Abstract
Little is known about the effects of mother’s intrahepatic cholestasis of pregnancy (ICP) on the health of sons born to these mothers. The purpose of the present study was to explore the health of sons born to mothers with ICP. The study design was a retrospective study of ICP mothers’ sons. In the region of Tampere University Hospital in Finland, 365 sons of mothers with ICP during 1969 to 1988 and 617 sons of mothers without ICP were sent a questionnaire in 2010. The response rates were 37.8% (n = 138) and 36.6% (n = 226), respectively. Only minor differences were reported between the two groups. Self-evaluated health was similar. There were no significant differences between the groups regarding symptoms and complaints, diagnosed diseases, mental health, and use of medicines. Cough was 10.8 percentage points less common among ICP mothers’ sons than among controls (p = .034). Urticaria was more common among ICP mothers’ sons, the difference in percentage points being 2.2 (p = .026). In general, a mother’s ICP does not affect her son’s health.
Introduction
Men’s health is affected by genetic, environmental and exposure agents, and their health behavior. Factors during pregnancy and labor are associated with men’s health in adulthood (Curhan et al., 1996). Intrahepatic cholestasis of pregnancy (ICP) is a reversible liver disorder during pregnancy, where the bile flow is impaired (Lammert, Marschall, Glantz, & Matern, 2000). ICP usually manifests in the third trimester of pregnancy and is characterized by mother’s pruritus, especially on the palms and soles and an increase in serum bile acid and transaminases (Reyes, 1997). The incidence of ICP varies geographically and is 0.1% to 1.5% in Europe, United States, Canada, and Australia (Geenes & Williamson, 2009). In Finland, the incidence is approximately 1.0% to 1.5% (Laatikainen & Tulenheimo, 1984).
The etiology of ICP remains unknown, but the disorder seems to be related to hormonal factors (Reyes, 1997, 2008). It has been proposed that ICP may be inherited by the X-chromosome or is autosomal-linked, and a variety of genes influence its pathogenesis (Eloranta et al., 2003; Karlsen & Hov, 2010; Mullenbach et al., 2005; Noe et al., 2005; Pauli-Magnus et al., 2004; Reyes, Ribalta, & Gonzalez-Ceron, 1976). Adenosine triphosphate binding cassette, subfamily B, member 4 (ABCB4/abcb4) gene is associated in up to 15% of the ICP cases. This gene, also known as multidrug resistant protein 3 (MDR3), encodes a transporter for phospholipids across the canalicular membrane of liver hepatocytes (Pan & Perumalswami, 2011; Poupon, 2005). Environmental factors may also be involved (Lammert et al., 2000; Reyes, 2008).
ICP does not cause severe problems for a mother during pregnancy, although itching can cause insomnia and use of medications (Geenes & Williamson, 2009). ICP increases the risk of stillbirth, fetal distress, and preterm delivery (Alsulyman, Ouzounian, Ames-Castro, & Goodwin, 1996; Glantz, Marschall, & Mattsson, 2004), although Apgar scores have been only slightly lower for ICP mothers’ newborns (Turunen, Sumanen, Haukilahti, Kirkinen, & Mattila, 2010).
ICP appears to have some effects on the mothers’ long-term health. Women with ICP have been observed to more often have hypothyroidism and liver, biliary, and pancreatic diseases (Ropponen, Sund, Riikonen, Ylikorkala, & Aittomäki, 2006; Turunen, Mölsä, Helander, Sumanen, & Mattila, 2012). Likewise, more breast cancer is reported (Turunen et al., 2012). Epilepsy has been more frequent among the daughters of ICP mothers than among controls (Vimpeli, Turunen, Helander, Mattila, & Sumanen, 2013). The health of ICP mothers’ sons has not been studied previously.
