Trial of Labor and Neonatal Outcomes in Extreme prematurity &lt;28 Weeks' Gestation

doi:10.21203/rs.3.rs-4885592/v1

BACKGROUND

The optimal mode of delivery for extremely preterm infants remains a subject of debate, particularly concerning the potential benefits of planned cesarean delivery.

OBJECTIVE

This study aimed to compare adverse neonatal outcomes between planned cesarean delivery and a trial of labor for singleton infants born before 28 weeks of gestation.

STUDY DESIGN

We conducted a retrospective cohort study of all singleton pregnancies delivered between 24^0/7 and 27^6/7 weeks of gestation at a single university-affiliated tertiary medical center. Patients were categorized into two groups: patients who opted a trial of vaginal delivery (TOL group) and those who had planned cesarean delivery (CD group). The primary outcome included neonatal death before discharge and severe neurological injury. Postnatal outcomes were recorded during hospitalization before discharge, and data were analyzed using an intention-to-treat analysis. Additional sub-analyses included women with spontaneous onset of labor without maternal or neonatal delivery indications and those within the gestational age range of 25^0/7 to 27^6/7 weeks.

RESULTS

A total of 199 patients were eligible for inclusion: 64 opted a trial of vaginal delivery (TOL group), while 135 underwent planned cesarean delivery (CD group). Within the TOL group, there was a higher incidence of delivery at 24^0/7- 24^6/7 weeks of gestation. Five women (7.8%) in the TOL group underwent intrapartum urgent CD. No disparities in the rates of primary or overall composite outcomes were observed between the TOL and CD groups (26.6% vs. 31.9%, p = 0.448 and 85.9% vs. 90.4%, p = 0.352, respectively). Adjusted multivariate analysis did not find significance between a trial of labor or planned cesarean delivery.

CONCLUSIONS

In extreme preterm births between 24–28 weeks of gestation no difference was found for the risk for adverse neonatal outcomes between those who had a trial of labor and those who underwent planned cesarean delivery.

cesarean delivery

mode of delivery

neonatal morbidity

neonatal mortality

preterm delivery

extreme preterm birth

Preterm birth (PTB) is the leading cause of neonatal morbidity and mortality (1, 2), which are inversely related to gestational age at delivery (3). In extreme PTB, commonly defined as birth < 28 weeks of gestation (4), neonatal mortality can reach up to 50% with similar rates of morbidity among survivors (5–7). Therefore, efforts are invested in both preventing extreme prematurity and optimizing medical care in those cases.

While some interventions, such as the administration of antenatal corticosteroids and magnesium sulphate, have been shown to be beneficial in decreasing neonatal complications (8–10), the optimal mode of delivery (MOD) in cases of PTB < 28 weeks of gestation remains controversial. Some studies suggest that in extreme prematurity, cesarean delivery (CD) is associated with reduced rates of neonatal mortality (11, 12) and improved long-term survival (13, 14) in comparison to vaginal delivery. Other studies, however, reported no significant neonatal differences related to MOD of extreme prematurity (15–21), while some reported an increased risk of neonatal morbidity with CD (22–24).

Nevertheless, most prior studies compared cases of CD with cases of successful vaginal delivery without taking into consideration a trial of labor (TOL). However, in cases of TOL, birth can be either vaginal or rather an emergent CD, which is usually performed in suboptimal conditions and can adversely affect perinatal outcome, and might underestimate the potential benefits of primary CD in those cases (18, 25). Other limitations of prior studies include a relatively small sample size (16), heterogeneity among groups with gestational age ranging up to 34 weeks (11, 17), and failure to adjust for potential confounding factors such as the indication or etiology of PTB (11, 18, 25).

Hence, our aim was to assess the optimal MOD for cases of extreme PTB occurring before 28 weeks of gestation, using an intention-to-treat approach. This was achieved by comparing outcomes between a TOL and planned CD without attempting labor.

Study Population

A retrospective cohort study of all patients who gave birth between 24^0/7 – 27^6/7 weeks of gestation in a single university-affiliated tertiary medical center (2011–2022). It was approved by the institutional review board (0284-08-TLV) which waived informed consent due to its retrospective design and anonymized data.

