Abstract
Objective:
To determine delivery outcome in women undergoing induction of labor for postdate pregnancy in relation to fetal gender.
Study Design:
A total of 365 nulliparous and 127 multiparous women carrying singleton postdate pregnancies with unfavorable cervix were enrolled. Clinical characteristics and delivery outcome were analyzed in relation to fetal gender.
Results:
Women carrying male fetuses showed higher rate of caesarean section than those carrying females, in both nulliparous and multiparous women. Moreover, women carrying male fetuses presented more frequently with (i) interval between induction of labor and delivery >24 hours (P < .0002); (ii) augmentation of labor after cervical ripening (P < .0391); (iii) meconium-stained liquor (P< .0126); and (iv) higher neonatal weight (P < .0011) than those carrying females.
Conclusion:
Male fetuses are more likely to be associated with higher rates of cesarean section. In maternal fetal medicine, gender differences may add prognostic information on the delivery outcome in women induced for postdate pregnancy.
Introduction
The sentence “Being male or female is one of the most important predictors of an individual’s health” by Kajantie and Phillips 1 addresses the fundamental aspects of human and animal lives. In fact, males and females show different adaptive mechanisms during life, from the intrauterine environment to adulthood. A higher intrauterine vulnerability of male fetuses has been shown 2 as well as a gender difference in intrauterine growth and perinatal morbidity and mortality. 2,3 Even when maternal diseases occur, that is maternal asthma, 4,5 preeclampsia, 6,7 or preterm delivery, 8,9 male and female neonates institute different mechanisms to cope. The coping abilities of male fetuses may be inferior to those of females leading to increased risks of intrauterine death. 10 An association between the outcome of labor at term and fetal gender has been described. In particular, nulliparous women going into labor spontaneously are more likely to encounter complications when the infant is male, 11 with higher rate of operative deliveries and caesarean sections. 12 However, it is still unknown whether a different delivery outcome exists between postdate women carrying male or female fetuses.
Postdate pregnancy is defined as pregnancy that continues past the expected date of confinement, extending beyond 41 to 42 completed weeks of gestation and represents the most common reason for induction of labor. 13 Induction of labor between 41 and 42 weeks is the current best practice in many countries to reduce the incidence of stillbirth and caesarean delivery rate without increasing adverse outcomes. 14,15 However, the response to labor induction in postdate pregnancies is variable and has been related to several maternal and fetal factors including parity, gestational age, body mass index (BMI), maternal age, Bishop score, neonatal birth weight, transvaginal ultrasound assessment of the cervix, and biochemical markers (fetal fibronectin and E3/E2 ratio). 16 –19 On the basis of these considerations, the present study aimed to investigate whether fetal gender may be related to the delivery outcome in women undergoing induction of labor for postdate pregnancy.
Materials and Methods
A retrospective study was conducted using data from the labor ward database between July 2004 and March 2011. All patients included in the study were healthy, carrying singleton cephalic pregnancies, and had been admitted consecutively to the University Hospital of Siena, at the Department of Pediatrics, Obstetrics and Reproductive Medicine to undergo induction of labor for postdate. At the time of admission, only women with an unfavorable cervix (Bishop score less than 6) were included (total n = 492; 365 nulliparous and 127 multiparous). Women with favorable cervix (Bishop score higher than 6) before induction, ruptured membranes, maternal pathologies, fetal congenital abnormalities, and intrauterine deaths were excluded from the study. The study was conducted after the local ethical committee approval.
Labor was induced by administering prostaglandin E2 vaginal pessary (dinoprostone; Propess 10 mg; Ferring AB, Limhamn, Sweden) that was removed 24 hours after the application or earlier in case of initiation of labor, spontaneous rupture of membranes, amniotomy (artificial rupture of the membranes), uterine hyperstimulation or hypertonus, fetal distress, or secondary systemic effects such as nausea, fever, vomiting, diarrhea, tachycardia, or hypertension. Fetal heart rate and uterine contractions were monitored through cardiotocography (CTG) 30 minutes before and 1 hour after dinoprostone administration in all patients.
Active labor was defined as 4 cm dilatation with regular contractions every 2 to 3 minutes. Augmentation of labor, through oxytocin administration or amniotomy, was started in the presence of unsatisfactory progress of labor. After using dinoprostone, oxytocin administration was delayed 30 to 60 minutes after pessary removal as recommended by the American College of Obstetricians and Gynecologists. 20 Our protocol included administration of intravenous oxytocin as previously described 20,21 and was continued for a maximum of 6 to 12 hours unless contraindications arose. 20 Amniotomy was performed at the discretion of the attending physician. During augmentation of labor, fetal heart rate and uterine contractions were monitored by CTG.
