Journal of Obstetrics and Gynaecology, 2014; Early Online: 1–4 © 2014 Informa UK, Ltd. ISSN 0144-3615 print/ISSN 1364-6893 online DOI: 10.3109/01443615.2014.968102
Pregnancy outcomes and prognostic factors in patients with intrahepatic cholestasis of pregnancy R. Madazli, M. A. Yuksel, M. Oncul, A. Tuten, O. Guralp & B. Aydin
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Department of Obstetrics and Gynecology, Cerrahpaşa Medical Faculty, Istanbul University, Istanbul, Turkey
The aim of this study was to describe maternal and fetal characteristics associated with intrahepatic cholestasis of pregnancy (ICP) and to determine clinical and biochemical predictors of fetal complications. A total of 89 singleton pregnancies with ICP were analysed, retrospectively. All data concerning laboratory results, symptom onset time, treatment response, delivery time and infant information were recorded in the study protocol. The mean gestational age at diagnosis was 32.6 3.4 weeks; mean time of delivery was 36.8 1.9 weeks. Binary logistic regression revealed that gestational age at diagnosis was predictive of preterm delivery (OR 2.3, 95% CI: 1.5–3.3, p 0.001). The incidence of respiratory distress syndrome (RDS), fetal growth restriction, fetal distress and preterm delivery were significantly higher in patients who were diagnosed before 30 weeks than after 34 weeks’ gestation (p 0.01). Gestational age at diagnosis is an important independent factor predicting adverse perinatal outcomes in patients with ICP. Keywords: Intrahepatic cholestasis, obstetrical outcome, ursodeoxycholic acid
can have severe consequences for the fetus, and is associated with an increased risk of spontaneous preterm delivery, fetal distress, meconium-stained amniotic fluid and intrauterine fetal demise (IUFD) (Arrese and Reyes 2006; Geenes and Williamson 2009; Mays 2010; Pathak et al. 2010). The pathogenesis of fetal complications is largely unknown and specific predictors of pregnancy outcomes have not been consistently identified. It is hypothesised that the risk of adverse fetal outcomes relates to the toxic effects of bile acids, the levels of which are increased in both maternal and fetal serum (Geenes et al. 2011). Human and rodent studies have shown that transplacental transfer of bile acids is impaired in ICP (Perez et al. 2006; Geenes et al. 2011). Furthermore, the morphology of placentas of ICP is markedly abnormal, and is associated with an increase in the number of syncytial knots (Geenes et al. 2011). Furthermore, ursodeoxycholic acid (UDCA), a drug commonly used in the management of ICP, has important implications in pregnancy outcomes and is demonstrated to have a protective effect on placental tissue both in vivo and in vitro (Paumgartner and Beuers 2002; Geenes et al. 2011). The aim of our study was to describe maternal and fetal characteristics associated with ICP and to determine clinical and biochemical predictors of fetal complications.
Introduction
Material and methods
Intrahepatic cholestasis of pregnancy (ICP) is defined as pruritus with onset in pregnancy, which is associated with abnormal liver function in the absence of other liver disease, which resolves following delivery (Kondrackiene and Kupcinskas 2008). Pruritus that usually presents in the second half of pregnancy, becomes progressively more severe as the pregnancy advances and predominantly affects the palms and soles, but can also be generalised. Many women report that their pruritus worsens at night and may become so extreme that it causes insomnia. The relationship between onset of pruritus and development of deranged liver function is not clear. It has been reported that itch may be present either prior to or after abnormal liver function is detected (Kenyon et al. 2001). The reported incidence of ICP varies between countries and populations in a range of 0.4–15% (Geenes and Williamson 2009; Wikstrom Shemer et al. 2013). The pathogenesis of ICP, although not well defined, is thought to be multifactorial, a combination of hormonal, genetic and inflammatory factors that impair bile secretory function, which acts to increase total serum bile acids (TBA) and elevate liver enzymes (Arrese and Reyes 2006; Geenes and Williamson 2009). ICP is relatively benign to women, however, it
A retrospective study of 89 patients with ICP who were followed up and delivered at the Istanbul University, Cerrahpasa Medical School Obstetrics and Gynecology Department, between 2003 and 2013, were included in the study. The study was approved by a local ethics committee. ICP was defined as persistent pruritus in combination with increased TBA ( 10 μmol/l) in the absence of any other liver or skin pathology. Clinical evaluation by a dermatologist was done to exclude primary skin diseases or other causes of itching. Gallstones or maternal liver pathology were excluded by history, trans-abdominal ultrasound and liver function tests. Patients with chronic liver diseases, skin diseases, allergic disorders, symptomatic cholelithiasis or ongoing viral infections affecting the liver (hepatitis A, B and C virus, cytomegalovirus, herpes simplex virus and Epstein–Barr virus) were excluded. Multiple pregnancies were also excluded. The gestational age was calculated according to reliable LMP and/or an early trimester ultrasound examination report. All patients studied had undergone treatment with UDCA (10–15 mg/kg per day) at the time they were diagnosed. Serum laboratory tests were obtained at the time of presentation before starting the treatment and the biochemical values evaluated
