Mother ’ s intrahepatic cholestasis does not affect her daughter ’ s health

Objective: To establish whether a mother’s intrahepatic cholestasis of pregnancy (ICP) has connections to her daughter’s health. Design: A retrospective study of daughters to ICP mothers. Setting: The region of Tampere University Hospital in Finland. Subjects: The study population comprised 575 women diagnosed with ICP during at least one pregnancy in the obstetric department of Tampere University Hospital in the period 1969-1988, and two controls chosen for each. Questionnaires were sent to these women and to their daughters: 305 daughters to ICP mothers and 642 to controls in autumn 2010. Eventually 187 daughters to ICP mothers responded (61.3%) and 373 to controls (58.1%). Main Outcome Measures: Evaluated health, symptoms and complaints, diagnosed diseases, mental health and use of medicines. Results: Only minor differences were detected between the two groups regarding the majority of items inquired. The only prominent difference between daughters to ICP mothers and those to controls concerned epilepsy, which was significantly more frequent among ICP mothers’ daughters, the prevalence being fourfold (3.2% vs 0.8%, p = 0.033). Conclusion: A mother’s ICP does not generally affect her daughter’s health. This can be considered an encouraging new finding for mothers with ICP in primary health care.


INTRODUCTION
Intrahepatic cholestasis of pregnancy (ICP) is a liver disorder which usually manifests in the third trimester of gestation as skin itching especially on the palms and soles and as increased serum bile acids and transaminases [1].Shortly after delivery the itching attenuates and abnormal laboratory values normalize, but the disease nonetheless recurs in future pregnancies in about 40% -60% of patients [2].The incidence of ICP varies geographically; in Finland and in Europe in general the figure is approximately 1% of pregnancies [3].
The ultimate cause of ICP remains unknown but the condition appears to be related to increased sex hormone synthesis and metabolism during pregnancy [1,4].In addition to this hormonal component there would also appear to be heritable and environmental factors [5][6][7].ICP is more common in multiple pregnancies [8] and with a positive family history [9].Advanced maternal age has been identified as a risk factor [10].Selenium deficiency may be implicated in the pathogenesis of ICP [11].
ICP has no significant maternal effects during pregnancy (albeit itching can be intensive), but may have severe consequences for the fetus, including fetal distress, premature deliveries and intrauterine fetal death [1,12].Active management such as early delivery by induced labor at 37 -38 weeks gestation has been commonly recommended to prevent especially intrauterine fetal death [13].Although delivery often occurs at earlier weeks of gestation, the newborns' Apgar scores are only slightly lower than normally [14].
In the Nordic countries, maternity care is organized in primary health care [15].Serum aminotransferase levels are routinely measured for early detection of ICP if a pregnant woman has experienced itching, has a history of ICP or in cases of a multiple pregnancy [9].In Finnish maternity care ICP is generally detected and appropri-ately managed, being thus only a minor risk for mothers and their children, good pregnancy outcome normally being attained [14].
A positive correlation has been discovered between the severity of ICP and fetal complication rates; when maternal serum bile acids exceed 40 µmol/L, the incidence of fetal complications begins to increase significantly [16].Currently the best pharmacologic treatment for the condition seems to be ursodeoxycholic acid (UDCA) [17].In severe ICP, treatment with UDCA improves all biochemical markers of cholestasis in the mother, itching included.Dexamethasone is also sometimes used.However, it remains unknown whether fetal complications could be reduced by pharmacologic treatment.
Approximately one out of six ICP patients has a positive family history, and in such cases the levels of serum transaminases are higher than in sporadic cases and the recurrence rate in subsequent pregnancies is 92% [9].In addition, the widely varying prevalence of ICP between different countries and ethnic groups [3,13] indicates a genetic basis for the disease.
ICP would appear to have some long-term effects on women's health.There is an increased occurrence of a number of liver, biliary and pancreatic diseases among women with a history of ICP [18].In addition, a higher frequency of breast cancer and hypothyreosis has recently been discovered [19].Conversely, the frequency of hypertension, high cholesterol and cardiac arrhythmia is lower.
It has been proposed that the dominant mode of inheritance of ICP is either autosomal or X-chromosomelinked [20][21][22].Several different cholestatic genes are evidently associated with the pathogenesis [23][24][25].In view of the genetic predisposition to the disease, the aim of this study was to investigate whether a mother's ICP has connections to her daughter's health.