Exclusion criteria included multiple gestations,and non-viable fetuses,. In our institute, at extreme prematurity patients are consulted regarding mode of delivery (MOD) and the choice of CD is given even in the lack of contraindication for trial of labor. The decision regarding MOD is then determined based on standard obstetrical indications, patients' preferences, and physicians' preferences. We included all qualifying pregnancies delivered during the study period.

Data source

Maternal and neonatal data were obtained from the computerized medical records. We retrieved maternal and pregnancy data, including: maternal age, body mass index (BMI), parity, surgical history, gestational age (GA) at delivery, mode of conception, onset of labor, indication for CD, antepartum corticosteroids administration (considered only if patients received full course), administration of Magnesium sulphate (Mg) for neuroprotection, and pregnancy complications.

The following data were collected from the neonatal records: Apgar score at 1 and 5 min, arterial blood PH, birthweight and neonatal complications: necrotizing enterocolitis (NEC), intraventricular hemorrhage (IVH), mechanical ventilation, bronchopulmonary dysplasia (BPD), periventricular leukomalacia (PVL), and newborn death before discharge. Postnatal outcomes were recorded during hospitalization before discharge.

Chorioamnionitis was defined based on clinical suspicion by obstetricians at the time of delivery. The diagnosis typically involved the presence of maternal fever of 38°C accompanied one of the following: fetal tachycardia (above 160 beats per minute), maternal leukocytosis > 15,000 in the absence of corticosteriods, purulent fluid from the external os, and uterine sensitivity. In some cases, chorioamnionitis was confirmed post-delivery through positive cultures from the placenta (26, 27).

Pathologic blood flow was defined as absent or reversed end-diastolic flow in the umbilical artery or absent or reversed "A-wave" in the ductus venosus.

Exposure

The exposure of interest was trial of labor. Neonatal outcomes were compared between those with vertex presentation who opted for vaginal delivery (TOL group) regardless of the eventual mode of delivery (vaginal/cesarean delivery) and those who opted for planned CD (CD group). Patients with a-priori indication for CD (e.g. non-vertex presentation, placenta previa) were included in the CD group. Patients who opted a TOL and had eventually maternal or fetal indications for urgent CD during labor, were included in the TOL group, in an intention-to-treat approach.

Outcomes

The primary outcome was a composite adverse neonatal outcome, defined as one or more of the following: (1) neonatal death prior to discharge; (2) severe neurological injury, defined as grade 3 or 4 intraventricular hemorrhage (28).

Overall composite outcome included any of the abovementioned or any of the following: (NEC) stage 2 or 3 (29), bronchopulmonary dysplasia (BPD) (30), periventricular leukomalacia (PVL), neonatal sepsis, disseminated intravascular coagulation (DIC), arterial blood PH < 7.1, or mechanical ventilation.

Statistical Analysis

The categorical variables were presented as frequency and percentage. Normality of the continuous variables was tested using the Kolmogorov–Smirnov test and given as means ± standard deviation if normally distributed or median and interquartile range if normality could not be assumed. Comparisons between the groups were performed with the Student t-test for normally distributed continuous variables and with the Mann-Whitney rank sum test for non-normally distributed continuous variables. The Chi-square and Fisher’s exact tests were used for comparing categorical variables.

A multivariable logistic regression model, controlling for variables found to be statistically different between groups with p < 0.1 in the univariate analysis, in addition to variables that were chosen a priori such as gestational age at birth, newborn birthweight, antepartum steroids, magnesium, and newborn sex, was used to identify variables independently associated with the study outcomes. Groups were analyzed according to intention to treat. Two distinct sub-analyses were conducted. The first focused on women experiencing spontaneous labor onset without maternal or neonatal delivery indications. The second analyzed women within the gestational age range of 25^0/7 to 27^6/7 weeks, considering the elevated mortality risk in newborns born before 25 weeks of gestation. All statistical analyses were performed using SPSS software (SPSS version 29, IBM, Chicago).

Among 131,019 women delivering between 24^0/7-27^6/7 weeks of gestation during the study period, 199 met the study criteria (Figure 1). The Trial of Labor (TOL) group comprised of 64 women (32.2%), among whom 5 (7.8%) eventually underwent urgent cesarean delivery (CD), with 4 (6.3%) due to non-reassuring fetal heart monitoring (NRFHM) and 1 (1.6%) due to placental abruption. The planned CD group comprised 135 women (67.8%), of whom 73 women (54.1%) had a contraindication for TOL. This included 67 cases (49.6%) with a fetus in a non-vertex presentation and 6 cases (4.4%) with placenta previa.