Correspondence: R. Madazli, Istanbul Universitesi, Cerrahpasa Tip Fakultesi, Kadin Hastaliklari ve, Dogum Anabilim Dali, Kocamustafapasa, Istanbul, Turkey. E-mail: [email protected]
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included serum TBA, aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transpeptidase (GGT), total bilirubin, unconjugated bilirubin and alkaline phosphatase (ALP) levels. Serum laboratory tests were repeated every week. Fetal wellbeing was monitored by cardiotocography, modified biophysical profile or Doppler ultrasonography weekly or bi-weekly according to gestational status. After the birth, Apgar scores and weight and health status were evaluated by paediatricians and recorded in infant charts. All data concerning obstetric-medical history, laboratory results, pruritus degree and infant characteristics were recorded in the study protocol. Pruritus was arbitrarily degreed in an ordinary scale: grade 1 intermittent, nocturnal, and slight; grade 2, continuous diurnal and nocturnal, from slight to moderate; grade 3 severe and grade 4 severe but also accompanied with insomnia or itching lesions. Spontaneous preterm birth was defined as delivery before 37 weeks’ gestation after spontaneous onset of labour. If there were no other complications, delivery decision was carried out after 38 weeks. The primary outcome measured in this study was preterm delivery and a composite outcome of one or more fetal or neonatal complications. These complications included fetal distress, meconium staining of amniotic fluid at delivery and respiratory distress. Fetal distress was defined by repetitive severe variable decelerations or repetitive late decelerations or fetal bradycardia of 110 b.p.m. lasting 3 min or longer, requiring emergent delivery. Respiratory distress was defined as any neonate that required intubation, continuous positive airway pressure (CPAP) or bag/mask ventilation postpartum. Comparison of parametric, normally distributed data was performed by Student’s t-test. The difference between two nonparametric samples was calculated using the Mann–Whitney test. Correlation analysis was assessed by Pearson’s correlation. Binary logistic regression was performed using the enter method to find the possible correlation between prognostic factors and adverse obstetric outcomes. Statistical analysis was conducted with SPSS version 15.0.
Results The clinical characteristics and fetal outcome of the study population are shown in Table I. The mean age of patients was 28.7 5.2 (range 19–44) and 76.4% were nulliparous. The mean gestational age at diagnosis was 32.6 3.4 weeks (range 20–37), mean duration of follow-up was 5.1 2.9 weeks (range 1–15) and mean gestational age at delivery was 36.8 1.9 weeks (range 29–41). Pregnancy ended before 37 and 34 weeks in 34.8% and 6.7% of the patients, respectively. Caesarean delivery rate was 30.3% in the study population. Cervical ripening or labour induction was done in 29 study subjects (32.6%), all after 37 weeks’ gestation. ICP was the predominant indication (89.7%) for induction. Of these inductions, nine women had abdominal delivery according to the clinical judgement of the attending physician. The incidences of gestational diabetes, pre-eclampsia and fetal growth restriction of the study population were 14.6%, 2.2% and 6.7%, respectively. Mean 1 min and 5 min Apgar scores were 8 1 and 9 1, respectively. The most common perinatal complications were: respiratory distress (12.9%); meconium staining of the amniotic fluid (2.2%); fetal distress (5.6%) and fetal growth restriction (6.7%). Fetal demise did not occur in any case. Table II describes the maternal laboratory values and changing trends of serum parameters after initiation of UDCA treatment. At the time of diagnosis, mean TBA was 45.7 5.5 μmol/l (range 12–298); mean AST was 91.6.1 12.1 U/l (range: 12–797); mean ALT was 127.9 15.2 U/l (range: 7–635); mean GGT was
Table I. Clinical characteristics and fetal outcome of the study population. n n Age (years) (mean SD) Nulliparous BMI (kg/m2) (mean SD) Gestational age at diagnosis (weeks) (mean SD) Duration of follow-up (weeks) (mean SD) Gestational age at delivery (weeks) (mean SD) Delivery 37 weeks 34 weeks Birth weight (g) (mean SD) Delivery methods Vaginal Caesarean section Induction ındications ICP PROM Oligohydramnios Pre-eclampsia Gestational diabetes Pre-eclampsia Fetal growth restriction 5 min Apgar score (mean SD) Respiratory distress Meconium Fetal distress Perinatal mortality
(%)
89 68
28.7 5.2 76.4 24.4 0.8 32.6 3.4 5.1 2.9 36.8 1.9
31 34.8 6 6.7 2,914 557 62 27
69.7 30.3
26 1 1 1 13 2 6 91 11 2 5
14.6 2.2 6.7 12.9 2.2 5.6 –