Failure to progress, or dystocia, was defined as the lack of progressive cervical dilatation or lack of descent of fetal vertex. Women were considered to have had a cesarean section for failure to progress if their medical records used any of the following terms to describe the reason for the cesarean: dysfunctional, prolonged, protracted, or unspecified long labor; cephalopelvic disproportion; failure to progress; malposition; prolonged or protracted first stage of labor; prolonged or protracted latent phase of labor; prolonged or protracted active phase of labor; arrest of dilation; secondary arrest of dilation; prolonged or protracted second stage of labor; arrest of descent; or deep transverse arrest. Women in whom cesarean sections were done because of failed induction were included only if their records also noted one of the above conditions to be a reason for cesarean. Tocophobia is a form of specific phobia defined as the fear of childbirth or pregnancy.
As reported previously, 22 the diagnosis of fetal distress in labor was performed in presence of 2 or more of the followings (1) pathological CTG trace, defined according to Royal College of Obstetricians and Gynecologists guidelines 23 ; (2) meconium-stained amniotic fluid; (3) admission to neonatal intensive care unit (NICU).
Clinical characteristics such as maternal age, gestational age, Bishop score, BMI, mode of delivery, indications for caesarean section, interval between induction and delivery, augmentation of labor with oxytocin/amniorhexis, presence of meconium-stained liquor, epidural usage, and neonatal characteristics such as neonatal weight, Apgar score, and NICU admission were all recorded. All data were analyzed comparing nulliparous and multiparous women, as a first step, and then in relation to fetal sex.
Statistical Analysis
Normal distribution of quantitative clinical data was assessed using the Kolmogorov-Smirnov test. Data analyzed by descriptive statistics are presented as means ± standard deviations. In the univariate analysis, quantitative differences between groups were assessed by unpaired t test, whereas qualitative variables were compared by Fisher exact test.
Statistical analysis was performed using the GraphPad Prism version 5.00 for Windows (GraphPad Software, Inc, San Diego, California). Statistical significance was considered whenever P < .05 for all statistical analyses.
Results
During the study, a total of 7683 neonates were born in our division, including (i) 6457 at term, of whom 3060 were males and 3397 were females and (ii) 1226 postdate, of whom 585 were males and 641 were females. There was no statistically significant difference between the number of males and females both in term and in postdate pregnancies. Among the postdate neonates, a total of 220 males and 272 females were born after induction of labor. In this group of women, the cesarean section rate was significantly higher in those carrying male than in those carrying female fetuses (37.3% vs 19.1%, respectively, P < .0001; odds ratio [OR]: 2.51, 95% confidence interval [95% CI]: 1.67-3.78; Tables 1 and 2).
Maternal Characteristics of the Population of Study
Abbreviation: BMI, body mass index.
Differences of Delivery and Neonatal Outcome Between Male and Females
Abbreviation: NICU, neonatal intensive care unit.
Splitting the group of women induced for postdate pregnancy on the basis of parity, a total of 164 males and 201 females were born among nulliparous women, while a total of 56 males and 71 females were born among multiparous women (Table 1). Similar to the total group, in both nulliparous and multiparous women the rate of cesarean section remained significantly higher in women carrying males than in those carrying females (n = 71 [43.3%] vs n = 51 [25.4%], P = .0004; OR: 2.24, 95% CI: 1.44-3.49—n = 11 [19.6%] vs n = 1 [1.4%], P = .0005; OR: 17.11, 95% CI: 2.13-137.2, respectively; data not shown).
Analyzing data on the total population in relation to fetal sex, maternal demographic and obstetric characteristics did not show any significant difference in terms of maternal age, BMI, parity, and Bishop score (Table 1). The interval between induction of labor and delivery was significantly higher in women carrying males than in those carrying females (20.8 ± 13.5 vs 7.0 ± 12.4 hours, P = .0002); similarly, augmentation of labor with oxytocin and/or amniotomy was performed significantly more often in males than in females (26.7% vs 18.7%, P = .0391; OR: 1.57, 95% CI: 1.02-1.56); finally, the presence of meconium-stained liquor occurred significantly more frequently in women carrying males than in those carrying females (16.4% vs 8.8%, P = .0126; OR: 2.02, 95% CI: 1.16-1.78). Epidural usage was not different in relation to fetal sex (Table 2).
