J. Perinat. Med. 2015; 43(2): 133–139
Review article Patrik Šimják, Antonín Pařízek*, Libor Vítek, Andrej Černý, Karolína Adamcová, Michal Koucký, Martin Hill, Michaela Dušková and L’uboslav Stárka
Fetal complications due to intrahepatic cholestasis of pregnancy Abstract: Intrahepatic cholestasis of pregnancy (ICP) is the most common liver disorder of pregnancy. Diagnosis is based on the clinical picture, particularly the presence of pruritus with a deterioration of liver function tests, and typically elevated serum levels of total bile acids. ICP manifests in the second half of pregnancy, predominantly during the third trimester. Symptoms of the disease resolve spontaneously after delivery. Etiology is still not fully understood. Genetic defects in specific transport proteins, elevated levels of sex hormones, and various environmental factors are thought to play a role in the development of this disorder. Although practically benign for the pregnant woman, ICP represents a serious threat to the fetus. It increases the risk of preterm delivery, meconium excretion into the amniotic fluid, respiratory distress syndrome, and sudden intrauterine fetal death. Identifying fetuses at risk of ICP complications remains challenging. The ideal obstetrical management of ICP needs to be definitively determined. The aim of this review is to summarize the current knowledge on fetal complications of ICP and describe management options for their prevention. Keywords: Fetal complications; intrahepatic cholestasis of pregnancy (ICP); intrauterine fetal death (IUFD); total bile acids (TBA); ursodeoxycholic acid (UDCA).
*Corresponding author: Doc. MUDr. Antonín Pařízek, CSc., First Faculty of Medicine, Department of Obstetrics and Gynaecology, Charles University in Prague and General University Hospital in Prague, Apolinářská 18, 128 51, Prague 2, Czech Republic, Tel.: +420 602 203 023, E-mail: [email protected] Patrik Šimják, Andrej Černý, Karolína Adamcová and Michal Koucký: First Faculty of Medicine, Department of Obstetrics and Gynaecology, General University Hospital, Charles University in Prague, Prague, Czech Republic Libor Vítek: Institute of Medical Biochemistry and Laboratory Diagnostics, First Faculty of Medicine, 4th Department of Internal Medicine, General University Hospital, Charles University in Prague, Prague, Czech Republic Martin Hill, Michaela Dušková and L’uboslav Stárka: Institute of Endocrinology, Prague, Czech Republic
DOI 10.1515/jpm-2014-0089 Received March 12, 2014. Accepted July 7, 2014. Previously published online August 5, 2014.
Introduction Intrahepatic cholestasis of pregnancy (ICP) is the most common liver disorder of pregnancy. The incidence in Europe varies from 0.4% to 2.0% [15, 20], but regional differences across the world are significant. Based on a large clinical study, the prevalence rate of ICP in the Czech Republic has been estimated to be almost 0.9% [6]. Diagnosis is based on the clinical picture, particularly the presence of pruritus with a deterioration of liver function tests (LFT), and typically elevated serum levels of total bile acids (TBA) above 8 μmol/L. ICP manifests in the second half of pregnancy, predominantly during the third trimester. Symptoms of the disease resolve spontaneously after delivery, but the risk of recurrence in subsequent pregnancies is 45%–70% [15]. The etiology is multifactorial, but higher rates of occurrence within families support a strong genetic background. Various mutations in the gene encoding multidrug resistance protein 3 (MDR3) have been identified in pregnancies complicated by ICP [12]. Mutations in genes coding for other membrane proteins and their regulatory partners have also been implicated in the pathogenesis of ICP. ICP is more common in multiple pregnancies, probably due to the higher levels of estrogen and progesterone. Placental sex hormones affect the functions of membrane transport proteins of hepatocytes and thus affect biliary lipid secretion [20]. Environmental factors such as selenium deficiency might also contribute to the development of ICP [18]. ICP is usually considered benign for pregnant women, nevertheless, there is an association between ICP and later development of some liver and biliary diseases [30]. Much more importantly, it represents a serious threat to the fetus, as ICP increases the risk of preterm delivery, meconium excretion into the amniotic fluid, respiratory distress syndrome (RDS),
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134 Šimják et al., Fetal complications due to intrahepatic cholestasis of pregnancy and sudden intrauterine fetal death (IUFD). A literature search of PubMed database was performed for relevant studies published from 2000 until now. A few important older studies were also included. As relevant, following keywords were used for literature search: intrahepatic cholestasis of pregnancy (ICP); fetal complications of intrahepatic cholestasis; intrauterine fetal death (IUFD); and management of ICP.
