Ideal timing of labor in terms of oxidative stress – which term period is best?

Introduction

Labor is a complex process divided into three stages; all have characteristics, risks, and management strategies. The first stage starts with regular contractions and dilatation and ends with 10 cm of dilatation and full cervical effacement. The first stage is divided into two phases, called the active and latent phases of labor. The second stage ends with the delivery of the fetus, and the third stage includes the delivery of the placenta [1].

In singleton pregnancies, the pregnancy lasts an average of 40 weeks (280 days) from the first day of the last menstrual period to the estimated due date. In the past, three weeks before and two weeks after this week were considered a ‘term’ pregnancy with the expectation of good newborn outcomes. In later years, studies have determined that newborn outcomes, especially respiratory morbidity, vary depending on the delivery timing during these five weeks. The frequency of adverse neonatal outcomes in uncomplicated term pregnancies is lowest between 39 0/7 and 40 6/7 weeks, compared to other weeks. For this reason, studies aiming to increase the quality of life have focused on the necessity of inducing pregnancies before 39 0/7 weeks if no medical reason prohibits it. According to the American College of Obstetricians and Gynecologists (ACOG), initiating labor induction before 39 weeks of pregnancy is not recommended without mandatory conditions for completed fetal lung maturity [2].

To facilitate data reporting, all clinicians should use a uniform approach when describing this period’s birth and gestational week. In 2013, ACOG and the Society for Maternal-Fetal Medicine recommended consistent terminology for term pregnancy. According to these recommendations, term pregnancy was divided into three groups: early-term (37 0/7–38 6/7 weeks of gestation), full-term (39 0/7–40 6/7 weeks of gestation), and late-term (41 0/7–41 6/7 weeks of gestation) to more accurately describe the label “term” [3].

In a previous study, fetal mortality was higher in post-term pregnancies than in full-term pregnancies. It was again higher in early-term pregnancies than full-term ones [4–6]. In other words, term pregnancies also differ in mortality and morbidity.

The human organism has a balance between the oxidative and antioxidant systems. Tissue damage is inevitable in case of deteriorated oxidative status. Thiols are protective organic components that work against the reactive oxygen species-mediated damages of albumin and protein parts of the tissues specifically [7]. Thiols contain sulfhydryl (SH) groups that react with oxidant molecules and change due to oxidation. Proteins mutate due to the changes in the thiol groups, resulting in structural and functional changes [8]. Erel and Neselioglu developed an automated method for measuring thiol-disulfide homeostasis (SH-SS homeostasis). Numerous clinical investigations have been performed using this novel method to observe the oxidative status of diseases [8].

Studies determining the ideal delivery week have focused on maternal and neonatal outcomes. In this study, we aim to reveal the ideal timing of labor in terms of oxidative stress for both mothers and fetuses in different periods of pregnancy. We believe this study may shed light on how molecules affect complications in different pregnancy term periods and will be a source for other studies.

Materials and methods

This prospective cohort study was conducted at the Obstetrics and Gynecology Clinic of Ankara City Hospital between April 2020 and 2021. A total of 232 healthy pregnant women admitted to the Obstetrics Department of our hospital were enrolled in the study. The study protocol was approved by the hospital’s Ethics Committee (E1-249-2020). A pre-participation consent document was requested from all participants, and this was filled out and signed voluntarily. All the patients were risk-free pregnant women with a healthy single fetus. Gestational age was calculated using the last menstrual period or dating method (ultrasound of the first trimester-based calculation to establish and confirm gestational age). Only term and spontaneous pregnancies were included in the study. Patients with abnormal laboratory results, gestational or pre-gestational chronic or acute diseases/infections, ruptured membranes before the active phase had begun, or those with fetal congenital defects were excluded. Patients requiring medication or those with drug, alcohol, or tobacco addiction were also excluded from the study. Demographic data, including age, gravidity, parity, body mass index, birth weight, and gestational week, were recorded.

All pregnant women who met the abovementioned criteria and volunteered at admission were included in the study. We divided the patients into three groups: Group 1 consisted of individuals at early term according to the last menstruation date. In contrast, Groups two and three included the pregnant women at full term and late term, respectively. “Term” label was used according to the recommendations of ACOG [9]. When the labor was in the active phase, 5 cm³ of blood from maternal venous vascular access was collected into a tube; sera were then parsed and stored at – 80 °C until the analysis day. After birth, the fetal cord was clamped, and the same procedure was carried out for the fetal umbilical arterial blood sample. APGAR Scores of 1–5th minutes were noted to observe fetal outcomes. After taking samples from sufficient patients, final analyses were made in the Ankara City Hospital biochemistry laboratory. If there was a cesarean section during labor for any reason (cephalopelvic disproportion, abnormal uterine bleeding, or placental abruption), the participant was excluded from the study. Five cesarean deliveries were in all three groups due to fetal distress until 55 patients each; these pregnant women were also excluded from the study.

For thiol/disulfide homeostasis tests, a specific spectrophotometric method defined by Erel and Neselioglu was performed using an autoanalyzer (Cobas 501, Roche, Mannheim, Germany) [8]. After determining native (SH) and total thiols (SH+SS), disulfide levels (SS) and disulfide/native thiol percentage ratios (SS/SH), which indicate index%, were calculated.