32.5 5.9 U/l (range: 8–521); mean unconjugated bilirubin was 0.51 0.5 μmol/l (range: 0.07–3); mean total bilirubin was 1.01 0.9 μmol/l (range: 0.17–5.9) and mean alkalene phosphatase was 220.4 16.1 U/l (15–772). In all of the cases, TBA was over 10 μmol/l. AST, ALT and GGT levels were above 40 U/l in 58 (65.2%), 63 (70.8%) and 18 (20.2%) of cases, respectively. Initial TBA concentration correlated positively with alkalene phosphatase (r 0.398, p 0.001), GGT (r 0.340, p 0.001), total bilirubin (r 0.320, p 0.002) and AST (r 0.209, p 0.049). Mean serum TBA, AST, ALT, GGT and alkalene phosphatase levels significantly decreased after the initiation of UDCA treatment (p 0.01). After initiation of the UDCA treatment, 16 patients (17.8%) had residual pruritus although intensity was reduced in all of them. In all patients, the pruritus resolved within 1–2 weeks postpartum. Gestational age at delivery significantly correlated with gestational age at diagnosis (r 0.579, r 0.001). There was no correlation between gestational age at delivery and initial maternal serum TBA, AST, ALT, GGT and alkalene phosphatase levels (p 0.05). Binary logistic regression showed that gestational age Table II. Changing trends of serum parameters after initiation of UDCA treatment (mean SD). At the initiation 7 days after 14 days after of treatment treatment treatment TBA (μmol/l) 45.7 5.5 37.6 4.5 29.2 3.2 AST (U/l) 91.6 12.1 77.1 11.3 48.4 5.9 ALT (U/l) 127.9 15.2 116.7 15.7 77.9 9.9 Gamma GT (U/l) 32.5 5.9 28.4 5.1 25.6 3.8 Total bilirubin (μmol/l) 1.01 0.9 0.93 0.7 0.91 0.7 Unconjugated bilirubin (μmol/l) 0.51 0.5 0.45 0.4 0.41 0.4 Alkalene phosphatase (U/l) 220.4 16.1 202.3 14.9 178.2 13.1
Pregnancy outcomes and prognostic factors in patients 3 Table III. The distribution of adverse perinatal outcomes with TBA values and gestational age at diagnosis. TBA (μmol/l) 20 n
Gestational age at diagnosis (weeks) 40
20–39
(%) n
(%)
n 18 43 RDS 3 16.6 5 11.6 Fetal distress 0 0 5 11.6 Fetal growth restriction 0 0 2 4.6 Delivery before 37 weeks 7 38.8 11 25.5
n
(%)
30 n
28 14 38 10.7 5 1 3.5 2 3 10.7 2 13 46.4 10
34
30–33
(%)
n
(%)
35.7 14.2 14.2 71.4
37 5 13.5 3 8.1 4 10.8 14 37.8
n
(%)
38 1 0 0 7
2.6∗ 0∗ 0∗ 18.4∗
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∗p 0.01.
at diagnosis was predictive of delivery before 37 weeks (OR 2.3, 95% CI 1.5–3.3, p 0.001). Table III demonstrates the distribution of adverse perinatal outcomes with TBA values and gestational age at diagnosis. The incidence of respiratory distress syndrome (RDS), fetal growth restriction, fetal distress and delivery before 37 weeks were significantly higher in patients who were diagnosed before 30 weeks than after 34 weeks’ gestation (p 0.01). The incidences of RDS, fetal growth restriction, fetal distress and delivery before 37 weeks were not significantly different from the TBA subgroups (p 0.05).
Discussion The mean age of patients and the rate of nulliparity in our study population are similar to those reported in the literature (Al Shobaili et al. 2011; Rook et al. 2012). The mean gestational age of clinical presentation of our patients is also in accordance with the literature (Oztekin et al. 2009; Al Shobaili et al. 2011). Approximately 80% of affected women are reported to present after 30 weeks’ gestation (Geenes and Williamson 2009) and this rate was found to be 84.3% in our patients with ICP. Although pruritus most frequently manifests in the 3rd trimester, ICP has been reported as early as 8 weeks (Berg et al. 1986). We have also diagnosed ICP as early as 20 weeks’ gestation. The incidence of gestational diabetes and pre-eclampsia were 14.6% and 2.2%, respectively, in our group. Pre-eclampsia and gestational diabetes, which are both common obstetric complications, were diagnosed in 2–8% and 3–5% of pregnancies, respectively (Wikstrom Shemer et al. 2013). There have been reports of the coexistence of ICP with pre-eclampsia, and gestational diabetes (Geenes and Williamson 2009). In a recent nationwide cohort study, ICP was strongly associated with gestational diabetes and pre-eclampsia (Wikstrom Shemer et al. 2013). Our data is in accordance with the increased incidence of gestational diabetes with ICP. The most sensitive laboratory abnormality in ICP is an increase in serum TBA concentrations, which may be the first or only laboratory abnormality (Pathak et al. 2010). Other laboratory abnormalities observed in ICP include elevations in ALT, AST, GGT and alkaline phosphatase (Kondrackiene and Kupcinskas 2008; Pathak et al. 2010). The incidences of elevated TBA, ALT, AST and GGT in our group were 100%, 70.8%, 65.2% and 20.2%, respectively. These findings are in accordance with the literature (Geenes and Williamson 2009). We have also observed a positive correlation between serum TBA, AST and GGT concentrations. UDCA, which is the most effective pharmacological treatment for ICP, has been shown to significantly reduce bile acids and liver enzymes (Bacq et al. 2012). We also observed that serum TBA, AST, ALT, GGT and alkalene phosphatase levels significantly decreased after the initiation of UDCA treatment.
