PEDIATRICS Vol. 117 No. 5 May 2006, pp. 1669-1672 (doi:10.1542/peds.2005-1801)
Intrahepatic Cholestasis of Pregnancy and Neonatal Respiratory Distress Syndrome
a Department of Pediatrics, Division of Neonatology
b Department of Obstetrics and Gynecology, Catholic University of the Sacred Heart, Rome, Italy
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONREFERENCES |
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OBJECTIVES. We sought to verify the association between maternal intrahepatic cholestasis of pregnancy (ICP) and neonatal respiratory distress syndrome (RDS) and to determine how bile acids levels alter the risk of developing neonatal RDS.
METHODS. We extracted data from our divisional database about all of the newborns born during the years 2000–2004. We compared 77 neonates born from pregnancies complicated by ICP with 427 neonates in the same range of gestational age born from noncomplicated pregnancies. We studied maternal bile acids levels immediately before delivery in mothers with ICP and measured bile acid levels during the first 24 hours of life in their newborns.
RESULTS. The incidence of RDS in newborns from cholestatic pregnancies was twice that the reference population (28.6% vs 14%). The multivariate analysis showed that the risk of RDS in these newborns was 
2.5 times higher than in control infants. Within the ICP group, maternal and neonatal bile acid levels of infants affected by RDS were not significantly higher than those of healthy infants. The multivariate analysis showed that a low gestational age was the most important risk factor, but the probability of respiratory distress syndrome also increased by 2
for every additional micromole of the interaction term "neonatal by maternal bile acids level."
CONCLUSIONS. Maternal ICP is significantly associated with the occurrence of RDS in the newborn. We hypothesize that bile acids can produce surfactant depletion in the alveoli reverting the reaction of phospholipase A2. This hypothesis could potentially be confirmed by bronchoalveolar lavage study.
Key Words: bile acid pneumonia • respiratory distress syndrome • pregnancy complications
Abbreviations: ICP—intrahepatic cholestasis of pregnancy • BA—bile acid • RDS—respiratory distress syndrome
Intrahepatic cholestasis of pregnancy (ICP) is a clinical syndrome of unknown pathophysiology, characterized by generalized pruritus and biochemical cholestasis, occurring during the second half of pregnancy and persisting until delivery.1 The incidence of ICP varies from 0.1% to 1.5% of pregnancies in Europe, North America, and Australia and from 9.2% to 15.6% in South American countries such as Bolivia and Chile.2 ICP may seriously impair the placental clearance of fetal bile acids (BAs), leading to a dangerous accumulation of these compounds within the fetus and the newborn.3 The elevation of maternal serum BA is thought to be the most appropriate biochemical parameter for diagnosing the ICP.4 This syndrome has been associated with increased fetal distress, premature delivery, perinatal mortality, and morbidity, but no adverse outcomes have been reported in the newborn, apart from 1 infant dead in the first hour after birth because of asphyxia.1–4 We have recently described 3 cases of respiratory distress syndrome (RDS) in near-term newborn infants in which the most common etiologies were excluded, and a causative role of BA was supposed, leading to the diagnosis of "BA pneumonia."5 In our article, we hypothesized that ICP and the abnormally high BA levels could have reversed the action of phospholipase A2 in the alveoli of our infants, causing a degradation of phosphatidylcholines to lysophosphatidylcholines, the relative lack of surfactant activity, and the consequent RDS.5
Therefore, we performed this retrospective study to establish the incidence of neonatal RDS after pregnancies complicated by ICP and to clarify whether neonatal RDS is associated with maternal ICP. The secondary aim of this study was to investigate whether neonatal RDS is related to the BA levels of the mother and/or the newborn.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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We conducted a retrospective cohort study extracting data from our divisional database about all newborns from pregnancies complicated by ICP born during the years 2000–2004. The control group consisted of infants born from women without any signs of ICP. Cases and controls were matched for gestational age (within 1 week) and date of delivery (within 3 months). Exclusion criteria included premature rupture of membranes, diabetes, and eclampsia. Infants with Apgar scores of <7 at 5 minutes, evidence of liver disease, or severe congenital malformations were also excluded. Gestational age estimate was based on postmenstrual date corrected by early gestation prenatal sonographic findings. ICP was diagnosed when plasma BA levels
10 µmol/L were associated with diffuse pruritus during the second half of gestation without any skin or other medical conditions known to be associated with pruritus.6 When ICP was diagnosed, the women underwent treatment with S-adenosyl-L-methionine (Samyr, Abbot Laboratories, Chicago, IL). Ursodeoxycholic acid (Deursil, Sanofi-Synthelabo, Milan, Italy) was added when BA level was >20 µmol/L.7–9 BA levels were measured weekly, and the last BA level detected before delivery has been considered for the purpose of this study. A blood sample was drawn from study group infants in the first 24 hours of life, and BA levels were measured. Total plasma BAs were analyzed with an enzymatic, colorimetric method (Enzabile, Biostat Diagnostic Systems, Stockport, United Kingdom).
