This retrospective study had two main findings. ICP showed a strong relationship with GDM and pre-eclampsia. Women diagnosed with ICP had a significantly increased risk for adverse perinatal outcomes. In our study, consistent with previous studies, we demonstrated a higher risk of GDM and preeclampsia in women with ICP compared to those without ICP (10,14).
The mechanisms underlying the direct association of ICP with GDM and preeclampsia remain unclear. Martineau et al. reported that ICP was characterized by glucose intolerance and dyslipidemia, consistent with the metabolic syndrome [15]. Women with ICP exhibited higher triglyceride, total cholesterol, LDL and VLDL levels and these indices were also related with an increased risk of preeclampsia and GDM [16, 17]. In our study, cholesterol levels were not evaluated. It has been shown that women with higher BMI and impaired metabolic pathways may also be at increased risk for adverse outcomes of pregnancy [18, 19]. Our study also showed that the incidence of GDM and pre-eclampsia was significantly increased in overweight pregnant women with ICP.
In our study, we observed a significant relationship between ICP and adverse perinatal outcomes. The relationship between the presence of ICP and spontaneous preterm delivery, iatrogenic preterm delivery, 5th minute Apgar score < 7 and NICU stay showed adverse effects of ICP on perinatal outcomes. On the other hand, there was no significant relationship between the presence of ICP and SGA and meconium. In the study published by Geenes et al. which included a very large population, it was found that the risk of meconium-stained amniotic fluid was higher in severe ICP. However, no neonatal meconium aspiration syndrome was shown in the study, and it was claimed that the need for neonatal intensive care was generally associated with preterm birth and the negative consequences it caused. In addition, in the same study, babies with SGA were found to be less in the cholestasis group than in the control group [20], which is similar to our study. Williamson et al. previously reported that ICP was associated with an increased risk of stillbirth [21]. ICP is characterized by fetal death without any clear cause, but since there is currently no specific way to monitor the fetus, the pregnancy is usually terminated beforehand to avoid adverse pregnancy outcomes. With effective management during pregnancy, there was no increased incidence of stillbirth in our study, in agreement with previously published studies. In patients diagnosed with ICP, the mean gestational age and birth weight at birth were found to be low. The Royal College of Obstetrics and Gynecology does not recommend active management, although optimal timing of delivery in ICP is difficult given the paucity of high-quality studies [22].
A recent meta-analysis showed an increased risk of stillbirth in women with ICP when serum bile acid concentrations were 100 µmol/L or more [23], but bile acid is not always a reliable monitoring index [5]. Relatedly, stillbirth may not have been detected since the highest serum acid level in our study group was 29.9 µmol/L. We encourage clinicians to monitor bile acid levels and recommend that they make an individualized decision about whether the risks of preterm birth outweigh the risks of disease.
In our study, both spontaneous and iatrogenic preterm birth were found higher in the ICP group. Especially, the high rate of iatrogenic preterm labor may reflect concerns with regard to the risk of fetal death or adverse outcome in pregnancies complicated by high maternal serum bile acids, and therefore the clinicians managing these pregnancies may have preferred a management strategy of induction of labor prior to 37 weeks despite emerging concerns about special education needs [24] and poorer school performance [25] in babies born late preterm. Spontaneous preterm labor may be explained by a dose-dependent bile acid effect on myometrial contractility, as has been demonstrated in rodents [26]. Further-more, myometrial cells from women with ICP are more responsive to oxytocin, and cells from normal women demonstrate an increased response to oxytocin in the presence of bile acids [27, 28].
PPH is defined as blood loss of more than 500 mL within 24 hours after delivery. In our study, there was a significant correlation between the presence of ICP and both mode of delivery and, the presence of postpartum hemorrhage (PPH). In the ICP group, the mean gestational week and, birth weight at delivery were found to be lower and, the rate of cesarean delivery and PPH were found to be higher. However, in these patients, postpartum hemorrhage was treated with conservative methods without the need for any surgical or additional procedures such as postpartum hysterectomy, uterine artery ligation, hypogastric artery ligation, balloon tamponade, b-lynch suturing. Additionally, no patient required massive blood product transfusion and no exitus occurred due to postpartum hemorrhage. The low frequency of postpartum hemorrhage in our study may be explained by the different definitions used or underestimation of blood loss. This study was conducted as a single-center, retrospective cohort study with large samples of ICP patients demonstrating the prevalence and characteristics of ICP in our hospital.
In our study, cesarean section rates were found to be higher in pregnancies in the ICP group. In a recent study Kong et al. demonstrated that women with severe ICP also had a significantly higher incidence of planned and unplanned CS compared with mild ICP subjects, as the indications for CS showed that fetal intolerance was higher in severe ICP compared with mild ICP [29] Shemer et al. reported that the risk of emergency cesarean section in ICP with spontaneous onset of labor did not differ from non ICP women with spontaneous onset of labor [30]. Generally, from studies of Brouwers et al and Stenhiles et al, we have known that intrahepatic cholestasis increases the risk of preterm labor, abnormal intrapartum fetal heart tracing and sudden intrapartum fetal death [4, 5]. These known risks are the most likely reasons why the patients with ICP have a higher frequency of cesarean section compared to spontaneous delivery.
There are undoubtedly some limitations of our study. This study can be considered as a retrospective study, which may raise some concerns about data quality. These risks are thought to be related to patient selection risks and information bias. Furthermore, we did not evaluate the relationship between ICP and GDM or ICP and pre-eclampsia for time of onset. The relationship between bile acid concentrations and the risk of GDM or pre-eclampsia was not evaluated. Therefore, it is necessary to further analyze the time frame for any relationship between ICP and GDM or pre-eclampsia and to better understand the potential mechanisms of any correlation.
In conclusion our study suggested that patients with ICP had increased risk of development of GDM and preeclampsia. Accordingly, we showed that it is associated with preterm birth and adverse perinatal outcomes.
The authors declare that they have no conflict of interest.