Journal of Obstetrics and Gynaecology, 2014; 34: 221–224 © 2014 Informa UK, Ltd. ISSN 0144-3615 print/ISSN 1364-6893 online DOI: 10.3109/01443615.2013.834878

OBSTETRICS

Uterine contractility in intrahepatic cholestasis of pregnancy P. Zhao, K. Zhang, Q. Yao & X. Yang

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Department of Obstetrics, Women’s Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China

This study aims to compare uterine activity in intrahepatic cholestasis of pregnancy (ICP) patients vs normal pregnancies, and to determine the relevance of ICP and excessive uterine activity. A total of 59 patients with ICP and 89 with normal pregnancies were selected. Liver function, total bile acids and uterine activity were evaluated; uterine contraction parameters were compared at the specified range of gestational age. Uterine contraction frequency was significantly higher in the third trimester patients with ICP. Aspartate transaminase (AST) appeared to correlate with contraction frequency (r ⴝ 0.357, p ⴝ 0.006) and Montevideo units (MVUs) (r ⴝ 0.349, p ⴝ 0.007). For each 50 U/l increase in AST, the hazard ratio of excessive uterine activity was increased by 1.31-fold (95% CI ⴝ 1.034– 1.663, p ⴝ 0.025). The present study demonstrates that third trimester uterine contractility increases in patients with ICP. These findings should be of note, given what is known about obstetric cholestasis, and should prompt further research. Keywords: Fetal monitoring, intrahepatic cholestasis of pregnancy, medical and surgical complications of pregnancy, uterine activity

Introduction Intrahepatic cholestasis of pregnancy (ICP) is a condition which predominantly occurs during the third trimester of pregnancy. It is characterised by pruritus, jaundice and abnormal liver function. ICP usually resolves shortly after delivery and often returns in subsequent pregnancies. In southern China, ICP is very common, with a prevalence rate of 2.3–3.4% (Ai et al. 2004). It has been related to high perinatal complications, including premature delivery (19–60%), rates of fetal distress (22–41%), intrauterine fetal death (0.4–1.6%) and meconium staining of the amniotic fluid (24.8%) (Beuers and Pusl 2006; Glantz et al. 2004). The cause of adverse fetal outcome is not fully understood. Previous studies have shown an association between bile acid levels and enhanced uterine contractility both in vitro and in animal models, which might be an explanation for spontaneous pre-term birth and fetal hypoxia. In vitro, bile acids have induced vasoconstriction of isolated human placental chorionic vessels and myometrial sensitivity to oxytocin and caused stronger uterine muscle contraction (Germain et al. 2003; Sepúlveda et al. 1991; Heikkinen et al. 1983). Whereas, in animal models, chronic administration of cholic acid to the fetal sheep circulation induces uterine contractions resulting in pre-term delivery; when incubated with cholic acid (Simpson 2002), a dose-related increase in myometrial response to oxytocin is shown in the myometrium of non-pregnant rat.

The above results demonstrate that patients with ICP might have increased uterine contractility. The aim of the present study was to measure the uterine contraction parameters of normal pregnancies and patients with ICP, in order to investigate their association. To our knowledge, the uterine contractility in patients with ICP has never been analysed.

Materials and methods Participants From March 2008 to July 2010, 59 patients with ICP at the Women’s Hospital School of Medicine, Zhejiang University, were enrolled into this prospective study after informed consents were obtained. Inclusion criteria were defined as below: 1. Increased fasting serum total bile acids with pruritus; 2. Bile acids and routine liver function tests resolved promptly after delivery, confirming retrospectively the diagnosis of ICP 3. Singleton pregnancy ⬎ 25 weeks. Exclusion criteria included: other known liver disease; dermatological disease; current treatment with ursodeoxycholic acid; ⬍ 25 weeks’ gestation; multiple pregnancies; abnormalities that would increase baseline uterine activity (e.g. polyhydramnios). All women in this cohort received biochemical parameters screening after they were confirmed with ICP. The uterine activity was recorded for two hours which was from 13:30 to 15:30 hours, using the external tocodynamometer with belt. The same study was done on the controls. No study was done in labour. This study was performed according to the principles of the Declaration of Helsinki and was approved by the Institutional Review Board and the Bioethical Committee of our hospital.