Although ICP is usually relatively benign to the mother, it is known that the risk of fetal complications is increased in pregnancies affected by ICP. These include increased risks of preterm delivery, respiratory distress, meconium-stained amniotic fluid, fetal distress and fetal demise (Kondrackiene and Kupcinskas 2008). Previous studies have reported meconium staining in 0–58%, and intrauterine fetal demise in 0.4–4.1%, of ICP cohorts (Geenes and Williamson 2009). This study reported no stillbirths and 2.2% incidence of meconium staining of amniotic fluid. This may be the result of increased antenatal surveillance and our policy of early delivery at around 38 weeks. Furthermore, when we diagnosed ICP, we started UDCA treatment in all cases. Although there are conflicting data regarding the effects of UDCA treatment on the perinatal outcome, several clinical trials and observational studies showed that UDCA treatment improved fetal outcomes (Palma et al. 1997; Bacq et al. 2012). On the other hand, some studies emphasised that, while pruritus and serum levels of total bile salts and ALT improved, perinatal outcomes with respect to the effect of UDCA are less clear (Pathak et al. 2010). We cannot, however, comment on this subject, as we administered UDCA treatment to all of our patients. It has been reported that the incidence of RDS in neonates born to mothers with ICP is increased (Geenes and Williamson 2009). This can be due in part to the earlier gestational age at delivery, but neonatal RDS has been demonstrated to be associated with ICP, based on analysis of bronchoalveolar lavage fluid of neonates born to mothers with ICP (Zecca et al. 2008). Bile acids can induce lung injury, leading to surfactant depletion, surfactant dysfunction and lung inflammation (Zecca et al. 2008; Geenes and Williamson 2009). Therefore, it is possible that the increased risk of neonatal RDS may be related to ICP itself. We have observed 12.9% incidence of RDS in neonates born to mothers with ICP. Of the 11 neonates that had RDS in our group, interestingly five (45.5%) were born at 37 or 38 weeks’ gestation. This observation highlights the influence of ICP on RDS. The main complication of ICP is prematurity, which is reported to be in the range of 19–60% of patients with ICP (Kondrackiene and Kupcinskas 2008; Geenes and Williamson 2009). The rate of prematurity varies greatly according to the study and may be increased because of the high rate of multiple pregnancies in patients with ICP and iatrogenic preterm deliveries. Exactly how ICP causes preterm births is uncertain; however, in vitro studies showed an increased response of myometrial strips from healthy woman to oxytocin and an increased oxytocin receptor expression after being incubated with cholic acid (Glantz et al. 2004). The rates of deliveries before 37 and 34 weeks in our group were 34.8% and 6.7%, respectively. Kondrackiene et al. (2007) demonstrated that early onset of pruritus and high levels of TBA were associated with preterm delivery. We have also observed
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that gestational age at diagnosis significantly correlated with gestational age at delivery. The binary logistic regression analysis revealed that the early onset of pruritus was the most important independent factor predicting premature delivery. However, we could not find a correlation between gestational age at delivery and initial maternal serum TBA levels. Prognostic factors for adverse perinatal outcomes in patients with ICP have been evaluated. High TBA levels have already been described as predictors of fetal outcome in some cohort studies (Kondrackiene and Kupcinskas 2008; Geenes and Williamson 2009). Bile acids have been shown to induce vasoconstriction of human placental chorionic veins and myometrial sensitivity to oxytocin (Sepulveda et al. 1991; Germain et al. 2003). In one study, a correlation between fetal complications (defined as preterm delivery, asphyxial events, meconium staining of amniotic fluid, placenta and membranes) and serum bile acid levels ( 40 pmol/l) was found (Glantz et al. 2004). However, we could not find a significant difference between the incidences of RDS, fetal growth restriction, fetal distress and preterm delivery between the TBA subgroups. However, fetal complications such as preterm delivery, RDS and FGR were significantly higher in patients who were diagnosed before 30 weeks than after 34 weeks’ gestation. This observation highlights the importance of the gestational age at which clinical symptoms appear. Early onset of pruritus especially before 30 weeks’ gestation is associated with increased adverse perinatal outcomes. Therefore, gestational age at diagnosis seems to be an important independent factor predicting adverse perinatal outcomes in patients with ICP and should be taken into consideration in the management of such pregnancies. Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
References Al Shobaili HA, Hamed HO, Al Robaee A, Alzolibani AA, Amin AF, Ahmad SR. 2011. Obstetrical and fetal outcomes of a new management strategy in patients with intra-hepatic cholestasis of pregnancy. Archives of Gynecology and Obstetrics 283:1219–1225. Arrese M, Reyes H. 2006. Intrahepatic cholestasis of pregnancy: A past and present riddle. Annals of Hepatology 5:202–205. Bacq Y, Sentilhes L, Reyes HB, Glantz A, Kondrackiene J, Binder T et al. 2012. Efficacy of ursodeoxycholic acid in treating intrahepatic cholestasis of pregnancy: A meta-analysis. Gastroenterology 143:1492–1501. Berg B, Helm G, Petersohn L, Tryding N. 1986. Cholestasis of pregnancy. Clinical and laboratory studies. Acta Obstetricia et Gynecologica Scandinavica 65:107–113.