Fetal complications of intrahepatic cholestasis of pregnancy The etiopathogenesis of the fetal complications of ICP still remains the subject of intensive research. It is generally believed that these complications are closely related to elevated maternal systemic levels of TBA. The fetus starts to synthesize bile acids from the end of the first trimester [10]. These bile acids are transported through the placenta and excreted through the maternal organism. Pregnant women may excrete large amounts of bile acids into the urine to control serum concentration of bile acids in the fetal compartment. When maternal bile acid concentrations are elevated, the fetal-maternal gradient is inverted, leading to an elevation of fetal TBA [39], though fetal levels do not usually reach maternal TBA levels [24]. Knowledge of the maternal serum concentrations of TBA allows only a rough estimate of TBA levels in the fetal compartment. Table 1 shows the risk of fetal complications in recent studies.
Preterm delivery Preterm delivery rate is estimated to be 11.7%–60% in women who suffer from ICP and occur mostly between the 32nd and 36th weeks of pregnancy [3, 13, 15, 28]. ICP is more frequent among multiple pregnancies and the rate of prematurity is higher among these pregnancies. A significant proportion of preterm labors results from iatrogenic interventions. Bile acids stimulate the expression of oxytocin receptors. The myometrium of women with ICP is, therefore, more sensitive to oxytocin [14], probably leading to increased uterine activity, which may lead to spontaneous preterm delivery.
Meconium-stained amniotic fluid Meconium-stained amniotic fluid (MSAF) occurs in 10%– 44% of ICP cases [15, 21]. The exact mechanism of meconium expulsion is not known. Nevertheless, it may result from fetal distress or from elevated TBA levels directly. Bile acids are known to stimulate the motility of the large intestine, and, therefore, may lead to meconium expulsion [19]. The incidence of MSAF correlates with severity of ICP [15]. A positive correlation between MSAF and gestational age, regardless of biochemical parameters, has also been described. The risk of meconium expulsion greatly increases after 38th week of pregnancy [2]. In another study, one-third of all MSAF occurred before the onset of labor and approximately one-third before the 37th week of pregnancy [29]. MSAF is a strong predictor
Table 1 Summary of studies containing incidence/risk of fetal complications of intrahepatic cholestasis of pregnancy. Source
Geenes et al. (2014) [13] Oztekin et al. (2009) [28] Zecca et al. (2006) [41] Lee et al. (2006) [21] Glantz et al. (2004) [15] Bacq et al. (1997) [3]
Fetal complications Preterm delivery
25%a Odds ratio (OR) 4.68, 95% confidence interval (CI) 3.67–5.98 11.7% – – 2.2% in mild ICPb 16.7% in severe ICPb 60.0%
Meconium-stained amniotic fluid
Respiratory distress syndrome
Intrauterine fetal death
16%a
–
1.5%a OR 3.05, 95% CI 1.29–7.21
– 28.6% – –
– – – 0.4%
– – 10.5%–12.5% 44% in severe ICPb –
Severe ICP cases defined as TBA ≥ 40 μmol/L. Mild ICP defined as TBA 10–39 μmol/L; severe ICP defined as TBA ≥ 40 μmol/L.
a
b
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–
–
Šimják et al., Fetal complications due to intrahepatic cholestasis of pregnancy 135
of adverse perinatal outcome. In animal studies, IUFD is always accompanied by previous MSAF [8].
Respiratory distress syndrome The incidence of RDS in the newborns of women affected by ICP is around 29% [42]. The elevation of TBA in fetal circulation reduces the activity of phospholipase A2 and causes the degradation of phosphatidylcholine in the fetal surfactant [15]. An alternative pathophysiological mechanism may include direct toxic effect of bile acids on type II pneumocytes, through an increase of intracellular Ca2+ [27]. TBAs are thought to be a causal factor for the development of bile acid-induced pneumonia [40]. TBA levels, exposure time, and gestational age at delivery correlate with the incidence of RDS. Together these variables can be used to calculate the RDS risk score, which shows 83.3% sensitivity and 87.5% specificity for predicting the development of RDS [41].
