Contributed equally
The effects of intrahepatic cholestasis of pregnancy (ICP) on hepatic function, changes of inflammatory cytokines and fetal outcomes were studied. In total, 663 pregnant women admitted to Daqing Longnan Hospital from July 2016 to December 2017 were selected. There were, 40 cases with ICP enrolled in the observation group, and 40 normal pregnant women were recruited in the normal group. They were also grouped according to hepatic function and inflammatory cytokines, with 40 cases in each group. Neonatal Apgar scores were recorded. The correlations of serum cholylglycine (CG) in pregnant women with umbilical artery systolic-to-diastolic (S/D) ratio in the third trimester of pregnancy, the alanine aminotransferase level, the high-sensitivity C-reactive protein (hs-CRP) level, neonatal Apgar score and gestational week were analyzed. The birth weight in the observation group was lighter than that in the normal group (P<0.05); the gestational week at birth was earlier than that in the normal group (P<0.05); Apgar score at birth was lower than that in the normal group (P<0.05), and the levels of inflammatory cytokines were higher than those in the control group (P<0.05). Apgar scores of newborns at birth and at 1 and 5 min after birth in the normal hepatic function and normal inflammatory cytokine groups were higher than those in the abnormal hepatic function group (P<0.05). The serum CG level in pregnant women was positively correlated with umbilical artery S/D ratio, the alanine aminotransferase level and the hs-CRP level in the third trimester of pregnancy, but negatively correlated with neonatal Apgar score and gestational week. Among patients with ICP, the higher the GG level in the body is, the higher the alanine aminotransferase, inflammatory cytokine and umbilical artery S/D ratio will be, which may cause lower neonatal Apgar score, neonatal asphyxia and premature delivery.
Intrahepatic cholestasis of pregnancy (ICP) is a specific disease during pregnancy, its clinical manifestations include cutaneous pruritus, formation of jaundice and abnormal hepatic function (
Currently, the treatment for ICP is mainly symptomatic support measures. Fetal development condition is closely monitored, and manual intervention is implemented to terminate pregnancy (
A total of 663 pregnant women admitted to Daqing Longnan Hospital (Daqing, China) from July 2016 to December 2017 were selected, and patients complicated with inflammatory diseases of the liver resulted from various factors, gestational diabetes, gestational hypertension, mental disease or abnormal coagulation function, those with thyroid dysfunction during pregnancy, those previously receiving liver- or gall-related operations, or long-term drinkers were excluded. At the same time, according to the diagnostic criteria for ICP in the Obstetrics and Gynecology (7th edition) published in the People's Medical Publishing House (China) (
All the patients and their family members signed the inclusion consent, and this study was approved by the Ethics Committee of the Daqing Longnan Hospital. These patients were aged 19–40 years with an average of 29.5±0.3 years. Times of pregnancy: 25 cases of primiparity, 15 cases of re-pregnancy and 10 cases who had previously undergone cesarean section. Additionally, 40 patients with normal pregnancy aged 19–40 years with a mean age of 29.6±0.3 years were selected as the normal group. Times of pregnancy: 26 cases of primiparity, 14 cases of re-pregnancy and 9 cases who had previously undergone cesarean section. There were no statistically significant differences in age, times of pregnancy and whether they had received previous cesarean section between the two groups (P>0.05). Comparisons of birth weight, gestational week at birth, Apgar score at birth, grade II or above amniotic fluid contamination, intrauterine fetal distress and neonatal jaundice between the two groups are detailed in
Differences in age, times of pregnancy and a history of implementation of cesarean section between the two groups were not statistically significant (P>0.05). In addition, according to whether inflammatory cytokines [with high-sensitivity C-reactive protein (hs-CRP) as the standard] were increased, the patients were divided into two groups. There were 40 patients with normal inflammatory cytokines aged 19–40 years with an average of 29.5±0.5 years included in the normal inflammatory cytokine group. Times of pregnancy: 28 cases of primiparity, 12 cases of re-pregnancy and 12 cases who had previously received cesarean section. Forty patients with abnormal inflammatory cytokines aged 19–40 years with an average age of 29.6±0.5 years were included into the abnormal inflammatory cytokine group. Times of pregnancy: 29 cases of primiparity, 11 cases of re-pregnancy and 13 cases who had previously received cesarean section. There were no statistically significant differences in age, times of pregnancy and implementation rate of cesarean section between the two groups (P>0.05).
All the included patients were given low-flow oxygen, local antipruritic or corticosteroid treatment. Reduction of the concentration of bile acids (ursodeoxycholic acid), vitamin K supplement, vascular dilation, liver protection and other symptomatic support treatments. Regular fetal heart rate monitoring and amniotic fluid index test were carried out. In addition, the levels of bile acid and serum CG in pregnant women and hepatic function of patients were regularly reviewed. Fetal lung maturation was closely monitored, and if necessary, cesarean section was implemented to terminate pregnancy based on the patient's CG level combined with fetal monitoring results. The normal control group was treated with routine pregnancy and delivery.
