Mode of delivery and neonatal outcomes with early preterm severe preeclampsia: does fetal growth restriction matter?

Abstract Objective Severe preeclampsia diagnosed at or prior to 34 weeks is an indication for preterm delivery. Many patients with severe preeclampsia develop fetal growth restriction as a result of the placental dysfunction associated with both conditions. The ideal mode of delivery in cases of preterm severe preeclampsia with fetal growth restriction remains controversial, with providers often proceeding directly to cesarean delivery rather than attempting a trial of labor due to theoretic concerns about the harms of labor in the face of placental dysfunction. There are limited data supporting this approach. This study evaluates whether the presence of fetal growth restriction affects the ultimate mode of delivery or neonatal outcomes among pregnancies with severe preeclampsia undergoing induction of labor at or before 34 weeks. Methods This was a retrospective cohort study of singletons with severe preeclampsia undergoing induction of labor ≤ 34 weeks at a single center between January 2015 and April 2022. The primary predictor was fetal growth restriction, defined as estimated fetal weight < 10th percentile for gestational age on ultrasound. Mode of delivery and neonatal outcomes were compared between those with and without fetal growth restriction using Fisher’s exact and Kruskal-Wallis tests, and multivariate logistic regression was used to obtain adjusted odds ratios. Results 159 patients were included (N = 117 without fetal growth restriction, N = 42 with fetal growth restriction). There was no difference in vaginal delivery between the groups (70% vs 67%, p = .70). While those with fetal growth restriction had a higher incidence of respiratory distress syndrome and longer neonatal hospital stay, these differences were not statistically significant after adjusting for gestational age at delivery. There were no significant differences in other neonatal outcomes, including Apgar score, cord blood gases, intraventricular hemorrhage, necrotizing enterocolitis, neonatal sepsis, and neonatal demise. Conclusion For pregnancies complicated by severe preeclampsia that require delivery ≤ 34 weeks, the likelihood of successful vaginal delivery following induction of labor does not differ based on presence of fetal growth restriction. Furthermore, fetal growth restriction is not an independent risk factor for adverse neonatal outcomes in this population. Induction of labor should be considered a reasonable approach and should be routinely offered to patients with concurrent preterm severe preeclampsia and fetal growth restriction.


Introduction
Severe preeclampsia (SPE) is a rare but life-threatening pregnancy complication characterized by severely elevated blood pressures and/or signs of end-organ dysfunction [1]. A large proportion of patients with SPE also develop fetal growth restriction (FGR) [2], which is thought to be related to the conditions' shared etiology of placental dysfunction [3,4]. Given the morbidity and mortality of this complication, SPE diagnosed 34 weeks is an indication for preterm delivery no later than 34 weeks, per recommendations from the American College of Obstetricians and Gynecologists (ACOG) [5]. While preterm SPE alone is not a contraindication to induction of labor (IOL), the ideal mode of delivery remains controversial for cases with concurrent SPE and FGR. Although there are no formal guidelines on management of such cases, some experts recommend foregoing IOL and proceeding directly to cesarean delivery in cases of SPE with FGR [6]. This recommendation often stems from concerns that the additional stress of labor on top of an already malfunctioning placenta will lead to a low likelihood of successful vaginal delivery and/or poor neonatal outcomes. There are limited clinical data to support this theoretical concern. Given this gap in knowledge, this study was designed to determine whether the presence of FGR affects the likelihood of successful vaginal delivery or adverse neonatal outcomes among pregnancies with SPE diagnosed 34 weeks who underwent IOL. We hypothesized that presence of FGR would not affect mode of delivery or neonatal outcomes among pregnancies with preterm SPE undergoing IOL.