Geenes V, Williamson C. 2009. Intrahepatic cholestasis of pregnancy. World Journal of Gastroenterology 15:2049–2066. Geenes VL, Lim YH, Bowman N, Tailor H, Dixon PH, Chambers J. 2011. A placental phenotype for intrahepatic cholestasis of pregnancy. Placenta 32:1026–1032. Germain AM, Kato S, Carvajal JA, Valenzuela GJ, Valdes GL, Glasinovic JC. 2003. Bile acids increase response and expression of human myometrial oxytocin receptor. American Journal of Obstetrics and Gynecology 189:577–582. Glantz A, Marschall HU, Mattsson LA. 2004. Intrahepatic cholestasis of pregnancy: Relationships between bile acid levels and fetal complication rates. Hepatology 40:467–474. Kenyon AP, Piercy CN, Girling J, Williamson C, Tribe RM, Shennan AH. 2001. Pruritus may precede abnormal liver function tests in pregnant women with obstetric cholestasis: A longitudinal analysis. British Journal of Obstetrics and Gynaecology 108:1190–1192. Kondrackiene J, Beuers U, Zalinkevicius R, Tauschel HD, Gintautas V, Kupcinskas L. 2007. Predictors of premature delivery in patients with intrahepatic cholestasis of pregnancy. World Journal of Gastroenterology 13:6226–6230. Kondrackiene J, Kupcinskas L. 2008. Intrahepatic cholestasis of pregnancy-current achievements and unsolved problems. World Journal of Gastroenterology 14:5781–5788. Mays JK. 2010. The active management of intrahepatic cholestasis of pregnancy. Current Opinion in Obstetrics and Gynecology 22: 100–103. Oztekin D, Aydal I, Oztekin O, Okcu S, Borekci R, Tinar S. 2009. Predicting fetal asphyxia in intrahepatic cholestasis of pregnancy. Archives of Gynecology and Obstetrics 280:975–979. Palma J, Reyes H, Ribalta J, Hernandez I, Sandoval L, Almuna R et al. 1997. Ursodeoxycholic acid in the treatment of cholestasis of pregnancy: A randomized, double-blind study controlled with placebo. Journal of Hepatology 27:1022–1028. Pathak B, Sheibani L, Lee RH. 2010. Cholestasis of pregnancy. Obstetrics and Gynecology Clinics of North America 37:269–282. Paumgartner G, Beuers U. 2002. Ursodeoxycholic acid in cholestatic liver disease: Mechanisms of action and therapeutic use revisited. Hepatology 36:525–531. Perez MJ, Macias RI, Marin JJ. 2006. Maternal cholestasis induces placental oxidative stress and apoptosis. Protective effect of ursodeoxycholic acid. Placenta 27:34–41. Rook M, Vargas J, Caughey A, Bacchetti P, Rosenthal P, Bull L. 2012. Fetal outcomes in pregnancies complicated by intrahepatic cholestasis of pregnancy in a northern California cohort. PLOS ONE 7:e28343. Sepulveda WH, Gonzalez C, Cruz MA, Rudolph MI. 1991. Vasoconstrictive effect of bile acids on isolated human placental chorionic veins. European Journal of Obstetrics, Gynecology, and Reproductive Biology 42:211–215. Wikstrom Shemer E, Marschall HU, Ludvigsson JF, Stephansson O. 2013. Intrahepatic cholestasis of pregnancy and associated adverse pregnancy and fetal outcomes: A 12-year population-based cohort study. British Journal of Obstetrics and Gynaecology 120:717–723. Zecca E, De Luca D, Baroni S, Vento G, Tiberi E, Romagnoli C. 2008. Bile acid induced lung injury in newborn infants: A bronchoalveolar lavage fluid study. Pediatrics 121:e146–e149.
Pregnancy outcomes and prognostic factors in patients with intrahepatic cholestasis of pregnancy R. Madazli, M. A. Yuksel, M. Oncul, A. Tuten, O. Guralp & B. Aydin
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Department of Obstetrics and Gynecology, Cerrahpaşa Medical Faculty, Istanbul University, Istanbul, Turkey
The aim of this study was to describe maternal and fetal characteristics associated with intrahepatic cholestasis of pregnancy (ICP) and to determine clinical and biochemical predictors of fetal complications. A total of 89 singleton pregnancies with ICP were analysed, retrospectively. All data concerning laboratory results, symptom onset time, treatment response, delivery time and infant information were recorded in the study protocol. The mean gestational age at diagnosis was 32.6 3.4 weeks; mean time of delivery was 36.8 1.9 weeks. Binary logistic regression revealed that gestational age at diagnosis was predictive of preterm delivery (OR 2.3, 95% CI: 1.5–3.3, p 0.001). The incidence of respiratory distress syndrome (RDS), fetal growth restriction, fetal distress and preterm delivery were significantly higher in patients who were diagnosed before 30 weeks than after 34 weeks’ gestation (p 0.01). Gestational age at diagnosis is an important independent factor predicting adverse perinatal outcomes in patients with ICP. Keywords: Intrahepatic cholestasis, obstetrical outcome, ursodeoxycholic acid
can have severe consequences for the fetus, and is associated with an increased risk of spontaneous preterm delivery, fetal distress, meconium-stained amniotic fluid and intrauterine fetal demise (IUFD) (Arrese and Reyes 2006; Geenes and Williamson 2009; Mays 2010; Pathak et al. 2010). The pathogenesis of fetal complications is largely unknown and specific predictors of pregnancy outcomes have not been consistently identified. It is hypothesised that the risk of adverse fetal outcomes relates to the toxic effects of bile acids, the levels of which are increased in both maternal and fetal serum (Geenes et al. 2011). Human and rodent studies have shown that transplacental transfer of bile acids is impaired in ICP (Perez et al. 2006; Geenes et al. 2011). Furthermore, the morphology of placentas of ICP is markedly abnormal, and is associated with an increase in the number of syncytial knots (Geenes et al. 2011). Furthermore, ursodeoxycholic acid (UDCA), a drug commonly used in the management of ICP, has important implications in pregnancy outcomes and is demonstrated to have a protective effect on placental tissue both in vivo and in vitro (Paumgartner and Beuers 2002; Geenes et al. 2011). The aim of our study was to describe maternal and fetal characteristics associated with ICP and to determine clinical and biochemical predictors of fetal complications.