Analytical techniques All recordings were carried out by a Sonicaid Team Monitor (Oxford Instruments Medical, Banbury) at a paper speed of 1 cm/min for approximately two hours. Each subject was applied and monitored exclusively by the nursing staff in the obstetric service. The tocograph was then examined and contraction parameters assessed in a two-hour window. The records of the contractions were determined as ‘usable’ if the baseline was above zero (0) and the peak of the recorded contraction was at least 20 mmHg above the baseline. The uterine activity monitor strips were analysed according to a standard protocol by two trained doctors. Regular audits, in which a sample of recordings with contractions was reanalysed, were conducted

Correspondence: X. Yang, Department of Obstetrics, Women’s Hospital, Zhejiang University School of Medicine, Xueshi Road, Hangzhou, Zhejiang Province, China. E-mail: [email protected]

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through the study to ensure consistent interpretation. Investigators and patients were not aware of the results of any of the uterine activity monitoring. It is important to mention the vulnerability of our methodology of measuring uterine activity with external tocodynamometer; it was selected because it is a widely accepted technique with no harm, especially in developing country. We are all well aware of the limitations of tocography. There are many factors that can influence the machine, so we took precautions to avoid such factors and to exclude false uterine contractions. Each participant was asked to read detailed instructions regarding the monitoring procedure, when there was a ‘not-to-do list’; conditions such as tensing the abdominal muscles and placing their hands on the guard-ring were included on the list. All recordings with potential contractions were read together by two trained doctors and would be excluded when they could not reach consensus as to the number of contractions. Moreover, placing the gauge accurately, over a fluid-filled part of the uterus provides an absolute measurement of intra-amniotic pressure possible through the abdominal wall. Its accuracy is equal to that of intra-amniotic instruments (⫾ 1 cm, water pressure) (Smyth 1957). One welltrained individual was required to place the transducers in the optimal position.

Definition of contraction parameters A contraction was defined as a deflection from a clear baseline; round peaked, double peaked and camelback contractions were included; contractions with a variable baseline, a flat peak, vertical up slopes/down slopes were excluded. Uterine contraction frequency was the mean number of contractions per hour. Uterine contraction duration was defined as the mean time in seconds between onset and offset of the contractions. Montevideo units (MVUs) was defined as the mean 10-minute intensity of all contractions multiplied by the mean 10-minute frequency of the contractions. All of the contraction parameters were calculated in a two-hour window.

Liver function tests Venous blood samples were obtained after a fasting period of 8 h. The serum was frozen at ⫺20°C until biochemical parameters were analysed. Routine laboratory automated techniques were used to determine serum biochemical markers of serum total bile acids (TBA), total bilirubin (TB), conjugated bilirubin (CB), alanine aminotransferase (ALT) and aspartate aminotransferase (AST).

Data analysis The results were presented as mean ⫾ SD. Differences between normally distributed groups were performed by Student’s t-test. Correlation analysis was assessed by Spearman’s rank correlation. Multivariate analysis of prognostic factors of uterine contractions was performed using binary multivariate logistic regression analysis. Factors found to be significant (p ⬍ 0.05) or having a trend toward significance (0.05 ⬍ p ⬍ 0.1) in univariate analysis were entered into the model. Data were analysed with SPSS for windows version 16.0. All reported p values were two-sided, with values ⬍ 0.05 considered statistically significant.

Results A total of 59 patients with ICP were included in the study with a median age of 27.0 (range 23–36) years old and a median gestational age of 34.0 (range 23–39) weeks. Of the women, 56 (94.9%) were primiparous and three (5.1%) were multiparous. Deliveries were after 36.0 ⫾ 2.3 weeks. Pre-term delivery occurred in 46.9% of cases compared with 10% in the control group; meconium staining of the amniotic fluid in 27.1% compared with just 5% in the control group. A total of 89 normal singleton pregnancies (28.7 ⫾ 3.6 years old, range 22–43 years) were recruited at 33.2 ⫾ 4.7 (range 23–39) weeks’ gestation from routine antenatal clinics after informed consent. Individuals in both groups were matched for age and parity and were representative of the same population area (Table I).