In terms of clinical presentation, from the maternal viewpoint, the main consideration is intense pruritus, which may become so intolerable that delivery is considered as early as 35 to 37 weeks (Pathak, Sheibani, & Lee, 2010). For the fetus, there is concern for meconium staining of the amniotic fluid, fetal respiratory distress, intrauterine fetal demise, and sudden death postnatally. Due to increased incidence of cardiac, adrenal, and neurologic disorders perinatally, one might expect an increased incidence of diseases for men. In view of the genetic background and the fetal and obstetric risks associated with ICP, the present study sought to establish whether there is a connection between a mother’s ICP and her son’s health.
Material and Method
In autumn 2010, a postal survey was conducted among sons of women who had suffered from ICP. The cohort comprised 982 men, 365 of whom were sons of ICP mothers and 617 sons of control mothers. The diagnoses in the hospital discharge register that referred to ICP were verified. Criteria for ICP diagnosis were the main symptoms, itching and abnormal laboratory tests, and at least one of the following: aspartate aminotransferase >35 U/L, alanine aminotransferase >40 U/L, or bile acids ≥6 µmol/L. The mothers had been diagnosed with ICP during pregnancy in the obstetric department of Tampere University Hospital during the period 1969 to 1988, and two control women were chosen for each, namely, the previous and following parturient in the maternity ward diary (Turunen et al., 2012). Once these criteria were fulfilled, there were no more inclusion or exclusion criteria. Because this study only deals with men’s (not women’s) questionnaires, the cohort size is not fully 2:1.
Postal addresses were obtained from the Population Register Centre in Finland. Eight stillborns and 27 deceased sons were excluded together with 82 whose addresses were not found. Of ICP mothers’ sons 138 (37.8%) and of controls’ 226 (36.6%) responded (Figure 1).
Flow chart of the survey population.
Men’s mean age was 30 years, the minimum being 21 years and maximum 40 years. In categorizing the respondents’ age, 30 years was set as a cutoff point. Education was classified as “high” for those who had completed high school and “low” for those who had not. The respondents’ body mass index (BMI) was categorized and 25 kg/m² was set as a cutoff point. With respect to age and BMI, the two groups were comparable. The groups were not comparable as to education. There were more in the higher education group among sons of ICP mothers (63.0%) than of controls (46.2%; p = .002; see Table 1).
Characteristics of Sons of ICP Mothers and Controls.
Note. ICP = intrahepatic cholestasis of pregnancy; BMI = body mass index.
The two groups received identical questionnaires. The questionnaire was composed of 39 items; the main aspects relevant to this study being present health, symptoms and complaints, diseases diagnosed by a doctor, use of medicines, and mental health. Smoking and alcohol usage were assessed.
The respondents were asked to evaluate their present health by choosing one of the following alternatives: good, fairly good, moderate, rather poor, and poor. There were questions concerning symptoms and complaints during the past 12 months. Questions regarding diseases diagnosed by a doctor were asked, which focused on gastrointestinal, endocrine and metabolic, urinary tract, heart and circulatory system, respiratory diseases, musculoskeletal system, and connective tissue disorders. It was further asked if the respondent had been diagnosed with cancer, migraine, urticaria, epilepsy, or some significant injury or disease. Respondents were also asked whether they had undergone any major surgery or had ever suffered hip, wrist, or vertebral fractures.
Use of medicines, natural health drugs, and vitamins during the past year was assessed. Mental health was evaluated by two mental health-related questions and the Depression Scale. The questions concerned whether the respondent had suffered from a mental health disorder or had undergone treatment for a mental health disorder. The Depression Scale is a validated Finnish test screening for the risk of present clinical depression (Salokangas, Poutanen, & Stengård, 1995). Points in the Depression Scale differ from 0 to 30. If the result is 9 or more points, the probability of depression is clinically relevant and 12 or more points refers to quite probably a depression diagnosis.
This study had the consent of the Ethics Committee of Pirkanmaa Hospital District (R02149). Responding to the questionnaire was regarded as consent to the survey and the subjects were not compensated for responding. Statistical analyses were made using the SPSS System for Windows, release 22.0. Results are presented as frequencies and percentages. Statistical significance was tested by the chi-square test.