Maternal and obstetrical characteristics are delineated in Table 1. Within the TOL group, there were higher rates of delivery occurring between 24^0/7-24^6/7 weeks of gestation and spontaneous onset of labor. Conversely, the planned CD group had higher rates of preeclampsia (PE)/Hemolysis, Elevated Liver enzymes, and Low Platelets (HELLP) syndrome, as well as non-reassuring fetal heart monitoring (NRFHM) (Table 1).

Table 1. Baseline characteristics of the TOL and planned CD Groups.

	TOL group (n=64)	Planned CD group (n=135)	p-value
Maternal age, mean (SD)	32.8 (6.4)	33.5 (6.2)	0.485
Gestational age, median (IQR)	26.0 (24.5-27.0)	25.6 (24.5-26.4)	0.593
Gestational age 24^0/7-24^6/7, n (%)	16 (25.0%)	17 (12.6%)	0.028
Gestational age 25^0/7-25^6/7, n (%)	11 (17.2%)	38 (28.1%)	0.094
Gestational age 26^0/7-26^6/7, n (%)	19 (29.7%)	35 (25.9%)	0.577
Gestational age 27^0/7-27^6/7, n (%)	18 (28.1%)	46 (34.1%)	0.401
Pre-gestational BMI, median (IQR)	21.8 (20.5-25.4)	23.0 (19.7-23.9)	0.887
IVF, n (%)	12 (18.8%)	33 (24.4%)	0.370
Nulliparity, n (%)	38 (59.4%)	64 (47.4%)	0.115
Previous CD, n (%)	6 (9.4%)	21 (15.6%)	0.234
Antepartum steroids, n (%)	43 (67.2%)	91 (67.9%)	0.919
Mg, n (%)	47 (73.4%)	83 (61.9%)	0.111
Spontaneous onset of labor, n (%)	64 (100%)	59 (43.7%)	<0.001
PPROM, n (%)	22 (37.3%)	27 (27.0%)	0.175
Uterine rupture, n (%)	0	6 (4.5%)	0.084
PE/HELLP, n (%)	0	20 (14.8%)	0.001
Placental abruption, n (%)	12 (18.8%)	28 (20.7%)	0.743
Chorioamnionitis, n (%)	7 (10.9%)	20 (14.8%)	0.456
Pathological blood flow, n (%)	0	7 (5.2%)	0.064
NRFHM, n (%)	4 (6.3%)	29 (21.5%)	0.007
Meconium, n (%)	10 (15.6%)	18 (13.4%)	0.679
Newborn weight, grams (mean ,SD)	857 (189)	818 (185)	0.823
Female sex, n (%)	25 (39.1%)	72 (53.3%)	0.060

Abbreviations: IVF, in-vitro-fertilization; CD, cesarean delivery; BMI, body-mass-index (kg/m²); Mg, magnesium for neuroprotection; PPROM, preterm premature rupture of membranes; PE, preeclampsia; HELLP, hemolysis elevated liver enzymes, low platelets; NRFHM , non-reassuring fetal heart monitor; SD, standard deviation; IQR, interquartile range

Table 2 presents neonatal outcomes. Among the entire cohort, neonatal death occurred in 48 cases (24.2%), with no significant differences observed between the TOL and planned CD groups (19.0% vs. 26.7%, p=0.244). Similarly, there were no significant differences between the TOL and CD groups concerning the rates of primary (26.6% vs. 31.9%, p=0.448) and overall composite outcomes (85.9% vs. 90.4%, p=0.352). Furthermore, the rates of individual components of secondary outcomes and overall composite outcomes did not vary between the groups (Table 2).