Intrauterine fetal death Sudden IUFD occurs in 0.4%–1.5% of pregnancies complicated by ICP [13, 15]. The majority of unexplained IUFD occurs after the 37th week of pregnancy. Mechanisms leading to IUFD remain as yet unknown and seem to be multifactorial. It is believed that bile acids play a key role in its pathogenesis, although IUFD can also occur with virtually physiological TBA levels [31]. No effective way of identifying fetuses at risk has yet been identified [22]. Several major mechanisms have been proposed to explain how the elevated maternal TBA levels associated with ICP affect the fetus. These include: a) Impacts on placental morphology. Chorangiosis, a higher surface volume of capillaries and terminal villi, and an increased number of syncytial knots have been observed in untreated ICP [38]. These changes are probably a result of long-lasting placental hypo perfusion or low-grade hypoxia. Experimental studies have shown that every IUFD in animals is accompanied by MSAF [8]. Once excreted, meconium is promptly absorbed into placenta and umbilical cord. Bile acids that are present in MSAF can cause vasoconstriction of the placental and umbilical vessels [32], which in turn can contribute to IUFD. b) Corticosteroid secretion, which is part of the fetal stress response, is suppressed in severe ICP. Elevated TBA levels are associated with lower concentrations of cortisol, dehydroepiandrosterone sulfate, and
corticotropin-releasing hormone in the fetal circulation [37, 43], presumably due to the toxic effects of bile acids on mitochondria. Cells that are metabolically active and produce stress hormones are vulnerable to the lack of energetic substrates. The impaired fetal ability to sustain stress contributes to IUFD. In fact, the majority (95%) of IUFDs occur when delivery is imminent or already in progress [15]. c) Elevated bile acids can cause fetal arrhythmias. Fetal atrial flutter and supraventricular tachycardia have been observed in the second and third trimesters of pregnancies complicated by ICP [1, 33], but similar changes in the maternal heart rhythm have not been found. One explanation may lie in the structural differences of the fetal heart. Myofibroblasts transiently appear in the fetal heart during the second and third trimesters. This same cell type can be found in adult hearts after an infarction, but they do not appear in the healthy adult heart [36]. Myofibroblasts form gap junctions with one another and with cardiomyocytes, altering the cardiac electrophysiology [25]. Fetal PR interval is significantly increased in ICP [35]. Both acute and chronic fetal exposure to taurocholate (TC) decrease conduction in the fetal heart, and ectopic electrical activity can arise [26]. This is probably due to its effect on muscarinic M2 receptors on the membrane of cardiomyocytes. TC serves as a partial agonist of this receptor, which reduces the rate of contraction and atrioventricular conduction, and influences the force of the contractions [34].
Diagnosis of intrahepatic cholestasis of pregnancy The diagnosis of ICP is based on pruritus and elevated maternal serum TBA concentrations ( > 8 μmol/L). In the majority of patients, alanine transaminase (ALT) activities are elevated as well. Bile acids are the most sensitive indicator for ICP, and their determination should be routinely performed in all pregnant women experiencing pruritus of unknown origin [11].
Management of intrahepatic cholestasis of pregnancy As explained earlier, bile acids play a major role in the development of fetal complications. Sudden IUFD remains
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136 Šimják et al., Fetal complications due to intrahepatic cholestasis of pregnancy the most feared one. The probability of all fetal complications is significantly higher once maternal serum TBA levels exceed 40 μmol/L [13, 15]. Adverse perinatal outcomes also correlate well with the duration of the disease and gestational age [2, 28, 41]. Women delivering after 38th week of pregnancy had significantly higher incidence of MSAF, abnormal cardiotocography, and need for neonatal nursery admission compared to those delivering between 35 and 38 weeks of gestation, regardless of maternal laboratory parameters [2]. The coincidence of other comorbidities such as the preeclampsia further increases the risk of adverse fetal outcome. As there are no methods for identifying fetuses at risk, our primary goal in the management of ICP should be towards reducing fetal exposure to toxic bile acids. This can be achieved by either decreasing the TBA levels in the maternal circulation or shortening the fetal exposure time by early induction of labor.