Results
The number of respondents was 365 in the group of ICP mothers’ sons and 617 in the group of controls’ sons. These were the base figures in percentage calculation. Table 2 presents symptoms and complaints during the past 12 months, Table 3 presents diagnosed diseases, and Table 4 presents medications used.
Symptoms and Complaints During the Past 12 Months Among Sons of ICP Mothers and Controls.
Note. ICP = intrahepatic cholestasis of pregnancy.
Diseases Diagnosed by a Doctor Among Sons of ICP Mothers and Controls.
Note. ICP = intrahepatic cholestasis of pregnancy.
Used Medications During the Past 12 Months Among Sons of ICP Mothers and Controls.
Note. ICP = intrahepatic cholestasis of pregnancy.
In general, there were only minor differences between the two groups. The two groups did not differ in respect to self-evaluated current health status. Of ICP mothers’ sons, 89.1% and of controls’ sons, 87.6% rated their health as good or fairly good.
The most common symptoms in both groups were backache, neck and shoulder pain, headache, and coughing. Of ICP mothers’ sons, 26.8% and of controls’ sons, 37.6% reported coughing during the past 12 months, the difference being 10.8 percentage points (p = .034). Otherwise, there were no significant differences between the groups with respect to other symptoms. Blushing, palpitation, and neck and shoulder pain were more common among ICP mothers’ sons in percentage points. In turn, nervousness, recurring stomach problems, sweating, and cough were more common among controls’ sons. Only concerning coughing was there a statistically significant difference, although the difference concerning blushing was close to significant (p = .053; see Table 2).
Among sons of ICP mothers, 52.2% and 65.9% of controls had smoked at least once in their life-time (p = .021). Currently, 29.7% of the ICP mothers’ sons smoked and 41.6% of controls’ sons, the difference being statistically significant (p = .023). There were no significant differences between the groups concerning smoking calculated in pack years. Of the ICP mother’s sons, 39.1% and 46.9% of controls’ sons smoked or had smoked regularly (p = .147). There was no difference between the groups regarding use of alcohol, number of used alcohol doses, or whether the respondent had ever considered reducing alcohol consumption.
There were only minor differences between the groups in respect to diagnosed diseases (see Table 3). Acute hepatitis and cholelithiasis were 1.4 percentage points more common among ICP mothers’ sons (p = .07). Migraine was the most common disease among ICP mothers’ sons with a prevalence of 8.7%. Some significant injury (6.5%), rise in liver function test results (6.5%), asthma (5.1%), kidney or urinary tract infection (5.1%), and cardiac arrhythmia (4.3%) were fairly common among ICP mothers’ sons. However, there were no significant differences between the groups.
Urticaria was the only disorder which was more common among ICP mothers’ sons. Altogether, 2.2% (n = 3) of ICP mothers’ sons and 0.0% (n = 0) of controls reported urticaria. The difference was statistically significant (p = .026). Diseases of the circulatory system were less common among ICP mothers’ sons, the findings not being statistically significant.
Of sons of ICP mothers, 12.3% and of controls, 12.4% had 9 or more points in the Depression Scale. ICP mothers’ sons, 5.1% and controls’, 6.2% had more than 12 points in the Depression Scale. Of the ICP mothers’ sons, 17.4% and 18.1% of controls had suffered from some mental health disorder or had have treatment for it, the difference being not statistically significant. Wrist, back, or hip fractures were reported by 10.1% of sons of ICP mothers and 9.3% of controls, the difference not being statistically significant.
The most used medicines among sons of ICP mothers were painkillers (89.1%), vitamins or trace elements (62.3%), asthma and antiallergic medication (23.9%), as well as gastric acid inhibitors (23.2%; see Table 4). Slightly more commonly, sons of ICP mothers had used painkillers (2.4 percentage points) and sleeping pills (2.3 percentage points) compared with sons of controls. A few more sons of controls had used dermatologic drugs (5.9 percentage points) and natural health drugs (4.7 percentage points). However, the differences were not statistically significant.