Introduction
Material and methods
Intrahepatic cholestasis of pregnancy (ICP) is defined as pruritus with onset in pregnancy, which is associated with abnormal liver function in the absence of other liver disease, which resolves following delivery (Kondrackiene and Kupcinskas 2008). Pruritus that usually presents in the second half of pregnancy, becomes progressively more severe as the pregnancy advances and predominantly affects the palms and soles, but can also be generalised. Many women report that their pruritus worsens at night and may become so extreme that it causes insomnia. The relationship between onset of pruritus and development of deranged liver function is not clear. It has been reported that itch may be present either prior to or after abnormal liver function is detected (Kenyon et al. 2001). The reported incidence of ICP varies between countries and populations in a range of 0.4–15% (Geenes and Williamson 2009; Wikstrom Shemer et al. 2013). The pathogenesis of ICP, although not well defined, is thought to be multifactorial, a combination of hormonal, genetic and inflammatory factors that impair bile secretory function, which acts to increase total serum bile acids (TBA) and elevate liver enzymes (Arrese and Reyes 2006; Geenes and Williamson 2009). ICP is relatively benign to women, however, it
A retrospective study of 89 patients with ICP who were followed up and delivered at the Istanbul University, Cerrahpasa Medical School Obstetrics and Gynecology Department, between 2003 and 2013, were included in the study. The study was approved by a local ethics committee. ICP was defined as persistent pruritus in combination with increased TBA ( 10 μmol/l) in the absence of any other liver or skin pathology. Clinical evaluation by a dermatologist was done to exclude primary skin diseases or other causes of itching. Gallstones or maternal liver pathology were excluded by history, trans-abdominal ultrasound and liver function tests. Patients with chronic liver diseases, skin diseases, allergic disorders, symptomatic cholelithiasis or ongoing viral infections affecting the liver (hepatitis A, B and C virus, cytomegalovirus, herpes simplex virus and Epstein–Barr virus) were excluded. Multiple pregnancies were also excluded. The gestational age was calculated according to reliable LMP and/or an early trimester ultrasound examination report. All patients studied had undergone treatment with UDCA (10–15 mg/kg per day) at the time they were diagnosed. Serum laboratory tests were obtained at the time of presentation before starting the treatment and the biochemical values evaluated
Correspondence: R. Madazli, Istanbul Universitesi, Cerrahpasa Tip Fakultesi, Kadin Hastaliklari ve, Dogum Anabilim Dali, Kocamustafapasa, Istanbul, Turkey. E-mail: [email protected]
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included serum TBA, aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transpeptidase (GGT), total bilirubin, unconjugated bilirubin and alkaline phosphatase (ALP) levels. Serum laboratory tests were repeated every week. Fetal wellbeing was monitored by cardiotocography, modified biophysical profile or Doppler ultrasonography weekly or bi-weekly according to gestational status. After the birth, Apgar scores and weight and health status were evaluated by paediatricians and recorded in infant charts. All data concerning obstetric-medical history, laboratory results, pruritus degree and infant characteristics were recorded in the study protocol. Pruritus was arbitrarily degreed in an ordinary scale: grade 1 intermittent, nocturnal, and slight; grade 2, continuous diurnal and nocturnal, from slight to moderate; grade 3 severe and grade 4 severe but also accompanied with insomnia or itching lesions. Spontaneous preterm birth was defined as delivery before 37 weeks’ gestation after spontaneous onset of labour. If there were no other complications, delivery decision was carried out after 38 weeks. The primary outcome measured in this study was preterm delivery and a composite outcome of one or more fetal or neonatal complications. These complications included fetal distress, meconium staining of amniotic fluid at delivery and respiratory distress. Fetal distress was defined by repetitive severe variable decelerations or repetitive late decelerations or fetal bradycardia of 110 b.p.m. lasting 3 min or longer, requiring emergent delivery. Respiratory distress was defined as any neonate that required intubation, continuous positive airway pressure (CPAP) or bag/mask ventilation postpartum. Comparison of parametric, normally distributed data was performed by Student’s t-test. The difference between two nonparametric samples was calculated using the Mann–Whitney test. Correlation analysis was assessed by Pearson’s correlation. Binary logistic regression was performed using the enter method to find the possible correlation between prognostic factors and adverse obstetric outcomes. Statistical analysis was conducted with SPSS version 15.0.