Materials and methods
This was a retrospective cohort study of all living singleton pregnancies that underwent IOL for SPE diagnosed 34 weeks at a single tertiary care referral center between January 2015 and April 2022. Those with contraindications to vaginal delivery (e.g., vasa previa, non-vertex fetal presentation) and/or contraindications to use of induction agents (e.g., medication allergies, active non-reassuring fetal heart tracing) were excluded. Diagnosis and management of SPE was made in accordance with ACOG recommendations [5,7]. All patients diagnosed with SPE 34 weeks were hospitalized and managed expectantly until delivery at 34 weeks or sooner, if warranted by significant changes in maternal or fetal status that precluded expectant management [5]. All deliveries at this institution are captured within the Perinatal Database, with information details regarding maternal demographics, labor characteristics, and pregnancy outcomes collected at the time of delivery by the managing clinicians. Daily chart review is performed by trained abstractors to ensure complete and accurate information; a monthly review of the database is performed by a physician for quality assurance. The Perinatal Database was used to identify patients who underwent IOL for SPE diagnosed 34 weeks during the aforementioned time period. Additional details regarding specifics of preeclampsia diagnosis, prenatal ultrasound findings, and neonatal outcomes were extracted from the electronic medical record by the primary author.
Fisher's exact and Kruskal-Wallis tests were used to compare those with and without FGR. Multivariate logistic regression was employed to generate odds ratios (OR) with 95% confidence intervals (CI) adjusted for GA at delivery and other relevant covariates. Statistical significance was set at a probability value of < 0.05. Statistical analyses were performed using STATA software (version 16.1, StataCorp, College Station, TX). This study was approved by the institutional Committee on Human Research (study number 11-07364).

Results
Of the 159 living singleton pregnancies complicated by SPE that underwent IOL 34 weeks within the study period, 42 patients met the criteria for FGR, while 117 patients did not. Among those with FGR, 45% (19) had severe FGR with EFW < 3rd percentile for GA, 33% (14) had elevated UA systolic-to-diastolic ratio, and 7% (3) had absent end diastolic flow on UA Doppler interrogation. Comparison of baseline characteristics for those with and without FGR is summarized in Table 1. There were no statistically significant differences in median maternal age at delivery, nulliparity, use of in vitro fertilization, chronic hypertension, obesity (defined as body mass index 30 kg/m 2 ), or tobacco use between the two groups. SPE was diagnosed at a significantly earlier GA among those with FGR compared to those without FGR (31 vs 33 weeks, p ¼ .003), and individuals with FGR delivered at a significantly earlier GA (33 vs 34 weeks, p < .001). As expected, the median EFW percentile based on the last ultrasound was significantly lower for the group with FGR compared to the group without FGR (3% vs 42%, p < .001).
Mode of delivery and neonatal outcomes are summarized in Table 2. The likelihood of successful vaginal delivery following IOL was no different between those with and without FGR (67% vs 70%, p ¼ .70, OR 0.86, 95% CI 0.41-1.83). This finding was unchanged when adjusting for the presence of chronic hypertension, GA at delivery, and GA at diagnosis of SPE (adjusted OR 0.92, 95% CI 0.39-2.16). There were no significant differences in neonatal outcomes of 5-min Apgar score < 5, UA base deficit 12, UA pH < 7.20, IVH, NEC, neonatal sepsis, and NND between the two groups. Those with FGR had a higher incidence of RDS on univariate analysis (61% vs 39%, p ¼ .02), but multivariate analysis adjusting for GA at delivery demonstrated no difference in this outcome by FGR status (adjusted OR 1.5, 95% CI 0.60-3.53). Additionally, the median neonatal LOS appeared longer among those with FGR compared to those without FGR (22 days vs 15 days, p ¼ .003), although this finding was not statistically significant after adjusting for GA at delivery. As anticipated, the median birth weight was significantly lower for pregnancies with FGR (1290 vs 2155 grams, p < .001), and the proportion of infants that were small for gestational age (SGA, defined as birth weight < 10th percentile for GA and sex) was significantly higher among pregnancies with FGR (68% vs 8%, p < .001).

Principal findings
In this cohort of 159 singleton pregnancies complicated by SPE that underwent IOL 34 weeks, the presence of FGR did not affect the likelihood of successful vaginal delivery. In fact, in both groups, the majority of patients experienced a successful vaginal delivery (67% with FGR, 70% without FGR). We also failed to find a difference in adverse neonatal outcomes between the two groups, after adjusting for GA at delivery.