Discussion
The two groups evinced only minor differences in most of the survey questions. The main findings were a lower frequency of cough during the past 12 months and ever-smoking among ICP mothers’ sons and a higher incidence of urticaria among ICP mothers’ sons. A trend for increased blushing and heart palpitation complaints during the prior 12 months was reported. Moreover, there was a trend for increased incidence of physician-diagnosed acute hepatitis or cholelithiasis, although this cannot be regarded as clinically relevant.
The material received was relevant and sufficient for this kind of analysis. Postal addresses were found for most sons and response activity was fairly good; 37.8% of ICP mothers’ sons and 36.6% of controls’ sons responded. The response rates did not differ markedly between the groups. Data were collected by a questionnaire filled in at home. The respondents were fairly young and the response rate might have been higher if the questionnaire had also been available on the Internet.
The two groups were not comparable in respect of education levels. This may be linked to the observation that ICP mothers’ more often have only one child in their families (Mölsä, Turunen, Mattila, & Sumanen, 2012). It may be speculated that in families with one child parents encourage the child to aspire to a higher education. As the groups differed in education level, it may be concluded that the two might evince differences in lifestyle diseases, which might explain the difference in smoking and cough.
Although it has been presented that daughters of ICP mothers have a higher frequency of epilepsy (Vimpeli et al., 2013), this was not reported among the sons. The methodologies in the studies of the daughters and the sons were basically the same, and consequently the two studies and their results are comparable. Women with a history of ICP show higher frequencies of several liver, biliary and pancreatic diseases, breast cancer, and hypothyroidism, but this was not the case among the sons. The sons being relatively young, not all diseases may have been detected. Nevertheless, hypothyroidism often emerges at a relatively young age, albeit more rarely among men than women.
The frequencies of the diseases noted in our cohort are quite similar to those in the average population in Finland. The prevalence of migraine among working-age men in Finland is 11% (Rantala, Sumanen, & Mattila, 2007). Previously, the cough symptom of chronic bronchitis has been reported by 12% (Aromaa & Koskinen, 2004) and asthma was reported in 8% of men in the Health 2011 survey (Koskinen, Lundqvist, & Ristiluoma, 2012). In our study, the frequency of cough symptoms may have been higher due to respiratory diseases. Infectious respiratory disease were reported by 22% of 30- to 44-year-old men in the Health 2000 survey (Aromaa & Koskinen, 2004). In the Health 2000 survey, backache was reported during the previous month by an average of 30% of men of the same age as in this study. On average, 80% of men had had back pain at some time. In our study, back pain during the past year was assessed and the results can thus be considered congruent. A permanent injury or disability caused by an accident was reported by 13% to 18% of men under 55 years old (Aromaa & Koskinen, 2004). This rate was lower in our cohort. The rise in liver function tests may be caused by obesity, medication, and alcohol consumption. There was no significant difference between the groups in this context, although ICP manifests as a rise in liver function tests.
Urticaria was more common among ICP mothers’ sons than controls. This finding can be considered clinically irrelevant as the frequencies were low. It may be speculated that ICP mothers’ sons are conscious of their health and make appointments with a doctor more often as they have a higher education level.
ICP has a genetic background, and consequently it may be speculated whether the genome of the sons of ICP mothers is different from that of control mothers’ sons. The treatment of ICP mothers and the fetal outcome did not appear to be associated with sons’ health in the long term. The current study limitations were the young age of the men limiting detection of diseases that would occur with aging, small sample size, likelihood of recall bias, unclear on severity of ICP which likely affects the chances of long-term sequela, the trimester of clinical presentation, peak bile acid levels (percentage of mothers with levels greater than 40), presence of jaundice, average gestation at delivery, percentage of men delivered before 37 weeks, and presence of other perinatal complications since those are likely to affect long-term health.
To our knowledge, this is the first survey to explore whether a mother’s ICP has effects on her son’s health in the long term. The health of women with a history of ICP and their daughters’ health has previously been studied (Turunen et al., 2012; Vimpeli et al., 2013). Based on our findings, a mother’s ICP does not affect her son’s health later in life, and mothers’ concerns may be relieved with this information.
Footnotes
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.