Table I. Demographics and uterine activity in patients with intrahepatic cholestasis of pregnancy (ICP) and normal pregnancies. Gestational age (weeks) ⱕ 28 Normal ICP p value 29–32 Normal ICP p value 33–36 Normal ICP p value ⱖ 37 Normal ICP p value ICP Mild ICP Severe ICP p value

Maternal age (years)

Gravidity

Parity

Gestational age (weeks)

MVUs

Contraction frequency

Contraction duration (s)

15 10

30.0 ⫾ 3.5 27.6 ⫾ 1.8 0.067

2.5 ⫾ 1.1 1.5 ⫾ 1.0 0.059

0.2 ⫾ 0.6 0.1 ⫾ 0.3 0.578

25.8 ⫾ 3.0 25.9 ⫾ 2.0 0.322

2.3 ⫾ 3.0 3.8 ⫾ 6.5 0.481

0.7 ⫾ 0.6 0.5 ⫾ 1.0 0.881

18 ⫾ 23 24 ⫾ 28 0.857

20 13

28.7 ⫾ 5.9 27.1 ⫾ 3.1 0.408

2.2 ⫾ 1.4 2.2 ⫾ 1.2 0.993

0.07 ⫾ 0.2 0 0.391

31.3 ⫾ 1.2 30.9 ⫾ 1.1 0.41

4.1 ⫾ 3.2 12.0 ⫾ 10.5 0.02

0.9 ⫾ 0.7 2.0 ⫾ 1.9 0.031

49 ⫾ 55 42 ⫾ 30 0.516

36 24

28.8 ⫾ 3.5 27.1 ⫾ 3.0 0.058

1.9 ⫾ 1.1 2.1 ⫾ 0.9 0.398

0.06 ⫾ 0.2 0.08 ⫾ 0.3 0.679

34.9 ⫾ 1.1 34.8 ⫾ 0.9 0.92

6.2 ⫾ 4.9 21.3 ⫾ 20.3 0.001

1.2 ⫾ 0.8 3.0 ⫾ 2.6 0.004

48 ⫾ 42 60 ⫾ 36 0.226

18 12

28.3 ⫾ 2.4 29.0 ⫾ 2.9 0.46

1.7 ⫾ 1.1 1.8 ⫾ 0.6 0.939

0.06 ⫾ 0.2 0 0.331

38.4 ⫾ 1.2 37.7 ⫾ 0.9 0.085

7.2 ⫾ 4.6 20.1 ⫾ 14.8 0.013

1.2 ⫾ 0.75 3.2 ⫾ 2.2 0.011

60 ⫾ 48 66 ⫾ 36 0.548

42 17

27.8 ⫾ 2.8 26.8 ⫾ 3.2 0.218

1.9 ⫾ 1.0 2.1 ⫾ 1.0 0.447

0.07 ⫾ 0.3 0 0.083

33.7 ⫾ 3.9 31.4 ⫾ 4.3 0.056

14.9 ⫾ 16.0 18.8 ⫾ 18.7 0.425

2.3 ⫾ 2.3 2.8 ⫾ 2.3 0.623

48 ⫾ 36 48 ⫾ 42 0.859

n

Patients with ICP were divided into four groups according to their gestational ages. Results are expressed as mean ⫾ SD. ICP, intrahepatic cholestasis of pregnancy; Normal, normal singleton pregnancy; Mild ICP: total bile acids levels ⬎ 10 μmol/l and ⬍ 40 μmol/l; Severe ICP; total bile acids levels ⱖ 40 μmol/l.

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Uterine contractility in ICP 223

Figure 2. Scatterplot of AST level vs uterine frequency in a 2-hour window.