Antenatal corticosteroids were administered in the form of one 12-mg intramuscolar dose of betamethasone, followed by a second dose 24 hours later, whenever delivery was expected to occur before week 34 of pregnancy. Neonatal RDS was defined as clinical signs of respiratory distress needing oxygen and nasal continuous positive pressure or mechanical ventilation with the typical radiograph appearance.10
Proportions were compared by 
2 analysis, whereas continuous variables were contrasted by the Student's t test. Gestational age was compared using the Mann-Whitney U test, because its distribution was not normal. Correlation between maternal and neonatal BA levels was estimated using Pearson's technique. Factors influencing the incidence of neonatal RDS in the whole population were analyzed with backward-stepwise logistic regression. Variables included in the model were gestational age, antenatal steroids, gender, and diagnosis of ICP. Factors possibly affecting the RDS occurrence in ICP newborns were also analyzed with backward stepwise logistic regression. In this case, variables included in the models were gestational age, antenatal steroids, gender, and the interaction term "neonatal BA level by maternal BA level," which is the product of neonatal BA level multiplied by the maternal BA level. Data were analyzed using SPSS 11.01 for Windows (SPSS Inc, Chicago, IL), and P < 0.05 was considered to be statistically significant.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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The prevalence of ICP among patients delivered at our institution during the study period was 0.8%. We included 77 infants from mothers with ICP and 427 control infants in this study. Indications for cesarean section were: nonreassuring cardiotocography (ICP: 46%; controls: 60%), previous cesarean section (ICP: 26%; controls: 21%) and maternal pathology (ICP: 8%; controls: 19%). Eight cesarean sections (20%) in the ICP group were electively performed because of severe cholestasis.
General characteristics of the 2 groups are reported in Table 1. Control infants had a lower gestational age and birth weight, whereas the incidence of males, cesarean section, and antenatal steroids treatment was not different. The percentage of infants delivered at <34 weeks' gestational age was 22.4% in the ICP group and 18.7% in the control group. The incidence of RDS was significantly higher in infants born from mothers with ICP (28.6% vs 14.1%; P = .001). Surfactant was administered to 24.6% of infants in the ICP group and to 12.2% of infants in the control group (P = .001). The mean BA level detected before delivery in women with ICP was 25.0 ± 17.8 µmol/L, whereas BA levels in the unaffected population of mothers and infants were not measured. Unfortunately, the interval between last maternal BAs level and delivery had a wide range between 1 day and 1 week.
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The multivariate analysis for factors affecting the RDS occurrence in the whole studied population is reported in Table 2. Among the studied factors, antenatal steroids did not reach the significance threshold, whereas the logistic regression confirmed that newborns from mothers with ICP have a risk of RDS occurrence significantly higher than control infants (P = .001). Gestational age (P = .024) and male gender (P = .037) were also significantly associated with the RDS occurrence.
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Within the ICP group, 22 infants were affected by RDS. They had a lower mean gestational age compared with healthy infants (34.2 ± 1.6 vs 36.2 ± 2.2 weeks; P < .01), but the rate of antenatal steroids treatment was not different (31% vs 26%).
Looking for factors possibly influencing the RDS occurrence in infants from mothers with ICP, the univariate analysis showed that the mothers of infants subsequently affected by RDS had BA levels not significantly higher than those who delivered healthy infants (29.6 ± 21.5 vs 23.5 ± 16.2 µmol/L; P = .157) and that the newborns affected by RDS had BA levels not significantly higher than healthy ones (52.5 ± 38.5 vs 44.8 ± 35.2 µmol/L; P = .450). Moreover, the correlation between maternal and neonatal BA levels was poor (r = 0.195; P = .278).