Results The clinical characteristics and fetal outcome of the study population are shown in Table I. The mean age of patients was 28.7 5.2 (range 19–44) and 76.4% were nulliparous. The mean gestational age at diagnosis was 32.6 3.4 weeks (range 20–37), mean duration of follow-up was 5.1 2.9 weeks (range 1–15) and mean gestational age at delivery was 36.8 1.9 weeks (range 29–41). Pregnancy ended before 37 and 34 weeks in 34.8% and 6.7% of the patients, respectively. Caesarean delivery rate was 30.3% in the study population. Cervical ripening or labour induction was done in 29 study subjects (32.6%), all after 37 weeks’ gestation. ICP was the predominant indication (89.7%) for induction. Of these inductions, nine women had abdominal delivery according to the clinical judgement of the attending physician. The incidences of gestational diabetes, pre-eclampsia and fetal growth restriction of the study population were 14.6%, 2.2% and 6.7%, respectively. Mean 1 min and 5 min Apgar scores were 8 1 and 9 1, respectively. The most common perinatal complications were: respiratory distress (12.9%); meconium staining of the amniotic fluid (2.2%); fetal distress (5.6%) and fetal growth restriction (6.7%). Fetal demise did not occur in any case. Table II describes the maternal laboratory values and changing trends of serum parameters after initiation of UDCA treatment. At the time of diagnosis, mean TBA was 45.7 5.5 μmol/l (range 12–298); mean AST was 91.6.1 12.1 U/l (range: 12–797); mean ALT was 127.9 15.2 U/l (range: 7–635); mean GGT was
Table I. Clinical characteristics and fetal outcome of the study population. n n Age (years) (mean SD) Nulliparous BMI (kg/m2) (mean SD) Gestational age at diagnosis (weeks) (mean SD) Duration of follow-up (weeks) (mean SD) Gestational age at delivery (weeks) (mean SD) Delivery 37 weeks 34 weeks Birth weight (g) (mean SD) Delivery methods Vaginal Caesarean section Induction ındications ICP PROM Oligohydramnios Pre-eclampsia Gestational diabetes Pre-eclampsia Fetal growth restriction 5 min Apgar score (mean SD) Respiratory distress Meconium Fetal distress Perinatal mortality
(%)
89 68
28.7 5.2 76.4 24.4 0.8 32.6 3.4 5.1 2.9 36.8 1.9
31 34.8 6 6.7 2,914 557 62 27
69.7 30.3
26 1 1 1 13 2 6 91 11 2 5
14.6 2.2 6.7 12.9 2.2 5.6 –
32.5 5.9 U/l (range: 8–521); mean unconjugated bilirubin was 0.51 0.5 μmol/l (range: 0.07–3); mean total bilirubin was 1.01 0.9 μmol/l (range: 0.17–5.9) and mean alkalene phosphatase was 220.4 16.1 U/l (15–772). In all of the cases, TBA was over 10 μmol/l. AST, ALT and GGT levels were above 40 U/l in 58 (65.2%), 63 (70.8%) and 18 (20.2%) of cases, respectively. Initial TBA concentration correlated positively with alkalene phosphatase (r 0.398, p 0.001), GGT (r 0.340, p 0.001), total bilirubin (r 0.320, p 0.002) and AST (r 0.209, p 0.049). Mean serum TBA, AST, ALT, GGT and alkalene phosphatase levels significantly decreased after the initiation of UDCA treatment (p 0.01). After initiation of the UDCA treatment, 16 patients (17.8%) had residual pruritus although intensity was reduced in all of them. In all patients, the pruritus resolved within 1–2 weeks postpartum. Gestational age at delivery significantly correlated with gestational age at diagnosis (r 0.579, r 0.001). There was no correlation between gestational age at delivery and initial maternal serum TBA, AST, ALT, GGT and alkalene phosphatase levels (p 0.05). Binary logistic regression showed that gestational age Table II. Changing trends of serum parameters after initiation of UDCA treatment (mean SD). At the initiation 7 days after 14 days after of treatment treatment treatment TBA (μmol/l) 45.7 5.5 37.6 4.5 29.2 3.2 AST (U/l) 91.6 12.1 77.1 11.3 48.4 5.9 ALT (U/l) 127.9 15.2 116.7 15.7 77.9 9.9 Gamma GT (U/l) 32.5 5.9 28.4 5.1 25.6 3.8 Total bilirubin (μmol/l) 1.01 0.9 0.93 0.7 0.91 0.7 Unconjugated bilirubin (μmol/l) 0.51 0.5 0.45 0.4 0.41 0.4 Alkalene phosphatase (U/l) 220.4 16.1 202.3 14.9 178.2 13.1
Pregnancy outcomes and prognostic factors in patients 3 Table III. The distribution of adverse perinatal outcomes with TBA values and gestational age at diagnosis. TBA (μmol/l) 20 n
Gestational age at diagnosis (weeks) 40
20–39
(%) n
(%)
n 18 43 RDS 3 16.6 5 11.6 Fetal distress 0 0 5 11.6 Fetal growth restriction 0 0 2 4.6 Delivery before 37 weeks 7 38.8 11 25.5
n
(%)
30 n
28 14 38 10.7 5 1 3.5 2 3 10.7 2 13 46.4 10
34
30–33
(%)
n
(%)
35.7 14.2 14.2 71.4
37 5 13.5 3 8.1 4 10.8 14 37.8
n
(%)
38 1 0 0 7
2.6∗ 0∗ 0∗ 18.4∗
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∗p 0.01.
at diagnosis was predictive of delivery before 37 weeks (OR 2.3, 95% CI 1.5–3.3, p 0.001). Table III demonstrates the distribution of adverse perinatal outcomes with TBA values and gestational age at diagnosis. The incidence of respiratory distress syndrome (RDS), fetal growth restriction, fetal distress and delivery before 37 weeks were significantly higher in patients who were diagnosed before 30 weeks than after 34 weeks’ gestation (p 0.01). The incidences of RDS, fetal growth restriction, fetal distress and delivery before 37 weeks were not significantly different from the TBA subgroups (p 0.05).