As our study was preliminary, a power analysis was not performed before the study started. Post-hoc analysis of 150 patients showed a power of 0.80 when we accepted the effect size 0.5 with alpha at a 0.05 significance level. IBM’s Statistical Package for the Social Sciences Statistics for Windows, version 20.0 (SPSS Inc., Chicago, IL, USA), was used for statistical analysis. We performed a Kolmogorov–Smirnov test, a Shapiro–Wilk test, or created histograms to analyze whether the data were normally distributed. Descriptive analyses for normally distributed variables were stated as mean ± standard deviation. Categorical variables were expressed as numbers (percentages) and compared using the Chi-square test. We used one-way ANOVA (post-hoc Bonferroni test) and independent t-tests to compare variables. Pearson’s correlation test was used to specify the correlation coefficient. All data were analyzed at a 95 % confidence interval, and p<0.05 was considered significant.

Results

Table 1 consists of the demographic features of the study participants, including age, gravidity, parity, week of gestation, the weight of the baby at birth, and newborn outcomes according to the APGAR score (1 and 5 min). Statistical analysis revealed that the birthweight was statistically different between Group 1 and Group 3 (heavier in Group 3) (p<0.05).

Table 2 demonstrates the differences between the three groups regarding thiol hemostasis. All the samples were studied separately for the neonates and mothers, including SH, SS, SS+SH, and SS/SH (both in maternal and fetal sera samples). The significance between groups was analyzed. In the thiol/disulfide balance, the amount of native and total thiol indicates the antioxidant status, while the amount of disulfide indicates the oxidant status. The balance is the percentage ratio of SS/SH (index %). Maternal native thiol and total thiol (antioxidant status) were significantly higher in Group 2 when compared with Group 1 and Group 3 (p<0.05 for native and total thiol). Maternal disulfide was significantly higher in Group 2 when compared with Group 1(p<0.05). The maternal index was not very different between the three groups.

Fetal native thiol and total thiol were significantly higher in Group 2 when compared with Group 1 and Group 3 (p<0.05 for both native and total thiol). Fetal disulfide and fetal index were not significantly different between the three groups.

A Pearson’s correlation test was performed to observe the correlation between thiol-disulfide levels and demographic parameters. One-minute APGAR was significantly correlated with maternal native and total thiol levels, with antioxidant status (p<0.05; r=0.199 and p<0.05; r=0.179, respectively). Fetal parameters were analyzed to determine the correlation; only fetal index was significantly correlated with one-minute APGAR (p<0.05, r=0.199).

Discussion

To the best of our knowledge. This is the first study evaluating the oxidative balance for mothers and fetuses in different periods of the term pregnancy term. We detected that native thiol and total thiol (native thiol + disulfide), showing an antioxidant effect, were significantly higher in full-term pregnancies when compared to early-term and late-term pregnancies. A positive correlation was found between maternal total/native thiol levels and 1st minute APGAR scores.

The oxidant and antioxidant systems must be balanced during a healthy pregnancy, although the period includes dynamic hormonal changes that affect oxidative status [10]. Hormonal changes and maternal and fetal metabolic needs entail specific alterations. The literature suggests that there are trimester-specific changes in the level of oxidative stress [10, 11]. These and other studies demonstrated that pre-term deliveries tend to have more oxidative stress [12]. Previous studies examined the thiol balance in high-risk pregnancies with complicated situations. In pregnancies complicated with meconium, native and total thiol levels were lower than in the control group. It is unknown whether the reason for this is the decrease in the maternal antioxidant levels in a pathological condition or the pathological condition occurring due to the low maternal antioxidant levels [13]. In another study, two groups of patients were compared; one group went through an elective cesarean section and the other a vaginal delivery. The native thiol level was higher in the cord blood of neonates with vaginal delivery; therefore, the researchers suggested vaginal delivery for less oxidative stress [14]. Our study consisted of low-risk term pregnancies to ensure standardization and determine the ideal delivery time for both mother and fetus according to oxidative balance. A comparison was made between different periods of term pregnancies (early-term, full-term, and late-term). Although vaginal birth is a physiological process, numerous studies about its timing exist. Many different opinions exist in many studies, but there is no clear consensus regarding maternal, fetal, or neonatal outcomes for timing delivery. Recent ACOG recommendations stated that “non-medically indicated delivery before 39 weeks gestation should be avoided and induction of labor between 41 0/7–42 0/7 weeks of gestation can be considered.” [3, 15] The primary purpose of our study is to support the decision of the most appropriate delivery time in terms of oxidant balance. As suggested by ACOG, a full-term pregnancy period seems to be the ideal delivery time, considering maternal and fetal complications. Our study shows a positive correlation between maternal native thiol levels and a 1st-minute APGAR score detected in term pregnancies (p=0.022; r=0.2). However, there was no significant difference in the 5th-minute APGAR scores when comparing the three groups. This situation leads us to believe that the mother tried to increase the native thiol ratio, which reflects the antioxidant status to guarantee the 1st-minute APGAR score to protect the fetus from adverse complications. A negative correlation between the neonatal index and the 1st-minute APGAR score was found (p=0.042; r=0.2), which means that the 1st-minute APGAR score decreases as the neonatal oxidative load increases. Although maternal and neonatal antioxidant levels differed in all three term gestational periods, no effect on newborn outcomes or complications was observed.

Conclusions

This study demonstrated that the mechanism that increases the antioxidant level of the mother works best in the period between 39 and 41 weeks of pregnancy. Antioxidants in thiol/disulfide homeostasis were at the highest level in this period and positively correlated with the 1st-minute APGAR score. It can be explained by the fact that the mother tends to increase the antioxidant level to protect the newborn from birth complications during the physiological birth process. Although maternal and neonatal antioxidant levels differ in all term pregnancy periods, this does not affect the newborn 5th minute APGAR score in low-risk pregnancies at vaginal delivery.