The multivariate analysis within the ICP group (Table 3) showed that gestational age (P = .014) and the BA interaction term (P = .042) were significantly associated with the risk of RDS, whereas antenatal steroids and gender were not significant. The RDS risk increases by 2 for every additional micromole of BA interaction term. Both logistic regressions well fit the data as demonstrated by the results of Hosmer-Lemeshow's goodness-of-fit statistic.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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ICP may lead to premature births in up to 60%, fetal distress in up to 33%, and intrauterine death in
2% of patients.2 To our knowledge, this is the first study demonstrating an association between maternal ICP and neonatal RDS. We compared a group of infants born from pregnancies complicated by ICP with a group of infants born from pregnancies without any sign of ICP in which other complications known to decrease fetal lung maturity have also been excluded. Although control infants have been selected in the same range of gestational age as infants from mothers with ICP, their mean gestational age and birth weight were lower. Nevertheless, we found that the incidence of RDS in infants from mothers with ICP was almost double that of control infants. The multivariate analysis shows that the risk to develop neonatal RDS is 2.5 times higher if the pregnancy is complicated by ICP. Considering our whole population of mild preterm and near-term infants, ICP seems to be the main risk factor for neonatal RDS, together with gestational age. It is unknown whether the effect of BA on neonatal lung could be because of bile aspiration from the amniotic fluid or the uptake from circulation. The former seems unlikely, because BA levels in the amniotic fluid do not correlate with perinatal morbidity.11 BA uptake from the circulation can be more probable, because the fetus is affected by a physiologic cholestasis, producing large amounts of circulating BA. These compounds cross the placenta mostly in the fetomaternal direction. The impaired maternal clearance produced by ICP can limit the passage of BA from fetus to maternal circulation thereby inducing a further elevation of BA levels in the fetal circulation,3, 12, 13 and high BA levels in the neonates could easily pass to the alveoli.
How can maternal ICP cause neonatal RDS? We have recently reported 3 near-term infants affected by what we called "BA pneumonia" in which a complete resolution of the RDS was obtained after 48 hours from surfactant treatment.5 Our speculation is that high BA levels in the fetus act to drive the phospholipase A2 reaction in the opposite direction from that expected in the lung. Phospholipase A2 plays a crucial role in the synthesis of surfactant in the lung, but in the gut it catalyzes the reverse reaction, favoring the hydrolyzation of long-chain phosphatidylcholines to their lysophosphatidylcholines. The direction in which this reaction proceeds is mainly determined by the bile/phospholipids ratio.14, 15 Reversing the action of phospholipase A2 can, therefore, produce a relative lack of surfactant activity in the alveoli, despite the degree of lung maturity achieved at this time of gestation.5 This hypothesis is indirectly confirmed by the work of Kaneko et al,16 who demonstrated microscopic findings of hyaline membranes and widespread atelectasis after intratracheal BA instillation in rabbits. These authors speculated that BA inhibited surfactant activity, because their findings disappeared when the rabbits were treated with exogenous surfactant. Another possible mechanism could be a direct chemical damage of the alveolar epithelium produced by BA, as proposed in animal studies.17
Like other authors,18 we were unable to demonstrate a direct correlation between maternal and neonatal BA levels because of the complexity of fetomaternal BA kinetics. Within the ICP group, we could not find significant differences among BA levels in mothers of newborns with or without RDS. This can be one of the limits coming from the retrospective design of our study. One possible explanation stays in the limited number of cases. A second possible explanation is that the interval between last maternal BA level and delivery varied between 1 day and 1 week. Finally, it is possible that the duration of exposure is more important than BA levels in increasing the RDS risk. For these reasons we entered the interaction term "neonatal BA levels by maternal BA levels" in the multivariate model in the attempt to find a numeric predictor of the risk of neonatal RDS associated with maternal ICP. Glantz et al1 showed that the probability of fetal complications increased by 1% to 2% per additional micromole of maternal BA.1 We just found that the RDS probability increases by 2 for every additional micromole of BA interaction term. This result is close to the limit of statistical significance and needs to be verified in a larger population.
Our study has some limitations: the retrospective design, the small number of cases, and the absence of sufficient BA data to evaluate the patterns in maternal BA levels during pregnancy as a function of time. For these reasons, several questions are still open. Is there a cutoff value for BA in the mother or in the newborn for predicting the RDS occurrence? Is there a minimum intrauterine BA exposure time to trigger RDS? Is the response dependent on chronic elevation of fetal BA levels, or would brief, limited high BA levels induce similar illness? What is the mechanism of action of BA, and are there intermediates in the pathway? Histologic examination of lung tissue would be difficult to perform on our patients, but some help can probably come from bronchoalveolar lavage, and we mean to work on it. Our study demonstrates that ICP can play a significant role in the genesis of RDS in near-term and mild preterm infants and suggests that further studies on this interaction and its mechanisms of action are warranted.
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ACKNOWLEDGMENTS |
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We are grateful to Dr G. La Torre, from the Biostatistics Laboratory of the Institute of Hygiene, for statistical assistance.
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FOOTNOTES |
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Accepted Oct 19, 2005.
Address correspondence to Enrico Zecca, MD, Department of Pediatrics, Division of Neonatology, Catholic University of the Sacred Heart, Largo Agostino Gemelli 8, 00168 Rome, Italy. E-mail: enrizecca{at}rm.unicatt.it
The authors have indicated they have no financial relationships relevant to this article to disclose.
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