The relevant data of newborns such as birth weight, gestational week at birth and Apgar score at birth, intrauterine and postpartum conditions such as the occurrence of grade II or above amniotic fluid contamination, intrauterine fetal distress and the proportion of neonatal jaundice, the levels of inflammation-related cytokines such as hs-CRP, interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), and Apgar scores at birth, and at 1 and 5 min after birth of newborns delivered by patients with different hepatic functions and different inflammatory cytokine levels were compared between the observation and control groups. The correlation of the level of CG in pregnant women with umbilical artery systolic-to-diastolic (S/D) ratio in the third trimester of pregnancy during antenatal inspection, the alanine aminotransferase level, the hs-CRP level, neonatal Apgar score and gestational week were analyzed.
Apgar score: Apgar score of newborns at birth was assessed in this study. The evaluation criteria included five items: skin color, heart rate pulse, respiratory rate, muscular tone and motor ability, and nerve reflex. The overall score ranged from 0 to 10 points. The total score below 7 points represented neonatal asphyxia and that below 4 points severe neonatal asphyxia. Amniotic fluid contamination was divided into 3 grades: grade I with light green amniotic fluid, grade II with dark green or yellow-green amniotic fluid and grade III with brownish yellow and viscous amniotic fluid. Intrauterine fetal distress was diagnosed according to the potential of hydrogen (pH) value of preserved umbilical venous blood during fetal labor to determine the delivery of infants. The pH value of umbilical venous blood below 7.25 indicated the presence of intrauterine fetal distress. Blood CG (3.2 µg/ml) in pregnant women was detected via the latex-enhanced immunoturbidimetry. The normal value of umbilical artery S/D ratio in the third trimester of pregnancy, i.e., the ratio of end-systolic peak (S) to end-diastolic peak (D) of umbilical artery is generally below 3. Alanine aminotransferase (0-40 U/l) was detected via Lai colorimetry. Inflammation-related cytokines including hs-CRP (latex-enhanced immunoturbidimetry, normal value in serum≤10 mg/l, cat. no. M020801; So-Fe Biomedicine, Co., Ltd., Shanghai, China), IL-6 (enzyme-linked immunosorbent assay, normal value in serum: 0.37–0.46 ng/l; cat. no. KE00007; ProteinTech Group, Inc., Wuhan, China) and TNF-α (spectrophotometry, normal value in serum: 5–100 ng/l; cat. no. 17590-1-AP; ProteinTech Group, Inc.) were tested.
Statistical Product and Service Solutions (SPSS) 21.0 (IBM Corp., Armonk, NY, USA) was adopted for statistical analysis. Measurement data were expressed as mean ± standard deviation (mean ± SD). The mean values, such as birth weight, gestational week and Apgar score at birth, were compared using the t-test. The percentages, such as grade II or above, amniotic fluid contamination, intrauterine fetal distress and neonatal jaundice percentages were compared between groups using the χ2 test. Spearmans correlation analyses of the serum CG level with umbilical artery S/D ratio in the third trimester of pregnancy during antenatal inspection, the level of alanine aminotransferase, the level of hs-CRP, neonatal Apgar score and gestational week were performed using the correlation coefficient method. P<0.05 was set as the statistically significant difference.
The birth weight of the observation group was lighter than that of the normal group (P<0.05), the gestational week at birth was earlier than that of the normal group (P<0.05), and Apgar score at birth was lower than that of the normal group (P<0.05) (
The proportions of grade II or above amniotic fluid contamination, intrauterine fetal distress and neonatal jaundice in the observation group were significantly higher than those in the normal group (P<0.05) (
The levels of hs-CRP, IL-6 and TNF-α among the inflammation-related cytokines in the observation group detected at the time of inclusion were notably higher than those in the control group (P<0.05) (
Apgar scores of newborns at birth and at 1 and 5 min after birth in the normal hepatic function group were evidently higher than those in the abnormal hepatic function group (P<0.05) (
Apgar scores of newborns at birth and at 1 and 5 min after birth in the normal inflammatory cytokine group were higher than those in the abnormal inflammatory cytokine group (P<0.05) (
The level of serum CG in pregnant women with ICP was positively correlated with umbilical artery S/D ratio in the third trimester of pregnancy during antenatal inspection (r=0.8508, P<0.001) (
ICP is a distinctive disease in the second and third trimesters of pregnancy, mainly manifested as pruritus, jaundice and abnormal hepatic function (
In the present study, all patients with cholestasis of pregnancy were treated with general prescription for ICP. Related conditions of newborns were compared between the two groups, and it was found, respectively, that birth weight, gestational week at birth and Apgar score at birth in the observation group were lighter, earlier and lower than those in the normal group, indicating that newborns delivered by these patients with ICP have lighter weight, earlier gestational week and lower birth Apgar scores. Additionally, comparisons of intrauterine and postpartum conditions between the two groups revealed that the incidence rates of grade II or above amniotic fluid contamination, intrauterine fetal distress and neonatal jaundice in the observation group were significantly higher than those in the normal group, further suggesting that the incidence rates of amniotic fluid contamination, intrauterine fetal distress and neonatal jaundice are obviously increased in patients with ICP. Comparison of the levels of inflammation-related cytokines between the two groups manifested that the levels of hs-CRP, IL-6, and TNF-α among the inflammation-related cytokines in the observation group detected at the time of inclusion were markedly higher than those in the control group, indicating that the levels of inflammatory cytokines in patients with normal hepatic function are significantly lower than those in patients with abnormal hepatic function. In addition, the study on changes in Apgar scores of newborns delivered by patients with different hepatic functions and different inflammatory cytokine levels demonstrated that Apgar scores of newborns at birth and at 1 min and 5 min after birth in the normal hepatic function and normal inflammatory cytokine groups were higher than those in the abnormal hepatic function group. This suggests that the hepatic function and the
The high-level cholic acid, especially high CG, in pregnant women with ICP, may cause the shrinkage of the placental villus (
In conclusion, in patients with ICP, as the level of CG in the body is increased, the levels of alanine aminotransferase and hs-CRP in pregnant women and umbilical artery S/D ratio are significantly increased. Moreover, this leads to lower Apgar score of newborns, neonatal asphyxia, shortened gestational week and premature birth.