Pharmacological treatment Despite the reluctance of official obstetrician authorities, the golden standard in the treatment of ICP is oral administration of ursodeoxycholic acid (UDCA), based on the recent guidelines of the European Association for the Study of the Liver Diseases [11]. This recommendation is further supported by recently published evidence suggesting multiple benefits for fetuses as well for newborns [4, 16]. UDCA, a beta epimer of chenodeoxycholic acid, is a more polar bile acid than primary bile acids, with substantial choleretic as well as other multiple chemoprotective effects. UDCA administered orally becomes the predominant bile acid in the maternal circulation. UDCA then stimulates the secretion of bile acids and other biliary lipids. It is taken in a dosage of 10–20 mg/kg/day, which in practice usually means giving 250 mg two to three times a day [11]. In severe cases, however, the UDCA intake can be temporarily increased to 1500 mg a day [5]. UDCA significantly eases maternal pruritus [4, 9, 15, 16]. It also reduces serum activities of ALT and gamma-glutamyl transferase, as well as concentrations of bilirubin and TBA, and significantly improves fetal outcomes [4, 9]. It is associated with decreases in total prematurity, fetal distress, and RDS [4, 16]. The incidence of MSAF is significantly lower in patients treated with UDCA when compared to placebo [9], and UDCA shows a good safety profile for both mother and fetus [4]. Adding S-adenosyl-l-methionin (SAM) can further accelerate the improvement of biochemical parameters [7]. TBA levels need to be measured repeatedly in order to evaluate the response to UDCA treatment and to identify fetuses at risk.
Timing of delivery Inducing labor early shortens the fetal exposure time to bile acids, but the decreased risk of IUFD needs to be weighed against the possible complications of prematurity. In routine practice, induction of labor after the 37th week of pregnancy is recommended for women suffering from ICP [5, 11]. The number of cesarean sections is not increased by the early induction of labor [9, 29], and active management is associated with a low incidence of maternal and neonatal complications [23]. Some authors advocate that maternal and fetal outcomes do not differ significantly between women with early term deliveries and those with expectant management [9]. Jain et al. suggest that pregnancies with ICP can be carried to a later gestation under careful surveillance, but they also agree that active management improves perinatal outcome [17]. However, with no effective way of identifying fetus at risk this practice lacks the potential to prevent IUFD [22]. We believe that expectant management should only be reserved for asymptomatic cases with TBA
Review article Patrik Šimják, Antonín Pařízek*, Libor Vítek, Andrej Černý, Karolína Adamcová, Michal Koucký, Martin Hill, Michaela Dušková and L’uboslav Stárka
Fetal complications due to intrahepatic cholestasis of pregnancy Abstract: Intrahepatic cholestasis of pregnancy (ICP) is the most common liver disorder of pregnancy. Diagnosis is based on the clinical picture, particularly the presence of pruritus with a deterioration of liver function tests, and typically elevated serum levels of total bile acids. ICP manifests in the second half of pregnancy, predominantly during the third trimester. Symptoms of the disease resolve spontaneously after delivery. Etiology is still not fully understood. Genetic defects in specific transport proteins, elevated levels of sex hormones, and various environmental factors are thought to play a role in the development of this disorder. Although practically benign for the pregnant woman, ICP represents a serious threat to the fetus. It increases the risk of preterm delivery, meconium excretion into the amniotic fluid, respiratory distress syndrome, and sudden intrauterine fetal death. Identifying fetuses at risk of ICP complications remains challenging. The ideal obstetrical management of ICP needs to be definitively determined. The aim of this review is to summarize the current knowledge on fetal complications of ICP and describe management options for their prevention. Keywords: Fetal complications; intrahepatic cholestasis of pregnancy (ICP); intrauterine fetal death (IUFD); total bile acids (TBA); ursodeoxycholic acid (UDCA).
*Corresponding author: Doc. MUDr. Antonín Pařízek, CSc., First Faculty of Medicine, Department of Obstetrics and Gynaecology, Charles University in Prague and General University Hospital in Prague, Apolinářská 18, 128 51, Prague 2, Czech Republic, Tel.: +420 602 203 023, E-mail: [email protected] Patrik Šimják, Andrej Černý, Karolína Adamcová and Michal Koucký: First Faculty of Medicine, Department of Obstetrics and Gynaecology, General University Hospital, Charles University in Prague, Prague, Czech Republic Libor Vítek: Institute of Medical Biochemistry and Laboratory Diagnostics, First Faculty of Medicine, 4th Department of Internal Medicine, General University Hospital, Charles University in Prague, Prague, Czech Republic Martin Hill, Michaela Dušková and L’uboslav Stárka: Institute of Endocrinology, Prague, Czech Republic
DOI 10.1515/jpm-2014-0089 Received March 12, 2014. Accepted July 7, 2014. Previously published online August 5, 2014.
