need for assisted ventilation; con rmed septicemia; necrotizing enterocolitis; pneumoatosis intestinalis; bronchopulmonary dysplasia; grade III or IV intraventricular hemorrhage and cystic periventricular leukomalacia. The secondary outcome was a composite maternal outcome, which was de ned as any of the following occurring up to 28 days postpartum: Death; severe hemorrhage; laparotomy; genital tract injury; thromboembolism requiring anticoagulation; systemic infection; major medical life-threatening illness; wound infection, dehiscence or breakdown. The full protocol and speci c methods of identi cation of each of these outcomes is detailed in the original manuscript 10 .
Utilizing the data from the initial TBS, in this secondary analysis we compared neonatal and maternal outcomes in the subgroup of women who required delivery prior to onset of labor. As the aim of the study was to assess the impact of PrlCS and IOL on maternal and neonatal outcomes, we did not follow the original randomization arms and the intention to treat analysis approach. Since, faced with the decision of IOL, some women randomized to the planned VD arm chose to undertake CS, we felt an analysis based on actual attempt of labor (IOL) versus no attempt (pre-labor CS) would be more appropriate.
Continuous outcomes compared between groups using mean ± standard deviations. Categorical data are presented as percentages, odd ratios (OR) and corresponding 95% con dence intervals (CI). The unit of analysis was the infant when assessing neonatal outcomes. Generalized estimating equations were used to account for the correlation between infants from the same pregnancy. Statistical signi cance was set to 0.05, two-sided. A sub-analysis of women that required a delivery for "advanced gestational age" in a twin pregnancy (gestational age between 37 5/7 weeks and 38 6/7 ) was performed as well. Since this analysis was secondary to a randomized clinical trial, no power calculations were performed. The original study and all secondary analyses were approved by the Research Ethics Board at the Sunnybrook Health Sciences Centre.

Results
In the original TBS, 2,804 women were included. A total of 1,347 (48.0%) women required delivery prior to the onset of spontaneous labor: 779 (57.8%) in the planned CS arm and 568 (42.2%) in the planned VD arm. Overall, 31 women (3.9%) in the planned CS arm and 190 women (33.4%) in the planned VD arm crossed over to the other group following a discussion regarding the need for delivery.
Of the 1,347 women who needed a delivery, 409 (30.4%) had an IOL and 938 (69.6%) PrlCS ( Figure 1). The groups were signi cantly different with regards to maternal age, parity, previous cesarean section status, antenatal corticosteroids use, estimated fetal weight of the second twin, and gestational age and presentation at delivery (Table 1). In the IOL group, 155 women (37.9%) had an intrapartum CS for both twins, and 14 (3.4%) had a CS for the second twin.
The rate of the primary neonatal outcome was comparable between the PrlCS and IOL groups (1.65% vs. 1.97%; p=0.61; OR 0.83; 95% CI 0.43-1.62). The rates of the individual components of the neonatal composite outcome were similar between the groups as well ( Table 2).
The maternal composite outcome was signi cantly lower in the PrlCS group: 7.25% vs. 11.25% (p=0.01; OR 0.61; 95% CI 0.41-0.91), and this difference stemmed primarily from the differences in hemorrhagic morbidity. Compared with women in the IOL group, women in the PrlCS group had signi cantly lower rates of hemorrhage (6.19% vs. 9.56%; p=0.02; OR 0.62; 95% CI 0.40-0.94), and required less postpartum uterine dilatation and curettage (0.32% vs. 1.47%; p=0.03; OR 0.21; 95% CI 0.05-0.86). The rate of severe perineal injury (3 rd or 4 th degree) in the IOL group was 0.98%. There were no signi cant differences between the two groups in respect to other individual maternal outcomes (Table 3).
We also performed a sub-analysis of women who had IOL or PrlCS for "advanced gestational age" in a twin pregnancy. The characteristics of these women were similar in terms of age, parity, gestational age at delivery, estimated fetal weight of each twin and antenatal steroid use. While the rate of the composite primary neonatal outcome was similar between the two sub-groups, maternal outcome was found to be signi cantly lower with PrlCS in comparison with IOL (0% vs. 9.41%; p=0.03; OR 0.15; 95% CI 0-0.7).
Again, this was mainly due to differences in the rates of hemorrhagic episodes. There were no signi cant differences between the two sub-groups with respect to individual neonatal or maternal outcomes (Table  4 & Table 5). PrlCS-pre-labor cesarean section. IOL-induction of labor.   × Genital Tract Injury: Need for hysterectomy; vulvar or perineal hematoma requiring evacuation; broadligament hematoma con rmed by means of ultrasonography, CT, or MRI; intraoperative damage to the bladder, ureter, or bowel requiring repair; stula involving the genital tract. † Wound infection: Infection requiring prolongation of hospital stay, infection requiring readmission to hospital, infection requiring repeated treatment as an outpatient. Table 4. Neonatal outcomes in women whose indication for delivery was "advanced gestational age". N/C-No Convergence. N/E-No Events. †Abnormal level of consciousness: Coma, stupor or decreased response to pain, hyperalert, drowsy, or lethargic. ‡Assisted ventilation for ≥24 hr by means of endotracheal tube, inserted within 72 hr after birth. Table 5. Maternal outcomes in women whose indication for delivery was "advanced gestational