Not applicable.
No funding was received.
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
LW and ZL collected the general data of patients and were responsible for patient treatment. XZ and YD recorded and analyzed the observational indexes. LG helped with Apgar score analysis. All authors have read and approved the final manuscript.
The study was approved by the Ethics Committee of Daqing Longnan Hospital (Daqing, China) and informed consents were signed by the patients and/or guardians.
Not applicable.
The authors declare that they have no competing interests.
Correlation analysis of the serum CG level in pregnant women with umbilical artery S/D ratio in the third trimester of pregnancy during antenatal inspection. The level of serum CG in pregnant women is positively correlated with umbilical artery S/D ratio in the third trimester of pregnancy during antenatal inspection (P<0.05).
Spearmans correlation analysis of the level of serum CG in pregnant women with ICP with changes in the level of alanine aminotransferase. The level of serum CG in pregnant women with ICP is positively related to the level of alanine aminotransferase (P<0.05).
Spearmans correlation analysis of the level of serum CG in pregnant women with ICP with changes in the level of hs-CRP. The level of serum CG in pregnant women with ICP is positively correlated with the level of hs-CRP (P<0.05).
Spearmans correlation analysis of the level of serum CG in pregnant women with ICP with neonatal Apgar score. There is a negative correlation between the level of serum CG in pregnant women with ICP and neonatal Apgar score (P<0.05).
Correlation analysis of the level of serum CG in pregnant women with ICP with gestational week. There is a negative relationship between the level of serum CG in pregnant women with ICP and gestational week (P<0.05).
Comparisons of relevant data between the two groups of newborns (mean ± SD).
Variables | Birth weight (g) | Gestational week at birth (week) | Apgar score at birth (point) |
---|---|---|---|
Observation group | 2,156.5±26.1 | 34.1±1.1 | 6.2±0.3 |
Normal group | 3,158.9±33.6 | 38.9±1.2 | 8.2±0.4 |
t value | 149.009 | 18.649 | 25.298 |
P-value | <0.001 | <0.001 | <0.001 |
Comparison of intrauterine and postpartum conditions between the groups (n).
Variables | Grade II or above amniotic fluid contamination | Intrauterine fetal distress | Neonatal jaundice |
---|---|---|---|
Observation group | 29 | 30 | 31 |
Normal group | 1 | 2 | 1 |
t value | 38.880 | 37.969 | 43.802 |
P-value | <0.001 | <0.001 | <0.001 |
Comparison of the levels of inflammation-related cytokines between the groups (mean ± SD).
Variables | hs-CRP (mg/l) | IL-6 (ng/l) | TNF-α (ng/l) |
---|---|---|---|
Observation group | 13.6±0.7 | 0.68±0.1 | 146.5±8.3 |
Normal group | 8.5±0.4 | 0.43±0.1 | 83.2±6.6 |
t value | 40.008 | 11.180 | 37.753 |
P-value | <0.001 | <0.001 | <0.001 |
Changes in Apgar scores of newborns with different hepatic functions (point, mean ± SD).
Variables | At birth | At 1 min after birth | At 5 min after birth |
---|---|---|---|
Normal hepatic function group | 8.2±0.4 | 8.5±0.5 | 9.1±0.3 |
Abnormal hepatic function group | 6.2±0.3 | 6.6±0.4 | 7.1±0.2 |
t value | 40.008 | 18.767 | 35.082 |
P-value | <0.001 | <0.001 | <0.001 |
Changes in Apgar scores of newborns with different levels of inflammatory cytokines (point, mean ± SD).
Variables | At birth | At 1 min after birth | At 5 min after birth |
---|---|---|---|
Normal inflammatory cytokine group | 8.3±0.4 | 8.5±0.5 | 9.2±0.3 |
Abnormal inflammatory cytokine group | 6.4±0.3 | 6.7±0.4 | 7.0±0.2 |
t value | 24.033 | 17.779 | 38.591 |
P-value | <0.001 | <0.001 | <0.001 |