Introduction Intrahepatic cholestasis of pregnancy (ICP) is the most common liver disorder of pregnancy. The incidence in Europe varies from 0.4% to 2.0% [15, 20], but regional differences across the world are significant. Based on a large clinical study, the prevalence rate of ICP in the Czech Republic has been estimated to be almost 0.9% [6]. Diagnosis is based on the clinical picture, particularly the presence of pruritus with a deterioration of liver function tests (LFT), and typically elevated serum levels of total bile acids (TBA) above 8 μmol/L. ICP manifests in the second half of pregnancy, predominantly during the third trimester. Symptoms of the disease resolve spontaneously after delivery, but the risk of recurrence in subsequent pregnancies is 45%–70% [15]. The etiology is multifactorial, but higher rates of occurrence within families support a strong genetic background. Various mutations in the gene encoding multidrug resistance protein 3 (MDR3) have been identified in pregnancies complicated by ICP [12]. Mutations in genes coding for other membrane proteins and their regulatory partners have also been implicated in the pathogenesis of ICP. ICP is more common in multiple pregnancies, probably due to the higher levels of estrogen and progesterone. Placental sex hormones affect the functions of membrane transport proteins of hepatocytes and thus affect biliary lipid secretion [20]. Environmental factors such as selenium deficiency might also contribute to the development of ICP [18]. ICP is usually considered benign for pregnant women, nevertheless, there is an association between ICP and later development of some liver and biliary diseases [30]. Much more importantly, it represents a serious threat to the fetus, as ICP increases the risk of preterm delivery, meconium excretion into the amniotic fluid, respiratory distress syndrome (RDS),
Brought to you by | Karolinska Institute Authenticated Download Date | 6/3/15 10:22 AM
134 Šimják et al., Fetal complications due to intrahepatic cholestasis of pregnancy and sudden intrauterine fetal death (IUFD). A literature search of PubMed database was performed for relevant studies published from 2000 until now. A few important older studies were also included. As relevant, following keywords were used for literature search: intrahepatic cholestasis of pregnancy (ICP); fetal complications of intrahepatic cholestasis; intrauterine fetal death (IUFD); and management of ICP.
Fetal complications of intrahepatic cholestasis of pregnancy The etiopathogenesis of the fetal complications of ICP still remains the subject of intensive research. It is generally believed that these complications are closely related to elevated maternal systemic levels of TBA. The fetus starts to synthesize bile acids from the end of the first trimester [10]. These bile acids are transported through the placenta and excreted through the maternal organism. Pregnant women may excrete large amounts of bile acids into the urine to control serum concentration of bile acids in the fetal compartment. When maternal bile acid concentrations are elevated, the fetal-maternal gradient is inverted, leading to an elevation of fetal TBA [39], though fetal levels do not usually reach maternal TBA levels [24]. Knowledge of the maternal serum concentrations of TBA allows only a rough estimate of TBA levels in the fetal compartment. Table 1 shows the risk of fetal complications in recent studies.
Preterm delivery Preterm delivery rate is estimated to be 11.7%–60% in women who suffer from ICP and occur mostly between the 32nd and 36th weeks of pregnancy [3, 13, 15, 28]. ICP is more frequent among multiple pregnancies and the rate of prematurity is higher among these pregnancies. A significant proportion of preterm labors results from iatrogenic interventions. Bile acids stimulate the expression of oxytocin receptors. The myometrium of women with ICP is, therefore, more sensitive to oxytocin [14], probably leading to increased uterine activity, which may lead to spontaneous preterm delivery.