Table 2. Comparison of neonatal outcomes in patients with a TOL and planned CD

	TOL group (n=64)	Planned CD group (n=135)	p-value
Primary composite outcome, n (%)^a	17 (26.6%)	43 (31.9%)	0.448
Overall composite outcome, n (%)^b	55 (85.9%)	122 (90.4%)	0.352
Death, n (%)	12 (19.0%)	36 (26.7%)	0.244
5-min Apgar < 7, n (%)	21 (32.8%)	52 (38.5%)	0.435
Umbilical arterial PH<7.1, n (%)	6 (9.4%)	6 (4.4%)	0.172
Mechanical ventilation, n (%)	45 (70.3%)	99 (73.3%)	0.656
BPD, n (%)	32 (50.0%)	68 (50.4%)	0.961
IVH, n (%)	9 (14.1%)	15 (11.1%)	0.550
NEC, n (%)	8 (12.5%)	15 (11.1%)	0.775
PVL, n (%)	5 (7.8%)	9 (6.7%)	0.768
Sepsis, n (%)	7 (10.9%)	15 (11.1%)	0.971
DIC, n (%)	1 (1.6%)	5 (3.7%)	0.409

Abbreviations:; BPD, bronchopulmonary dysplasia; IVH, intraventricular hemorrhage (grade 3/4); NEC, necrotizing enterocolitis (stage 2/3); PVL, periventricular leukomalacia; DIC, disseminated intravascular coagulation; SD, standard deviation; IQR, interquartile range

a Defined as one or more of the following: newborn death prior to discharge, severe neurological injury.

^b Defined as one or more of the following: newborn death prior to discharge, severe neurological injury, NEC (stage 2/3), BPD, PVL, mechanical ventilation, neonatal sepsis, arterial ph< 7.1, and DIC

Multivariate analysis, adjusted for gestational age, newborn birthweight, gender, magnesium for neuroprotection, antepartum steroids, spontaneous onset of labor, uterine rupture, non-reassuring fetal heart rate, HELLP syndrome, and pathological blood flow, did not find significant differences between a TOL and CD.

In order to determine the potential impact of TOL on neonatal outcomes, we conducted a sub-analysis, limited to pregnancies with spontaneous onset of labor. The TOL group consisted of 44 deliveries, while the CD group comprised 39 deliveries. Within the TOL group, one delivery (2.3%) required conversion to urgent CD. Notably, among the CD group, 92.3% had a predetermined indication for CD (non-cephalic presentation), while the remaining opted for CD without TOL.

Maternal and obstetrical characteristics were comparable between the groups (Table 3).

Table 3. Subgroup analysis - baseline characteristics of the TOL and planned CD groups with spontaneous onset of labor.

	TOL (n=44)	Planned CD group (n=39)	p-value
Maternal age, (mean ,SD)	33.0 (6.4)	34.5 (6.4)	0.801
Pre- gestational BMI, median (IQR)	21.8 (20.5-25.4)	23.0 (19.7-23.9)	0.593
Gestational age, median (IQR)	26.0 (24.5-27.0)	25.6 (24.5-26.4)	0.887
Gestational age 24^0/7-24^6/7, n (%)	14 (31.8%)	9 (23.1%)	0.375
Gestational age 25^0/7-25^6/7, n (%)	9 (20.5%)	10 (25.6%)	0.575
Gestational age 26^0/7-26^6/7, n (%)	11 (25.0%)	10 (25.6%)	0.947
Gestational age 27^0/7-27^6/7, n (%)	10 (22.7%)	10 (25.6%)	0.757
Conception (IVF), n (%)	7 (15.9%)	6 (15.4%)	0.948
Nulliparity, n (%)	29 (65.9%)	18 (46.2%)	0.070
Previous CD, n (%)	5 (11.4%)	5 (12.8%)	0.839
Antepartum steroids, n (%)	30 (68.2%)	26 (68.4%)	0.981
Mg, n (%)	32 (72.7%)	22 (57.9%)	0.158
PPROM, n (%)	15 (37.5%)	11 (44.0%)	0.603
Non-vertex presentation, n (%)	0	36 (92.3%)	<0.001
Placenta previa, n (%)	0	0	NA
Meconium, n (%)	7 (15.9%)	3 (7.7%)	0.251
Newborn weight, grams (mean ,SD)	835 (202)	847 (165)	0.326
Female sex, n (%)	16 (36.4%)	20 (51.3%)	0.171

Abbreviations: IVF, in-vitro-fertilization; CD, cesarean delivery; BMI, body-mass-index (kg/m²); Mg, magnesium for neuroprotection; PPROM, preterm premature rupture of membranes; SD, standard deviation; IQR, interquartile range

Similarly, rates of primary and overall composite outcomes were similar between the groups (Table 4).