Results in the context of what is known
IOL has been previously evaluated in cases of isolated SPE [9][10][11] and in cases of isolated FGR [12][13][14], and appears to be safe when either condition exists alone. Less is known about cases where SPE and FGR coexist, and whether the presence of FGR affects outcomes following IOL. There are concerns about the safety of labor in the setting of placental insufficiency, which underlies both conditions [3]. Wu and Zhang have raised the possibility that uterine contractions during labor reduce uterine blood flow, which increases the risk of fetal hypoxia [15]. They discuss that this can be dangerous in the setting of SPE with FGR, since pathophysiological changes in preeclampsia lead to vascular spasms and diminished placental perfusion [15]. Additionally, others have recommended avoiding acute hypoxia during delivery when FGR is caused by  chronic hypoxia as a consequence of placental insufficiency [16][17]. These concerns have led some experts to recommend avoiding labor in cases of preterm SPE with FGR [6], despite lack of supporting evidence in the literature. Our results question this approach.
In prior studies examining individuals with SPE and very low birth weight infants, the reported rate of successful vaginal delivery following IOL has ranged from 34-65% [18,19]; the 67% success rate of vaginal delivery we report among FGR cases exceeds these estimates. Although these prior studies found no difference in neonatal outcomes among those who underwent IOL and those who underwent unlabored cesarean delivery, they only included cases with coexisting SPE and FGR; they did not compare cases with and without FGR to determine whether the presence of FGR affected outcomes. One study did examine this and reported that the presence of a SGA infant did not affect the likelihood of successful vaginal delivery following IOL in cases of preterm SPE [20]. Our current study contributes to a small but growing body of evidence demonstrating that the presence of FGR may not affect the mode of delivery or neonatal outcomes following IOL for preterm SPE.

Clinical implications
Our findings suggest that IOL should be considered a reasonable approach for pregnancies complicated by SPE 34 weeks, regardless of whether FGR is present. The high success rate of IOL and comparable neonatal outcomes we report may serve to allay fears that growth-restricted fetuses will be less likely to tolerate labor than appropriately grown fetuses. Rather than proceeding directly to cesarean delivery for those with preterm SPE and FGR, IOL should be considered for these patients. Cesarean deliveries pose numerous risks for the birthing individual, including intraoperative complications, prolonged recovery time, and abnormal placentation in future pregnancies [21]. Some studies have also reported an association between cesarean delivery and an increased risk of neonatal complications in preterm SGA newborns [22]. Our findings encourage individualized clinical decision-making that may reduce the number of unnecessary cesarean deliveries performed in the population of patients with preterm SPE.

Research implications
Based on the current literature, it is unclear whether the presence of FGR should affect the decision of whether to labor in the setting of preterm SPE; we found that it should not. The next step in this line of work is to determine whether the degree of FGR affects the likelihood of successful vaginal delivery or adverse neonatal outcomes. Although EFW was dichotomized in this study, it is a continuous variable, and it is possible that those with more severe FGR may have different outcomes than those with more moderate FGR. Future studies should also examine long-term outcomes among growth-restricted vs normally grown infants who undergo IOL for preterm SPE. A prior study demonstrated that labor is associated with increased oxidative stress in FGR newborns [23], and oxidative stress is associated with inflammation and chronic disease [24]. Tracking outcomes throughout childhood and adolescence can determine if labor predisposes growth-restricted neonates born to mothers with SPE to conditions like obesity and diabetes later in life.

Strengths and limitations
This study is limited by its small sample size in the setting of a rare condition, which may have led to insufficient power to detect small differences in neonatal outcomes. All patients belonged to a single institution, which may limit the generalizability of our results; for example, our reported vaginal delivery rates following IOL for preterm SPE are higher than those that have been reported elsewhere [9][10][11]18]. Because this was a retrospective study, data collection was limited to what was available in the electronic medical record. Furthermore, ascertainment of outcomes was restricted to those captured in infants' charts during their hospital stay at our institution. It is possible that some infants were transferred to outside institutions, and outcomes that occurred elsewhere were missed. Despite these limitations, this study has strengths including our institution's policy of offering IOL for all cases of SPE unless contraindicated, allowing for a direct comparison of outcomes by presence of FGR.

Conclusions
The presence of FGR did not affect the likelihood of vaginal delivery or adverse neonatal outcomes following IOL in patients with SPE diagnosed 34 weeks in this single center study. Based on these findings, we suggest consideration of IOL for patients with SPE 34 weeks regardless of presence or absence of FGR, assuming no other contraindications to vaginal delivery or use of induction agents are present. We also recommend future studies with longer follow-up intervals to evaluate the effects of IOL and delivery mode on premature, growth-restricted infants born to individuals with SPE.

Disclosure statement
No potential conflict of interest was reported by the author(s).

Funding
The author(s) reported there is no funding associated with the work featured in this article.