MATERIAL AND METHODS
To assess the health history of women who had suffered from ICP, a postal survey was conducted among ICP patients and control women in autumn 2010.The cohort comprised 575 women who had been diagnosed with ICP during at least one pregnancy in the obstetric department of Tampere University Hospital in the period 1969-1988, and two control women chosen for each [19].
At the same time, a slightly different questionnaire was sent to the daughters of these women.Postal addresses were obtained from the Population Register Centre in Finland.After excluding 11 stillborn and seven deceased daughters as well as 60 whose addresses could not be obtained, the questionnaire was sent to 947 daughters (305 to ICP and 642 to control mothers' daughters); 187 daughters to ICP mothers (61.3%) and 373 to controls (58.1%)responded (Figure 1).
While categorizing the respondents' age, 30 years was set as a cut-off point.Education was classified as "high" for those who had taken the matricular examination (gymnasium/grammar school) and "low" for those who had not.Concerning respondents' BMI, 25 kg/m² was set as a cut-off point.With respect to age, educational level and body mass index (BMI) the two groups were comparable (Table 1).
The two groups received identical questionnaires.The questionnaire comprised 65 items and the main aspects pertinent to this study were present health, symptoms and complaints, diseases diagnosed by a doctor, use of medicines and mental health.Respondents were asked to evaluate their current health by choosing one of the following alternatives: good, fairly good, moderate, fairly poor and poor [19].They were also asked whether any of 24 common symptoms or complaints had bothered them during the past year.Further, they were asked whether a doctor had ever diagnosed any of the diseases listed in the questionnaire, including gastrointestinal, endocrinological, urological, gynecological, oncological, bone-and articulation-related, respiratory and cardiovascular diseases.A few separate disorders were also listed, for example migraine, epilepsy and anemia.Respondents were further asked whether they had ever undergone any major medical surgery, and a history of hip, wrist and vertebral fractures was inquired after.
Respondents' mental health was estimated by two mental health-related questions and the Depression Scale.The two questions were devised to establish whether a respondent had ever suffered from a mental disorder and been treated for a mental disorder.The Depression Scale is a validated Finnish test screening for the risk of present clinical depression [26].
Use of medicines, natural health drugs as well as vitamins and trace elements during the last 12 months were inquired after.Three options were given for the mode of use: non-use, occasional use and regular use.
Statistical analyses were made using the SPSS System for Windows, release 20.0.Results are presented as frequencies and percentages.Statistical significance was tested by the chi-squared test.

RESULTS
The two groups did not differ in respect of respondents' own evaluation of their current health status.Of ICP mothers' daughters 87.1% and of controls' daughters 86.0% assessed their health as good or fairly good.Symptoms and complaints are shown in Table 2 and diagnosed diseases in Table 3.
There were only minor differences between the two  A prominent difference between daughters of ICP mothers and those of controls concerned epilepsy, which was significantly more frequent among ICP mothers' daughters, the prevalence being fourfold (3.2% vs 0.8%, p = 0.033).

DISCUSSION
There were only minor differences between the two groups regarding most of the survey questions.The main finding was a higher frequency of epilepsy among daughters to ICP mothers, the difference being fourfold.
Postal addresses were found for the majority of the study population.Response rates did not differ markedly between the groups (61.3% and 58.1%) and they were relatively high for a postal survey.Data were collected by a questionnaire to be filled in at home.As most of the respondents were relatively young, a better response rate might have been achieved by an online survey.
Since we only studied daughters we cannot generalize the findings to apply also to the sons of ICP mothers.However, the majority of the diseases observed in this study were not gender-dependent.Antenatal corticosteroids are sometimes administered in ICP [17], and also to women expected to deliver preterm because they reduce the newborn's respiratory and cardiac problems [27].However, corticosteroids have increased the risk of epilepsy especially among male infants.Neuro-sensory development seems to be more sensitive to external factors in the fetal life of boys than of girls.
Although higher frequencies of several liver, biliary and pancreatic diseases, breast cancer and hypothyreosis have been discovered among women with a history of ICP, this was not the case regarding their daughters.However, by reason of the considerable age difference between mothers and daughters at the time of the postal survey, the two groups cannot be compared with each other as to the incidence of the above-mentioned conditions.On the other hand, at least hypothyreosis often emerges at a relatively young age.
It may be speculated that epilepsy can be the result of fetal distress or premature delivery, though there are con-tradictory study results concerning such a hypothesis.Recently it has been noted that very premature birth and perinatal distress have associations with epilepsy [28] and that preterm infants have higher rates of seizures than full-term infants [29].Conversely, it has been also claimed that low birth weight and fetal distress do not cause epilepsy [30].
To our knowledge this is the first study to explore the association between mothers' ICP and their daughters' health in later life.Based on our findings a mother's ICP will not affect her daughter's health.It has recently been reported that women with a history of ICP have, in most cases unnecessarily, limited their number of children for health reasons more often than women without ICP, and they also more often have a single child compared to controls [31].
Pregnancy follow-up and screening ICP takes place at maternity clinics in primary health care.Based on the findings here, our conclusion is that healthcare professionals can reassure mothers with ICP that the condition does not generally have any long-term adverse effects on their daughters' health in later life.

Figure 1 .
Figure 1.Flow chart of the survey population.

Table 1 .
Characteristics of daughters to ICP mothers and to controls.

Table 2 .
Symptoms and complaints during the past 12 months among daughters to ICP mothers and to controls.

Table 3 .
Diseases diagnosed by a doctor among daughters to ICP mothers and to controls.