Meconium-stained amniotic fluid Meconium-stained amniotic fluid (MSAF) occurs in 10%– 44% of ICP cases [15, 21]. The exact mechanism of meconium expulsion is not known. Nevertheless, it may result from fetal distress or from elevated TBA levels directly. Bile acids are known to stimulate the motility of the large intestine, and, therefore, may lead to meconium expulsion [19]. The incidence of MSAF correlates with severity of ICP [15]. A positive correlation between MSAF and gestational age, regardless of biochemical parameters, has also been described. The risk of meconium expulsion greatly increases after 38th week of pregnancy [2]. In another study, one-third of all MSAF occurred before the onset of labor and approximately one-third before the 37th week of pregnancy [29]. MSAF is a strong predictor
Table 1 Summary of studies containing incidence/risk of fetal complications of intrahepatic cholestasis of pregnancy. Source
Geenes et al. (2014) [13] Oztekin et al. (2009) [28] Zecca et al. (2006) [41] Lee et al. (2006) [21] Glantz et al. (2004) [15] Bacq et al. (1997) [3]
Fetal complications Preterm delivery
25%a Odds ratio (OR) 4.68, 95% confidence interval (CI) 3.67–5.98 11.7% – – 2.2% in mild ICPb 16.7% in severe ICPb 60.0%
Meconium-stained amniotic fluid
Respiratory distress syndrome
Intrauterine fetal death
16%a
–
1.5%a OR 3.05, 95% CI 1.29–7.21
– 28.6% – –
– – – 0.4%
– – 10.5%–12.5% 44% in severe ICPb –
Severe ICP cases defined as TBA ≥ 40 μmol/L. Mild ICP defined as TBA 10–39 μmol/L; severe ICP defined as TBA ≥ 40 μmol/L.
a
b
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–
–
Šimják et al., Fetal complications due to intrahepatic cholestasis of pregnancy 135
of adverse perinatal outcome. In animal studies, IUFD is always accompanied by previous MSAF [8].
Respiratory distress syndrome The incidence of RDS in the newborns of women affected by ICP is around 29% [42]. The elevation of TBA in fetal circulation reduces the activity of phospholipase A2 and causes the degradation of phosphatidylcholine in the fetal surfactant [15]. An alternative pathophysiological mechanism may include direct toxic effect of bile acids on type II pneumocytes, through an increase of intracellular Ca2+ [27]. TBAs are thought to be a causal factor for the development of bile acid-induced pneumonia [40]. TBA levels, exposure time, and gestational age at delivery correlate with the incidence of RDS. Together these variables can be used to calculate the RDS risk score, which shows 83.3% sensitivity and 87.5% specificity for predicting the development of RDS [41].
Intrauterine fetal death Sudden IUFD occurs in 0.4%–1.5% of pregnancies complicated by ICP [13, 15]. The majority of unexplained IUFD occurs after the 37th week of pregnancy. Mechanisms leading to IUFD remain as yet unknown and seem to be multifactorial. It is believed that bile acids play a key role in its pathogenesis, although IUFD can also occur with virtually physiological TBA levels [31]. No effective way of identifying fetuses at risk has yet been identified [22]. Several major mechanisms have been proposed to explain how the elevated maternal TBA levels associated with ICP affect the fetus. These include: a) Impacts on placental morphology. Chorangiosis, a higher surface volume of capillaries and terminal villi, and an increased number of syncytial knots have been observed in untreated ICP [38]. These changes are probably a result of long-lasting placental hypo perfusion or low-grade hypoxia. Experimental studies have shown that every IUFD in animals is accompanied by MSAF [8]. Once excreted, meconium is promptly absorbed into placenta and umbilical cord. Bile acids that are present in MSAF can cause vasoconstriction of the placental and umbilical vessels [32], which in turn can contribute to IUFD. b) Corticosteroid secretion, which is part of the fetal stress response, is suppressed in severe ICP. Elevated TBA levels are associated with lower concentrations of cortisol, dehydroepiandrosterone sulfate, and
corticotropin-releasing hormone in the fetal circulation [37, 43], presumably due to the toxic effects of bile acids on mitochondria. Cells that are metabolically active and produce stress hormones are vulnerable to the lack of energetic substrates. The impaired fetal ability to sustain stress contributes to IUFD. In fact, the majority (95%) of IUFDs occur when delivery is imminent or already in progress [15]. c) Elevated bile acids can cause fetal arrhythmias. Fetal atrial flutter and supraventricular tachycardia have been observed in the second and third trimesters of pregnancies complicated by ICP [1, 33], but similar changes in the maternal heart rhythm have not been found. One explanation may lie in the structural differences of the fetal heart. Myofibroblasts transiently appear in the fetal heart during the second and third trimesters. This same cell type can be found in adult hearts after an infarction, but they do not appear in the healthy adult heart [36]. Myofibroblasts form gap junctions with one another and with cardiomyocytes, altering the cardiac electrophysiology [25]. Fetal PR interval is significantly increased in ICP [35]. Both acute and chronic fetal exposure to taurocholate (TC) decrease conduction in the fetal heart, and ectopic electrical activity can arise [26]. This is probably due to its effect on muscarinic M2 receptors on the membrane of cardiomyocytes. TC serves as a partial agonist of this receptor, which reduces the rate of contraction and atrioventricular conduction, and influences the force of the contractions [34].