Discussion The mean age of patients and the rate of nulliparity in our study population are similar to those reported in the literature (Al Shobaili et al. 2011; Rook et al. 2012). The mean gestational age of clinical presentation of our patients is also in accordance with the literature (Oztekin et al. 2009; Al Shobaili et al. 2011). Approximately 80% of affected women are reported to present after 30 weeks’ gestation (Geenes and Williamson 2009) and this rate was found to be 84.3% in our patients with ICP. Although pruritus most frequently manifests in the 3rd trimester, ICP has been reported as early as 8 weeks (Berg et al. 1986). We have also diagnosed ICP as early as 20 weeks’ gestation. The incidence of gestational diabetes and pre-eclampsia were 14.6% and 2.2%, respectively, in our group. Pre-eclampsia and gestational diabetes, which are both common obstetric complications, were diagnosed in 2–8% and 3–5% of pregnancies, respectively (Wikstrom Shemer et al. 2013). There have been reports of the coexistence of ICP with pre-eclampsia, and gestational diabetes (Geenes and Williamson 2009). In a recent nationwide cohort study, ICP was strongly associated with gestational diabetes and pre-eclampsia (Wikstrom Shemer et al. 2013). Our data is in accordance with the increased incidence of gestational diabetes with ICP. The most sensitive laboratory abnormality in ICP is an increase in serum TBA concentrations, which may be the first or only laboratory abnormality (Pathak et al. 2010). Other laboratory abnormalities observed in ICP include elevations in ALT, AST, GGT and alkaline phosphatase (Kondrackiene and Kupcinskas 2008; Pathak et al. 2010). The incidences of elevated TBA, ALT, AST and GGT in our group were 100%, 70.8%, 65.2% and 20.2%, respectively. These findings are in accordance with the literature (Geenes and Williamson 2009). We have also observed a positive correlation between serum TBA, AST and GGT concentrations. UDCA, which is the most effective pharmacological treatment for ICP, has been shown to significantly reduce bile acids and liver enzymes (Bacq et al. 2012). We also observed that serum TBA, AST, ALT, GGT and alkalene phosphatase levels significantly decreased after the initiation of UDCA treatment.
Although ICP is usually relatively benign to the mother, it is known that the risk of fetal complications is increased in pregnancies affected by ICP. These include increased risks of preterm delivery, respiratory distress, meconium-stained amniotic fluid, fetal distress and fetal demise (Kondrackiene and Kupcinskas 2008). Previous studies have reported meconium staining in 0–58%, and intrauterine fetal demise in 0.4–4.1%, of ICP cohorts (Geenes and Williamson 2009). This study reported no stillbirths and 2.2% incidence of meconium staining of amniotic fluid. This may be the result of increased antenatal surveillance and our policy of early delivery at around 38 weeks. Furthermore, when we diagnosed ICP, we started UDCA treatment in all cases. Although there are conflicting data regarding the effects of UDCA treatment on the perinatal outcome, several clinical trials and observational studies showed that UDCA treatment improved fetal outcomes (Palma et al. 1997; Bacq et al. 2012). On the other hand, some studies emphasised that, while pruritus and serum levels of total bile salts and ALT improved, perinatal outcomes with respect to the effect of UDCA are less clear (Pathak et al. 2010). We cannot, however, comment on this subject, as we administered UDCA treatment to all of our patients. It has been reported that the incidence of RDS in neonates born to mothers with ICP is increased (Geenes and Williamson 2009). This can be due in part to the earlier gestational age at delivery, but neonatal RDS has been demonstrated to be associated with ICP, based on analysis of bronchoalveolar lavage fluid of neonates born to mothers with ICP (Zecca et al. 2008). Bile acids can induce lung injury, leading to surfactant depletion, surfactant dysfunction and lung inflammation (Zecca et al. 2008; Geenes and Williamson 2009). Therefore, it is possible that the increased risk of neonatal RDS may be related to ICP itself. We have observed 12.9% incidence of RDS in neonates born to mothers with ICP. Of the 11 neonates that had RDS in our group, interestingly five (45.5%) were born at 37 or 38 weeks’ gestation. This observation highlights the influence of ICP on RDS. The main complication of ICP is prematurity, which is reported to be in the range of 19–60% of patients with ICP (Kondrackiene and Kupcinskas 2008; Geenes and Williamson 2009). The rate of prematurity varies greatly according to the study and may be increased because of the high rate of multiple pregnancies in patients with ICP and iatrogenic preterm deliveries. Exactly how ICP causes preterm births is uncertain; however, in vitro studies showed an increased response of myometrial strips from healthy woman to oxytocin and an increased oxytocin receptor expression after being incubated with cholic acid (Glantz et al. 2004). The rates of deliveries before 37 and 34 weeks in our group were 34.8% and 6.7%, respectively. Kondrackiene et al. (2007) demonstrated that early onset of pruritus and high levels of TBA were associated with preterm delivery. We have also observed
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that gestational age at diagnosis significantly correlated with gestational age at delivery. The binary logistic regression analysis revealed that the early onset of pruritus was the most important independent factor predicting premature delivery. However, we could not find a correlation between gestational age at delivery and initial maternal serum TBA levels. Prognostic factors for adverse perinatal outcomes in patients with ICP have been evaluated. High TBA levels have already been described as predictors of fetal outcome in some cohort studies (Kondrackiene and Kupcinskas 2008; Geenes and Williamson 2009). Bile acids have been shown to induce vasoconstriction of human placental chorionic veins and myometrial sensitivity to oxytocin (Sepulveda et al. 1991; Germain et al. 2003). In one study, a correlation between fetal complications (defined as preterm delivery, asphyxial events, meconium staining of amniotic fluid, placenta and membranes) and serum bile acid levels ( 40 pmol/l) was found (Glantz et al. 2004). However, we could not find a significant difference between the incidences of RDS, fetal growth restriction, fetal distress and preterm delivery between the TBA subgroups. However, fetal complications such as preterm delivery, RDS and FGR were significantly higher in patients who were diagnosed before 30 weeks than after 34 weeks’ gestation. This observation highlights the importance of the gestational age at which clinical symptoms appear. Early onset of pruritus especially before 30 weeks’ gestation is associated with increased adverse perinatal outcomes. Therefore, gestational age at diagnosis seems to be an important independent factor predicting adverse perinatal outcomes in patients with ICP and should be taken into consideration in the management of such pregnancies. Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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