Table 4. Subgroup analysis - neonatal outcomes of TOL and planned CD groups comparing only cases with spontaneous onset of labor.

	TOL group (n=44)	Planned CD group (n=39)	p-value
Primary composite outcome, n (%)^a	11 (25.0%)	9 (23.1%)	0.838
Overall composite outcome, n (%)^b	39 (88.6%)	35 (89.7%)	0.871
Death, n (%)	10 (23.3%)	7 (17.9%)	0.554
Apgar < 7 (5 min), n (%)	17 (38.6%)	12 (37.5%)	0.920
Umbilical arterial PH <7.1, n (%)	5 (11.4%)	1 (2.6%)	0.122
Mechanical ventilation, n (%)	31 (70.5%)	31 (79.5%)	0.345
BPD, n (%)	24 (54.5%)	25 (64.1%)	0.377
IVH, n (%)	6 (13.6%)	4 (10.3%)	0.637
NEC, n (%)	5 (11.4%)	6 (15.4%)	0.590
PVL, n (%)	4 (9.1%)	3 (7.7%)	0.819
Sepsis, n (%)	3 (6.8%)	5 (12.8%)	0.355
DIC, n (%)	0	0	NA

Abbreviations BPD, bronchopulmonary dysplasia; IVH, intraventricular hemorrhage (grade 3/4); NEC, necrotizing enterocolitis (stage 2/3); PVL, periventricular leukomalacia; DIC, disseminated intravascular coagulation; SD, standard deviation; IQR, interquartile range

a Defined as one or more of the following: newborn death prior to discharge, severe neurological injury.

^b Defined as one or more of the following: newborn death prior to discharge, severe neurological injury, NEC (stage 2/3), BPD, PVL, mechanical ventilation, neonatal sepsis, arterial ph< 7.1, and DIC

Given the significant disparities in preterm birth rates within the gestational age range of 24^0/7-24^6/7 weeks, we conducted a supplementary sub-analysis excluding this period and focusing on pregnancies within the range of 25^0/7-27^6/7weeks. Within this gestational age range, the TOL group experienced higher rates of magnesium treatment for neuroprotection and spontaneous onset of labor. Conversely, the CD group exhibited increased prevalance of NRFHM and PE/HELLP syndrome (Table 5).

Table 5. Subgroup analysis - baseline characteristics of the TOL and planned CD groups between 25^0/7-27^6/7 weeks of gestation.

	TOL group (n=48)	Planned CD group (n=118)	p-value
Maternal age, mean (SD)	32.6 (6.9)	33.2 (6.0)	0.097
Gestational age, median (IQR)	26.5 (26.0-27.2)	26.4 (25.6-27.2)	0.597
Gestational age 25^0/7-25^6/7, n (%)	11 (22.9%)	37 (31.4%)	0.277
Gestational age 26^0/7-26^6/7, n (%)	19 (39.6%)	35 (29.7%)	0.216
Gestational age 27^0/7-27^6/7, n (%)	18 (37.5%)	46 (39.0%)	0.859
Pre-gestational BMI, median (IQR)	21.7 (20.7-23.8)	22.5 (20.3-25.0)	0.531
IVF, n (%)	9 (18.8%)	29 (24.6%)	0.418
Nulliparity, n (%)	28 (58.3%)	56 (47.5%)	0.204
Previous CD, n (%)	4 (8.3%)	19 (16.1%)	0.189
Antepartum steroids, n (%)	35 (72.9%)	78 (66.7%)	0.433
Mg, n (%)	37 (77.1%)	70 (59.8%)	0.035
Spontaneous onset of labor, n (%)	48 (100%)	45 (38.1%)	<0.001
PPROM, n (%)	14 (31.1%)	25 (27.8%)	0.687
Uterine rupture, n (%)	0	4 (3.4%)	0.193
PE/HELLP, n (%)	0	20 (16.9%)	0.002
Placental abruption, n (%)	11 (22.9%)	24 (20.3%)	0.712
Chorioamnionitis, n (%)	6 (12.5%)	19 (16.1%)	0.556
Pathological blood flow, n (%)	0	7 (5.9%)	0.085
NRFHM, n (%)	4 (8.3%)	28 (23.7%)	0.023
Meconium, n (%)	7 (14.6%)	17 (14.5%)	0.993
Newborn weight, grams (mean ,SD)	922 (164)	834 (190)	0.098
Female sex, n (%)	21 (43.8%)	63 (53.4%)	0.260