Figure 1. Mean uterine contraction per hour by gestational age. ICP, intrahepatic cholestasis of pregnancy; Normal, normal singleton pregnancy.

All enrolled women were divided into four groups, according to their gestational age (group 1, ⱕ 28; group 2, 29–32; group 3, 33–36; group 4, ⱖ 37). Demographics and uterine activity were compared between patients with ICP and the control group. Individuals in both groups were matched for maternal age, gravidity, parity and gestational age (Table I); all were Asians. When compared with normal controls, individuals of group 1 presented no significant difference in contraction frequency or MVUs. However, the other three groups (groups 2, 3 and 4) showed higher contraction frequency (p ⫽ 0.031, 0.004 and 0.011, respectively) and greater MVUs (p ⫽ 0.020, 0.001 and 0.013, respectively). There were no significant differences in contraction duration. ICP was categorised into mild and severe. Total bile acid (TBA) levels ⬎ 10 μmol/l and ⬍ 40 μmol/l were considered ‘mild ICP’; TBA levels ⱖ 40 μmol/l were considered ‘severe ICP’. Individuals in both groups were matched for maternal age, gravidity, parity and gestational age (Table I). No significant differences were found in contraction frequency (p ⫽ 0.623), MVUs (p ⫽ 0.425) or contraction duration (p ⫽ 0.859) between mild and severe ICP. AST appeared to correlate with contraction frequency (r ⫽ 0.357, p ⫽ 0.006) and MVUs (r ⫽ 0.349, p ⫽ 0.007). When four or more contractions per hour were abnormal, binary logistic regression analysis revealed that AST was the independent parameter predicting abnormal contraction frequency. When AST level increased by 50 U/l, the hazard ratio of abnormal contraction increased by 1.31-fold (95% CI ⫽ 1.034–1.663, p ⫽ 0.025). The TBA was not associated with uterine activity (r ⫽ 0.123, p ⫽ 0.368, for contraction frequency; r ⫽ 0.131, p ⫽ 0.336, for MVUs).

Discussion Two major findings were confirmed in this study. First, third trimester patients with ICP tend to develop significantly greater uterine contractibility than normal pregnancies, regardless of the timing of delivery (pre-term or term, see Figure 1). This finding provides a possible mechanism to explain the increased fetal morbidity observed in patients with ICP. Increased uterine contraction may lead to adverse fetal outcomes: when contractions occur, the maternal spiral arteries are compressed and placental

perfusion is decreased, in whose well being is already compromised by the accumulation of bile acids, this will exacerbate fetal risk and cause fetal academia, as well as meconium staining of the amniotic fluid. In this study, meconium staining occurred in 61.5% of third trimester cases with abnormal contractions, while it only occurred in 17.9% of the same population without abnormal contractions. Secondly, abnormal uterine activity, which usually leads to preterm labour and/or meconium staining, was associated with the AST. For each 50 U/l increase in AST, the hazard ratio of developing abnormal uterine activity (uterine contraction frequency ⱖ 4) increased by 1.31-fold. This result, which agrees with the findings of Ch’ng et al. (2003), is useful in preventing early delivery of patients with ICP. Pre-term delivery is one of the major consequences and it has been reported (Katz et al. 1986) that persistent uterine contractions at a frequency of ⬎ 4/h predicted an 80% likelihood of pre-term labour. Moreover, patients with ⱖ 4 contractions/h after institution of rest and hydration, were still much more likely to develop pre-term labour, than those who had fewer contractions (Welch et al. 1990). The above results indicate that AST could be used as an independent parameter predicting pre-term labour; patients with ICP will benefit from regular liver function tests. For those cases with elevated AST (upper limit: 40 U/l), regular visits to the clinic for monitoring the uterine activity or ambulatory home monitoring with a tocodynamometer would help to identify pre-term contractions. It is interesting that we did not find any correlation between ALT levels and uterine contraction. There might be an explanation for this. As we know, AST is distributed both in the cytoplasm and mitochondria of hepatocytes, while ALT is distributed mainly in the cytoplasm. Mild cell injury results in release of cytoplasmic ALT, while severe injury releases cytoplasmic and mitochondrial AST. Severe ICP causes excessive uterine contractions that lead to pre-term labour; meanwhile more damage is caused to the liver cells which release both AST, which is why uterine contractions were only correlated with AST (Figure 2). There was no difference in uterine activity between second trimester patients with ICP and control groups. It has been well documented that the uterine contractility strongly associates with gestational ages and it is usually very low in mid-pregnancy. Anderson and Turnbull (1968) studied 29 patients in mid-pregnancy; no ‘usable’ spontaneous uterine contractions were recorded, and at an infusion rate of 8 mU/min of oxytocin, the mean intensity of uterine contractions increased significantly with gestation but never exceeded 25 mmHg. Meanwhile, other researchers have demonstrated that active tension developed by uterine muscle