Diagnosis of intrahepatic cholestasis of pregnancy The diagnosis of ICP is based on pruritus and elevated maternal serum TBA concentrations ( > 8 μmol/L). In the majority of patients, alanine transaminase (ALT) activities are elevated as well. Bile acids are the most sensitive indicator for ICP, and their determination should be routinely performed in all pregnant women experiencing pruritus of unknown origin [11].
Management of intrahepatic cholestasis of pregnancy As explained earlier, bile acids play a major role in the development of fetal complications. Sudden IUFD remains
Brought to you by | Karolinska Institute Authenticated Download Date | 6/3/15 10:22 AM
136 Šimják et al., Fetal complications due to intrahepatic cholestasis of pregnancy the most feared one. The probability of all fetal complications is significantly higher once maternal serum TBA levels exceed 40 μmol/L [13, 15]. Adverse perinatal outcomes also correlate well with the duration of the disease and gestational age [2, 28, 41]. Women delivering after 38th week of pregnancy had significantly higher incidence of MSAF, abnormal cardiotocography, and need for neonatal nursery admission compared to those delivering between 35 and 38 weeks of gestation, regardless of maternal laboratory parameters [2]. The coincidence of other comorbidities such as the preeclampsia further increases the risk of adverse fetal outcome. As there are no methods for identifying fetuses at risk, our primary goal in the management of ICP should be towards reducing fetal exposure to toxic bile acids. This can be achieved by either decreasing the TBA levels in the maternal circulation or shortening the fetal exposure time by early induction of labor.
Pharmacological treatment Despite the reluctance of official obstetrician authorities, the golden standard in the treatment of ICP is oral administration of ursodeoxycholic acid (UDCA), based on the recent guidelines of the European Association for the Study of the Liver Diseases [11]. This recommendation is further supported by recently published evidence suggesting multiple benefits for fetuses as well for newborns [4, 16]. UDCA, a beta epimer of chenodeoxycholic acid, is a more polar bile acid than primary bile acids, with substantial choleretic as well as other multiple chemoprotective effects. UDCA administered orally becomes the predominant bile acid in the maternal circulation. UDCA then stimulates the secretion of bile acids and other biliary lipids. It is taken in a dosage of 10–20 mg/kg/day, which in practice usually means giving 250 mg two to three times a day [11]. In severe cases, however, the UDCA intake can be temporarily increased to 1500 mg a day [5]. UDCA significantly eases maternal pruritus [4, 9, 15, 16]. It also reduces serum activities of ALT and gamma-glutamyl transferase, as well as concentrations of bilirubin and TBA, and significantly improves fetal outcomes [4, 9]. It is associated with decreases in total prematurity, fetal distress, and RDS [4, 16]. The incidence of MSAF is significantly lower in patients treated with UDCA when compared to placebo [9], and UDCA shows a good safety profile for both mother and fetus [4]. Adding S-adenosyl-l-methionin (SAM) can further accelerate the improvement of biochemical parameters [7]. TBA levels need to be measured repeatedly in order to evaluate the response to UDCA treatment and to identify fetuses at risk.
Timing of delivery Inducing labor early shortens the fetal exposure time to bile acids, but the decreased risk of IUFD needs to be weighed against the possible complications of prematurity. In routine practice, induction of labor after the 37th week of pregnancy is recommended for women suffering from ICP [5, 11]. The number of cesarean sections is not increased by the early induction of labor [9, 29], and active management is associated with a low incidence of maternal and neonatal complications [23]. Some authors advocate that maternal and fetal outcomes do not differ significantly between women with early term deliveries and those with expectant management [9]. Jain et al. suggest that pregnancies with ICP can be carried to a later gestation under careful surveillance, but they also agree that active management improves perinatal outcome [17]. However, with no effective way of identifying fetus at risk this practice lacks the potential to prevent IUFD [22]. We believe that expectant management should only be reserved for asymptomatic cases with TBA