Abbreviations: IVF, in-vitro-fertilization; CD, cesarean delivery; BMI, body-mass-index (kg/m²); Mg, magnesium for neuroprotection; PPROM, preterm premature rupture of membranes; PE, preeclampsia; HELLP, hemolysis elevated liver enzymes, low platelets; NRFHM , non-reassuring fetal heart monitor; SD, standard deviation; IQR, interquartile range

Table 6 delineates neonatal outcomes in patients with a TOL and planned CD between 25^0/7-27^6/7 weeks of gestation. Notably, no significant difference were found between the groups regarding primary and overall composite outcomes. However, the TOL group displayed a trend towards lower rates of neonatal mortality compared to the CD group, although statistical significance was not achieved (10.4% vs. 22.9%, p=0.065).

Table 6. Subgroup analysis - comparison of neonatal outcomes in patients with a TOL and planned CD between 25^0/7-27^6/7 weeks of gestation.

	TOL group (n=48)	Planned CD group (n=118)	p-value
Primary composite outcome, n (%)^a	9 (18.8%)	33 (28.0%)	0.216
Overall composite outcome, n (%)^b	40 (83.3%)	105 (89.0%)	0.321
Death, n (%)	5 (10.4%)	27 (22.9%)	0.065
5-min Apgar < 7, n (%)	16 (33.3%)	41 (34.7%)	0.862
Umbilical arterial PH <7.1, n (%)	3 6.3%)	5 (4.2%)	0.583
Mechanical ventilation, n (%)	33 (68.8%)	86 (72.9%)	0.592
BPD, n (%)	27 (56.3%)	61 (51.7%)	0.594
IVH, n (%)	6 (12.5%)	11 (9.3%)	0.540
NEC, n (%)	7 (14.6%)	12 (10.2%)	0.418
PVL, n (%)	4 (8.3%)	8 (6.3%)	0.726
Sepsis, n (%)	5 (10.4%)	12 (10.2%)	0.962
DIC, n (%)	1 (2.1%)	5 (4.2%)	0.500

Abbreviations:; BPD, bronchopulmonary dysplasia; IVH, intraventricular hemorrhage (grade 3/4); NEC, necrotizing enterocolitis (stage 2/3); PVL, periventricular leukomalacia; DIC, disseminated intravascular coagulation; SD, standard deviation; IQR, interquartile range

a Defined as one or more of the following: newborn death prior to discharge, severe neurological injury.

^b Defined as one or more of the following: newborn death prior to discharge, severe neurological injury, NEC (stage 2/3), BPD, PVL, mechanical ventilation, neonatal sepsis, arterial ph< 7.1, and DIC

Principal Findings

In the current study we aimed to determine the effect of MOD on neonatal outcome in cases of singleton pregnancies delivered at <28 weeks of gestation. Our main findings were: While the rates of neonatal death did not reach statistical significance, it is possible that this outcome reflects the tendency for patients with urgent maternal or neonatal indications to undergo cesarean delivery. This could potentially account for the observed higher mortality rates in the CD group; 2) The rate of short term neonatal morbidity was not significantly different between TOL and CD groups; 3) In deliveries where a TOL was pursued, the majority of women attained vaginal delivery with relatively few cases needed an urgent CD. In addition, in those with spontaneous onset of labor, TOL was not associated with increased risk of neonatal morbidity compared to planned CD.

Results in the Context of What is Known

Mode of delivery for early preterm neonates has been a source of significant debate, a controversy that is mirrored in our study outcomes. Our study did not find significant differences in neonatal mortality and morbidity when comparing mode of delivery (MOD) within the gestational age range of 240/7-276/7 weeks.

The question regarding optimal mode of delivery in early preterm neonates was recently addressed by two separate studies (18,25). In one study, the authors did not find increased neonatal morbidity or mortality in vaginal delivery compared to CD (18), while in the other study, the authors found that vaginal delivery was associated with increased risk for neonatal morbidity and mortality in cephalic fetuses, with the opposite results for non-cephalic fetuses (25). However, these studies were mainly limited by failure to adjust for potential confounding factors such as the indication of an early delivery. In addition, in both studies there is a lack of data concerning patients who had initially a trial of vaginal delivery and were taken for CD due to fetal or maternal indications, which in turn could have biased the results

Previous studies showed potential link between cesarean deliveries (CD) and an increased risk for adverse neonatal outcomes. Malloy et al., noted a decreased risk of neonatal death among infants born through CD at 22-25 weeks of gestation (11). Similarly, Jarde et al. performed a meta-analysis encompassing singleton pregnancies below 28 weeks and found that cesarean deliveries were significantly correlated with reduced adjusted odds of death in those infants with vertex presentation (12).

Conversely, other investigations have indicated that the mode of delivery might not have a substantial impact on neonatal outcomes (15–21). Zahedi-Spung et al. recently conducted a retrospective study involving singleton pregnancies delivered between 22 to 29 weeks’ gestation (18). Although cesarean delivery was linked with decreased risk for death in the delivery room or within 24 hours after birth, it did not lead to an overall improvement in morbidity or mortality. This also aligns with the findings of a large retrospective study by Hiersch et al. who explored the association of MOD and neonatal outcomes in twin pregnancies between 240/7-276/7 weeks of gestation and did not observed and significant differences between those who had a TOL and those who underwent cesarean delivery (19).

In contrast, Bauer et al. reported an elevated risk of neonatal morbidity associated with CD compared to vaginal delivery in preterm births < 26 weeks of gestation (23). They also observed higher survival rates among newborns delivered vaginally. Additionally, Werner et al. suggested that neonatal mortality rates were comparable among newborns born between 24 and 34 weeks of gestation, while noting elevated rates of neonatal morbidity in the cesarean delivery group (22,24). More recently, Bitas et al. conducted an extensive study assessing mode of delivery and neonatal outcomes among 22-28 weeks of gestation (25). Their findings indicated that CD posed an increased risk for neonatal death in cephalic presentations compared to vaginal delivery (VD), while non-cephalic presentations showed higher risks for neonatal mortality and morbidity.

In a recent meta-analysis led by Demertzidou et al., 27 retrospective studies on singleton pregnancies were examined to assess how the mode of delivery influences the perinatal outcomes of fetuses born before 32 weeks' gestation. The findings revealed that in infants delivered before 28 weeks, vaginal delivery notably heightened the risk of neonatal death within 28 days post-birth, regardless of presentation, particularly with breech presentation. However, when assessing survival before discharge, there was no discernible difference between the delivery groups (31).

Clinical and research implications

Overall, there is a lack of clear evidence regarding the optimal MOD for extremely preterm births. It appears that, ultimately, mortality and morbidity in this vulnerable group born before 28 weeks’ gestation are predominantly determined by their extreme prematurity. This may overshadow any minor variations linked to the mode of delivery, with no definitive neonatal benefit identified when contemplating MOD in extremely premature infants. While the lack of differences between groups could potentially be attributed to insufficient power, we believe this is less likely given that the point estimates were similar overall between the study and control groups. We hope that the findings of this study can assist caregivers when discussing the mode of delivery in cases of extreme preterm deliveries. Furthermore, they underscore the impact of extreme prematurity, highlighting the need for continued research to better understand the complex factors influencing neonatal outcomes in this population. It is noteworthy that although this study did not assess maternal outcomes or long-term infant and child outcomes, it revealed no significant neonatal benefit associated with cesarean delivery at this gestational age. However, it emphasizes the pivotal role of individualized decision-making in clinical practice. Patient preferences and future pregnancy plans are paramount considerations in guiding clinical decisions. This recommendation recognizes the multifaceted nature of clinical scenarios and highlights the importance of patient-centered care, which encompasses thoughtful consideration of maternal outcomes and further future evaluation.

Strengths and limitations

Our study boasts several noteworthy strengths. First, it had a specific focus on a highly distinct cohort of early preterm infants born between 240/7-276/7 weeks of gestation, which sets it apart from the majority of prior studies that primarily concentrated on infants with gestational ages below 34 weeks. Furthermore, while most prior studies concluded their results based on the actual mode of delivery, our study proposed a different perspective in which we included patients who had a vaginal trial of labor, whether they delivered eventually vaginally or were taken to cesarean delivery, to those who did not have a vaginal trial of labor, in an intention to treat approach, which assist to refine results and to negate possible confounders.. In addition, another significant advantage of our study lies in the detailed comparison we conducted between spontaneous VD and primary indication for CD. This sub-analysis allowed us to mitigate the influence of other variables that could potentially affect neonatal outcomes, particularly scenarios where deliveries commenced as vaginal but then required an immediate transition to cesarean delivery, due to medical indications.