Discussion
The initial TBS found no major differences in perinatal morbidity or mortality between planned vaginal delivery and planned cesarean section in women with twin gestations at 32 0/7 -38 6/7 with the rst twin in cephalic presentation 10 . A recent secondary analysis of the TBS showed no change in neonatal or maternal outcomes between the study arms in women who presented with spontaneous labor 11 . In this secondary analysis we reviewed the outcomes of those women who did not have a spontaneous onset of labor, but had either IOL or PrlCS. Analysis of this group comes with the di culty of cross over between the original randomization groups. The high cross over rate from the original TBS planned vaginal delivery arm to the PrlCS group may be partially explained by higher rate of non-cephalic presentation at delivery (either twin) found in the PrlCS group in compare to the IOL group. An increased risk for intrapartum CS following IOL in twins 8 is another possible factor affecting maternal decision to choose PrlCS over IOL. An earlier gestational age at delivery at the PrlCS group might represents higher risk fetuses with indications for delivery at an earlier stage of pregnancy. Hypothetically, higher risk fetuses are prone to increase rate of neonatal morbidity and mortality. Despite this, perinatal outcomes were comparable between the PrlCS and IOL groups, which may represent an overall more favorable result for PrlCS if the groups had been evenly matched in fetal risk level.
Our results correlate with the original TBS regarding neonatal outcomes, but differ in showing lower risk of adverse maternal outcomes in PrlCS, compared with IOL. The composite maternal outcome was higher in the IOL group mainly due to differences in hemorrhagic morbidity. This held true among the subset of women whose delivery was indicated due to "advanced gestational age" in a twin pregnancy.
We are aware of the high rate of intra-partum CS in the IOL group, compared to what has been reported in singleton pregnancies following IOL 12,13 . We postulate that a prior higher risk for CS in twins 14 in addition to late maternal age and increased rate of nulliparity (both has been associated with an intra-partum CS following IOL) can explain this nding 15,16 . The increased maternal morbidity in the IOL group may be explained by the high rate of intra-partum CS in these women (41.3%).
There is minimal evidence regarding the relative safety of IOL versus CS of twins for women not in labor.
Previous studies compared IOL in twins with IOL in singletons 7 The strength of this secondary analysis lies in its size, multiple site recruitment and high rate of follow up on which to base results. It is a pioneer study to compare maternal outcomes in twin gestations that required delivery while not in labor. One might consider loss of intention to treat as a study weakness, as intention to treat analysis aims to give an unbiased estimate of treatment effect and preserves prognostic balance 21,22 . However, an analysis where attempted vaginal delivery (IOL) was compared to no attempt at vaginal delivery (PrlCS) gives results more akin to true life. This garners more representative results for clinical application and is bene cial when counseling patients with twins facing IOL. The main limitations of this study include the secondary analysis nature, not planned a priori, and therefore not powered to detect signi cant change between attempted modes of delivery in those who did not labor spontaneously. Lastly, neonatal complications found in this study may be impacted by confounding factors, such as gestational age at delivery or other obstetric complications, and not be exclusively related to mode of delivery.

Conclusion
In twin pregnancies between 32 0/7 and 38 6/7 weeks of gestation who require delivery prior to onset of labor, our limited data suggests no fetal or neonatal bene t in either IOL or CS but possible maternal bene t with CS.

Declarations
Ethics approval and Consent to participate: The Twin Birth Study and all secondary analyses were approved by the Research Ethics Board at the Sunnybrook Health Sciences Centre.
Availability of data and materials: