Intended delivery mode and neonatal outcomes in pregnancies with fetal growth restriction

Abstract Objective: To compare neonatal outcomes in pregnancies with fetal growth restriction (FGR) by intended delivery mode. Methods: This is a retrospective cohort study of singleton pregnancies with FGR that were delivered ≥34.0 weeks gestation. Neonatal outcomes were compared according to the intended delivery mode, which the attending obstetrician determined. Of note, none of the subjects had a contraindication to labor. Crude and adjusted odds ratios (ORs) and corresponding confidence intervals (CIs) were calculated via logistic regression models to assess the potential association between intended delivery mode and neonatal morbidity defined as a composite outcome (i.e. umbilical artery pH ≤7.1, 5-min Apgar score ≤7, admission to the neonatal intensive care unit, hypoglycemia, intrapartum fetal distress requiring expedited delivery, and perinatal death). A sensitivity analysis excluded intrapartum fetal distress requiring emergency cesarean delivery from the composite outcome since only patients with spontaneous labor or labor induction could meet this criterion. Potential confounders in the adjusted effects models included maternal age, body mass index, hypertensive disorders, diabetes, FGR type (i.e. early or late), and oligohydramnios. Results: Seventy-two (34%) patients had an elective cesarean delivery, 73 (34%) had spontaneous labor and were expected to deliver vaginally, and 67 (32%) underwent labor induction. The composite outcome was observed in 65.3%, 89%, and 88.1% of the groups mentioned above, respectively (p < 0.001). Among patients with spontaneous labor and those scheduled for labor induction, 63% and 47.8% required an emergency cesarean delivery for intrapartum fetal distress. Compared to elective cesarean delivery, spontaneous labor (OR 4.32 [95% CI 1.79, 10.42], p = 0.001; aOR 4.85 [95% CI 1.85, 12.66], p = 0.001), and labor induction (OR 3.92 [95% CI 1.62, 9.49] p = 0.002; aOR 5.29 [95% CI 2.01, 13.87], p = 0.001) had higher odds of adverse neonatal outcomes. Conclusion: In this cohort of FGR, delivering at ≥34 weeks of gestation, pregnancies with spontaneous labor, and those that underwent labor induction had higher odds of neonatal morbidity than elective cesarean delivery.


Introduction
Fetal growth restriction (FGR) due to impaired placental function is among the significant determinants of perinatal morbidity and mortality worldwide [1].Managing pregnancies with FGR is challenging; one of the leading clinical concerns is the optimal time and mode of delivery to reduce the risk of adverse perinatal outcomes.
There are two well-recognized phenotypes of FGR (i.e.early and late), which differ in many aspects, such as gestational age at diagnosis, Doppler profile and progression, and perinatal outcome [2].For early-onset FGR, monitoring and delivery timing according to the Trial of Randomized Umbilical and Fetal Flow in Europe (TRUFFLE) protocol, has shown to provide better-than-expected outcomes regarding infant survival without neurological impairment [3].For FGR fetuses occurring at late pregnancy, however, there is no international consensus on the timing and delivery mode.The hypoxemia characterizing this latter group of fetuses and the reduced tolerance to hypoxemia that fetuses near term seem to have, compared to fetuses at earlier gestational age, challenge the decision of optimal timing and mode of delivery [4].Different international societies [5,6] suggest labor induction (LI) at 37-38 weeks of gestation for lateonset FGR according to the estimated fetal weight (EFW) and Doppler evaluation; nevertheless, these recommendations are primarily based on non-randomized studies with heterogeneous populations and explored outcomes [4,7,8].The present study aimed to compare the neonatal outcomes according to the intended delivery mode in pregnancies diagnosed with FGR that were delivered �34 weeks of gestation.

Material and methods
This single-center retrospective cohort study was conducted at the Maternal-Fetal Medicine Department of the Instituto Nacional de Perinatologia in Mexico City from January 2017 through December 2021.Women with a singleton pregnancy and a diagnosis of FGR according to the international Delphi consensus criteria [9] (i.e.either EFW or abdominal circumference [AC] < 3 rd centile or EFW or AC <10 th centile combined with abnormal Doppler findings or a decrease in growth centiles) that delivered �34.0 weeks of gestation were included for analysis.A reliable last menstrual period date for gestational age was confirmed based on a first-trimester ultrasound (i.e.cephalocaudal length).Pregnancies with a contraindication to labor (e.g.placental previa, absent or reversed umbilical artery diastolic flow, etc.), fetuses with structural or chromosomal anomalies, multiple pregnancies, and those with incomplete medical records were excluded.All scans were performed by maternal-fetal medicine specialists using commercially available machines (Voluson E8 or 730 Expert, GE Healthcare, Zipf, Austria) according to standardized guidelines for fetal biometry [10].EFW and centiles were derived using the Hadlock formula [11,12] and growth charts [13].Doppler evaluation included umbilical artery pulsatility index (UA-PI), middle cerebral artery pulsatility index (MCA-PI), cerebroplacental ratio (CPR), ductus venosus pulsatility index (DV-PI), and mean uterine arteries pulsatility index (UtA-PI) [12].The monitoring, time, and mode of delivery of all pregnancies were at the discretion of the attending obstetrician.The primary outcome was a composite adverse neonatal outcome (ANeO), defined as the presence of one or more of the following, umbilical artery pH �7.1, Apgar score at 5 min �7, neonatal intensive care unit admission in the first 48 h of life, hypoglycemia (<45 mg/dl [2. 5 mmol/l] in the first 24 h of life), intrapartum fetal distress (defined as category II cardiotocographic monitoring trace not recovering after intrauterine resuscitation maneuvers or category III) requiring expedited delivery, and perinatal death.Demographic data, medical history, fetal biometric parameters, and perinatal outcomes were collected from the electronic medical records.

Statistical analysis
Neonatal outcomes were compared according to the intended delivery mode, which the attending obstetrician determined, an elective cesarean delivery (CD), spontaneous labor (SL), or LI.Logistic regression models were used to calculate crude and adjusted odds ratios (aORs) and their corresponding confidence intervals (95% CI) to assess the presence and magnitude of a potential association between intended delivery mode and neonatal morbidity.The following covariates were included in the adjusted effects models, maternal age, body mass index (BMI), hypertensive disorders of pregnancy, diabetes, FGR type (i.e.early or late) [9], and oligohydramnios.Since only patients with SL or LI could require an expedited delivery due to intrapartum fetal distress, a sensitivity analysis was performed to exclude this variable from the composite outcome.The study population was compared using standardized differences.Based on the sample size n of approximately 70 patients per group (i.e.210), an absolute standardized difference greater than 1:96 � ffi ffi ffi 2 p =n ¼ 0:20 would indicate an imbalance between groups [14].Data are presented as mean (standard deviation [SD]), median (interquartile range [IQR]), or n (%).Statistical analyses were performed in Stata (Version 15.1, StataCorp LLC, Texas, USA).

Ethics statement
Since this was a retrospective analysis of anonymized data, the study was exempt from a formal ethics committee review and approval according to our institution's regulations.In addition, all women gave their written consent to use their routinely collected hospital data for retrospective studies without patient identifiers.

Results
During the study period, 212 pregnancies met the inclusion criteria and were included in the analysis (Table 1).From the total cohort, 72 (34%) had an elective CD, 73 women (34%) had SL, and 67 (32%) were scheduled for LI, according to the clinical decision of the attending obstetrician.Baseline maternal characteristics are presented in Table 1.The most frequently observed maternal comorbidities were hypertensive disorders of pregnancy and diabetes.Women in the elective CD group were older, and their gravidity was higher when compared to the other two groups.Most fetuses were identified as late FGR according to the international Delphi consensus criteria [9], 88.9% in the elective CD group, 95.9% in the SL, and 76.1% in the LI group.The mean last fetal growth centile was higher for the LI group (Table 1).Furthermore, Doppler abnormalities are also described in Table 1.UtA-PI >95 th centile was the most frequent abnormality in the total cohort.While there were no cases of UA-IP >95 th centile as a single Doppler abnormality, this finding was observed in two cases in association with other Doppler abnormalities (Supplementary Table 1).As per inclusion criteria, there were no cases of abnormal DV-PI.
Among the patients with SL and those undergoing LI, 46 (63%) and 32 (47.8%) ultimately had an emergency CD for intrapartum fetal distress.Furthermore, 13 (19.4%) of the LI group had a CD due to failed labor induction (Table 2).The LI group had a higher gestational age at delivery and mean birth weight (Table 2).Composite ANeO occurred in 81% of the entire cohort.There were no perinatal deaths.ANeO presented in 65.3% (47) of those who had elective CD, 89% (65) of pregnancies with SL, and 88.1% (59) of those undergoing LI (p < 0.001,