Concerning indications for caesarean section, fetal distress was the most frequent in women carrying males and its incidence was significantly higher than in those carrying females (53.6% vs 34.6%, P = .034; OR: 2.19, 95% CI: 10.6-4.48). Conversely, no differences were observed between males and females in the rate of failure to induction, failure to progress of labor, and tocophobia (Table 2).
Finally, neonatal clinical characteristics showed a significantly higher neonatal weight in males than in females (P < .0011), while the 5-minute Apgar score and NICU admission rates were not different in relation to fetal sex (Table 2).
Comment
The present study shows that postdate pregnant women undergoing induction of labor are more likely to encounter complications when carrying a male newborn.
These data extend recent evidence showing that male infants tolerate induction of labor performed between 37 and 42 weeks of gestation than female infants. 12 The previous report analyzed a population of women carrying singleton cephalic pregnancies induced for maternal and fetal indications, spontaneous rupture of membranes, and postdate pregnancies. 12 Postdate pregnancy itself is a condition in which labor does not occur within the physiological term of gestation, suggesting a disturbance in the physiological processes regulating the onset of labor. Therefore, this condition represents a potential risk factor for both the mother and the fetus, which may be greater in male fetuses who are usually larger and are known to fare poorly compared to female fetuses in many situations. Therefore, in order to investigate the relationship between delivery outcome and fetal gender in the induction of labor, we focused exclusively on postdate pregnancies.
Analyzing the entire population stratified on the basis of parity, we found that the rate of vaginal delivery was statistically higher in multiparous than in nulliparous women, as expected. 24 Among postdate women, the group carrying a female fetus was larger than the group carrying male fetus; however, the difference was not statistically significant. The rate of caesarean section was increased in women carrying male fetuses, in both multiparous and nulliparous groups.
In the presence of a male fetus, there was higher incidence of (i) interval between induction of labor and delivery, (ii) augmentation of labor with oxytocin and/or amniorhexis; (iii) meconium-stained liquor; and (iv) high birth weight. The finding of an increased interval between induction and delivery and higher recourse to augmentation of labor in male fetuses than in female fetuses let us hypothesize a different fetoplacental response to the induction of labor between the fetal genders. The reason of an increased rate of cesarean section for fetal distress in male fetuses was not clear but could be the result of developmental differences between male and female fetuses. 25,26 Different catecholamine levels at birth have been found in relation to fetal gender. 27 This adaptive difference may also explain in part the higher incidence of meconium-stained liquor associated with a high rate of caesarean section in association with male sex.
Several studies reported a gender difference in gene, protein, and steroid pathways of the fetal–placental unit and may help to explain our present data. Fetal sex affects the placental immune system regulating apoptosis, prostaglandin synthesis, vascular permeability, and programming of the fetal immune system. 28 In particular, the administration of betamethasone is associated with increased placental 11b-HSD2 activity in female but not male placentas, suggesting that females are able to adjust the glucocorticoid metabolic activity to preserve female fetal adrenal function. 28 The reason why occasionally labor does not onset within the usual physiological term of gestation is still unknown but a cause may lie in altered levels of circulating placental hormones. In particular, the X-linked recessive deficiency of placental steroid-sulfatase enzyme leads to abnormally low estrogen production in the affected male fetus, with a subsequent prolongation of pregnancy. 29 Therefore, considering that the placental steroidogenesis between male and female placentas is different and that the steroid pathway is crucial for the onset of labor, we speculate that this might be an underlying cause for the worse outcome of delivery in induction of labor for postdate pregnancy as also shown by the altered E3/E2 in postdates pregnant women with failure of induction of labor. 17
In conclusion, after induction for postdate pregnancy women with male fetuses are more likely to undergo caesarean delivery. However, the reason of this phenomenon remains still unknown. In this context, it would be interesting to investigate whether the adaptive mechanisms to the stress of labor after induction for postdate pregnancy are different between males and females. However, in order to evaluate this, further studies are necessary. In maternal–fetal medicine, gender differences may represent a novel parameter to add significant prognostic information in relation to the outcome of delivery in women induced for postdate pregnancy. As in previous studies, male fetuses appear more vulnerable than their sisters.
Footnotes
Acknowledgments
The authors thank the midwives of the Obstetric Unit of Siena for their contribution in the collection of the data for this study.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.