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was a function of its fibre length; at optimal length tension was maximal. Since the uterine muscle fibres in mid-pregnancy are 10–30% below their optimal length, it is possible that the uterus is insensitive to such a stimulator as TBA, and cannot generate detectable contractions. However, no significant differences of uterine contraction parameters were found between mild and severe ICP. Since stratified groups were categorised by TBA level, the result indicated that TBA levels correlate neither with uterine activity nor with ICP severity, which agrees with previous studies (Mullally and Hansen 2002). In brief, the present study confirms the relevance of ICP and uterine contractibility. Third trimester patients with ICP tend to have significantly greater uterine activity and special attention should be given on monitoring the uterine activity. These findings should be of note given what is known about obstetric cholestasis, and should prompt further research. Further studies should employ an accurate non-invasive signal processing method, taking into account all the factors affecting surface uterine pressure. We do think transabdominal electrohysterography is also a promising candidate. Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

References Ai Y, Liu SY, Yao Q. 2004. Clinical characteristics of 1241 cases of intrahepatic cholestasis of pregnancy. Zhonghua Fu Chan Ke Za Zhi 39:217–220.

Anderson AB, Turnbull AC. 1968. Spontaneous contractility and oxytocin sensitivity of the human uterus in mid-pregnancy. Journal of Obstetrics and Gynaecology of the British Commonwealth 75:271–277. Beuers U, Pusl T. 2006. Intrahepatic cholestasis of pregnancy—a heterogeneous group of pregnancy-related disorders? Hepatology 43: 647–649. Ch’ng C L, Morgan M, Kingham JGC. 2003. Prospective study of obstetric cholestasis in South Wales. Journal of Obstetrics and Gynaecology 23:S44. 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. Heikkinen J, Ylöstalo P, Mäentausta O, Jänne O. 1983. Bile acids in maternal serum, umbilical cord serum and amniotic fluid of healthy women, women with pruritus and patients with intrahepatic cholestasis of pregnancy. Journal of Obstetrics and Gynaecology 4:17–20. Katz M, Gill PJ, Newman RB. 1986. Detection of preterm labour by ambulatory monitoring of uterine activity: a preliminary report. Obstetrics and Gynecology 68:773–778. Mullally BA, Hansen WF. 2002. Intrahepatic cholestasis of pregnancy: review of the literature. Obstetrical and Gynecological Survey 57:47–52. Sepúlveda WH, González 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. Simpson LL. 2002. Maternal medical disease: risk of antepartum fetal death. Seminars in Perinatology 26: 42–50. Smyth CN. 1957. The guard-ring tocodynamometer; absolute measurement of intra-amniotic pressure by a new instrument. Journal of Obstetrics and Gynaecology of the British Empire 64:59–66. Welch RA, Martin RW, Gookin KS, Knuppel RA, Lake MF, Hill WC et al. 1990. Relationship of uterine contractility to preterm labor. Obstetrics and Gynecology 76:36S–38S.

Uterine contractility in intrahepatic cholestasis of pregnancy.

This study aims to compare uterine activity in intrahepatic cholestasis of pregnancy (ICP) patients vs normal pregnancies, and to determine the releva...
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