However, our study has several limitations. First, its retrospective design poses inherent constraints in terms of data collection and potential biases, in which we tried to overcome, and it should be taken into account when interpreting the results of our study. Furthermore, it should be noted that to be adequately powered (80%) to compare the study group with the control group, we will require approximately 720 patients in each group.

Additionally, there was significant variation in presentation among our groups. The majority of newborns delivered via cesarean delivery, were not in cephalic presentation, whereas fetuses in the TOL were in cephalic presentation, contributing to heterogeneity. Moreover, in most cases, women with indications for early delivery within this gestational age range due to conditions such as PE/HELLP syndrome, or NRFHM, undergo CD without attempting a TOL. Although several indications for immediate delivery were included in our analysis, since it was not powered, they may have additional impact in which we could not demonstrate in our results. Consequently, our findings warrant caution due to this diversity within our study groups.

It is worth noting that the cohort spans from 2011 to 2023, and neonatal mortality rates may have varied over this period. However, despite potential fluctuations, neonatal mortality rates remained consistent, estimated at around 24% for the gestational age range studied annually.

This study observed no disparity in the risk of adverse neonatal outcomes between individuals who pursued a trial of labor and those who underwent planned cesarean delivery among singleton early preterm births between 24 and 28 weeks of gestation. It is conceivable that extreme prematurity plays a pivotal role in determining neonatal outcomes within these cohorts. Moreover, our study implies that women who opt for a trial of labor have favorable prospects of achieving vaginal delivery, particularly given the relatively low rates of urgent cesarean deliveries. Nevertheless, it is imperative to interpret these findings judiciously due to the aforementioned limitations. Future prospective studies should validate these results and gather information on the reasons behind selecting the delivery method to confirm these findings

• TOL

• Trial Of Labor

• CD

• Cesarean Delivery

• SD

• Standard Deviation

• IQR

• Interquartile Range

• IVF

• In-Vitro-Fertilization

• BMI

• Body Mass Index (kg/m²)

• Mg

• Magnesium for neuroprotection

• PPROM

• Preterm Premature Rupture of Membranes

• PE

• Preeclampsia

• HELLP

• Hemolysis Elevated Liver Enzymes, Low Platelets

• NRFHM

• Non-Reassuring Fetal Heart Monitoring

• BPD

• Bronchopulmonary Dysplasia

• IVH

• Intraventricular Hemorrhage

• NEC

• Necrotizing Enterocolitis

• PVL

• Periventricular Leukomalacia

• DIC

• Disseminated Intravascular Coagulation

Ethics approval and consent to participate
All methods were conducted in compliance with applicable guidelines and regulations. This study adhered to the principles outlined in the Declaration of Helsinki. It was approved by the institutional review board (0284-08-TLV) which waived informed consent due to its retrospective design and anonymized data.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Corresponding author

Itamar Gilboa, [email protected]

Funding

None

Author Contribution

IG, LH and ML conceived and designed the study; IG, DG, NZ, and BM participated in data acquisition; IG and DG performed data analysis; IG, YY, LH and ML interpreted data for the work; IG, YY, AL, EA, LH and ML drafted the article and all other co-authors revised it for important intellectual content; all authors gave final approval of the final version and agree to be accountable for all aspects of the work.

Acknowledgements

Not applicable.

Data Availability

The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

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No competing interests reported.

Trial of Labor and Neonatal Outcomes in Extreme prematurity <28 Weeks' Gestation

Status:

Version 1

Abstract

Figures

INTRODUCTION

METHODS

Study Population

Data source

Exposure

Outcomes

Statistical Analysis

RESULTS

DISCUSSION

CONCLUSION

Abbreviations

Declarations

Consent for publication

Competing interests

Corresponding author

Funding

Author Contribution

Acknowledgements

Data Availability

References

Additional Declarations

Status:

Version 1