Discussion
The findings of this cohort suggest that among FGR fetuses delivering �34 weeks of gestation, elective CD seems to be associated with less neonatal morbidity compared to pregnancies where SL is expected and those undergoing LI.Although considered a milder form of the disease, FGR occurring in late pregnancy is still associated with significant morbidity [15].In our study, 81% of the cohort had an ANeO, consistent with previous reports [16][17][18].Likewise, in the present study, intrapartum fetal distress as an indication for emergency cesarean delivery presented in more than half of those pregnancies expected to deliver vaginally.The chronic hypoxemia (e.g.reduced impedance of blood flow in the brain expressed as a low CPR or MCA-PI) characterizing FGR fetuses and the reduced tolerance to hypoxemia that fetuses near term seem to have compared to fetuses at earlier gestational age could probably increase the risk of acute superimposed hypoxemia during labor and delivery [19][20][21].
Cesarean delivery would seem less likely to significantly impact placental perfusion and fetal hemodynamics than SL or LI.Moreover, the excess risk of morbidity recognized in our cohort for patients with SL and those undergoing LI remained significant even after controlling for potential confounders.As expected, the reported effect was attenuated for the sensitivity analysis, where intrapartum fetal distress requiring expedited delivery was excluded from the composite outcome.
As reflected by the clinical decision-making in our cohort, there is no consensus on the timing and mode of delivery in FGR fetuses occurring in late pregnancy.However, international societies [5,6] suggest LI at 37-38 weeks of gestation.Several studies [4,6,7,17,22,23] have reported on the mode of delivery and neonatal outcomes in pregnancies with late FGR.The different study designs, explored outcomes and heterogeneous populations probably explain the contrasting observations with complex clinical interpretations.To our knowledge, the only randomized interventional trial on FGR at or close to term is the DIGITAT trial [6], while a randomized controlled trial (TRUFFLE-2) to   establish the optimum method and timing of delivery in late FGR fetuses is still ongoing [24].Based on the DIGITAT study findings, LI does not affect the rate of ANeO or neurodevelopment and behavioral outcome at two years of age compared to expectant management in singleton pregnancies with suspected FGR beyond 36 weeks of gestation [6].However, the study comprised a heterogeneous population of small fetuses, including those considered constitutionally small by the international Delphi consensus criteria [9], limiting the interpretation of the results.
Our study has some strengths.First, the cohort comprises a population of FGR fetuses, in which the scans were performed by maternal-fetal medicine specialists according to standardized guidelines [10,25], and the diagnosis adhered to the most recent and recognized FGR criteria [9].Second, to try to limit the impact of confounding by indication, whereby those undergoing scheduled cesarean delivery may appear to have worse outcomes, none of the pregnancies had a contraindication to labor (e.g.placenta previa, absent or reversed umbilical artery diastolic flow).Third, the major maternal and pregnancy clinical characteristics potentially affecting the primary outcome were similar among groups and were accounted for in the statistical analysis.However, we acknowledge the limitations of our study.First, given the study's retrospective nature, the outcomes were subject to intervention bias, as reflected by the cesarean delivery rate.The latter is of utmost importance as some of the ANeOs of interest can be related to both the condition (i.e.placental insufficiency resulting in hypoxia) and its treatment (i.e.relatively premature delivery).The cohort size hampered the sub-analysis according to FGR type and Doppler findings (i.e.UA-PI, CPR), which may limit the generalizability of our results.Likewise, the relatively small sample size limited a comprehensive individual analysis of the different ANeO components due to their low frequency.However, studying them as a composite outcome provides valuable information to guide clinical care and contributes to the discussion about the optimal mode of delivery in the setting of late-onset FGR.Due to the limitations highlighted above, large-scale and multicenter studies in different settings comparing the impact of time and method of delivery in FGR fetuses delivering �34 weeks of gestation will be needed to confirm our findings.Moreover, we identified a group of FGR fetuses diagnosed as early-onset FGR who go on beyond 32 weeks without meeting the delivery criteria established by the TRUFFLE protocol [3].We hypothesize that this group of fetuses' clinical phenotype and corresponding perinatal outcomes could differ from those diagnosed as late-onset FGR.Nevertheless, the same recommendations on timing and mode of delivery may apply to both.Future studies will be needed to examine this observation in more detail.Finally, residual confounding could impact the certainty of the reported effects, as is the case for most observational studies [26,27].

Conclusions
In this cohort of FGR, delivering at �34 weeks of gestation, pregnancies with spontaneous labor and those that underwent labor induction had higher odds of neonatal morbidity than elective cesarean delivery.

Table 1 .
Table 2).A breakdown of the components of the ANeO and their frequencies by intended delivery mode is presented in Supplementary Table 2. Compared to elective CD, patients with SL where a vaginal delivery was expected (OR 4.32 [95% CI 1.79, 10.42], p ¼ 0.001) and those that underwent LI (OR 3.92 [95% CI 1.62, 9.49], p ¼ 0.002) had higher odds of ANeO (Table3and Supplementary Table2).These findings persisted even when controlling for potential confounders Patient and pregnancy characteristics.

Table 3 .
Logistic regression analysis for the association of intended delivery mode with a composite adverse neonatal outcome in fetuses with fetal growth restriction.

Table 4 .
Logistic regression analysis for the association of intended delivery mode with a composite adverse neonatal outcome in fetuses with fetal growth restriction excluding expedited delivery due to intrapartum fetal distress from the composite outcome.