Late Pregnancy Vitamin D Deficiency is Associated with Doubled Odds of Birth Asphyxia and Emergency Caesarean Section: A Prospective Cohort Study.

OBJECTIVES: The aim of this prospective cohort study was to investigate the associations between maternal vitamin D status in late pregnancy and emergency caesarean section (EMCS) and birth asphyxia, in a population based sample of women in Sweden. METHODS: Pregnant women were recruited at the antenatal care in Sweden and 1832 women were included after exclusion of miscarriages, terminated pregnancies and missing data on vitamin D status. Mode of delivery was retrieved from medical records. EMCS was defined as caesarean section after onset of labour. Birth asphyxia was defined as either 5 min Apgar score < 7 or arterial umbilical cord pH < 7.1. Serum was sampled in the third trimester of pregnancy (T3) and 25-hydroxyvitamin D (25OHD) was analysed by liquid chromatography tandem mass spectrometry. Vitamin D deficiency was defined as 25OHD < 30 nmol/L, and associations were studied using logistic regression analysis and expressed as adjusted odds ratios (AOR). RESULTS: In total, 141 (7.7%) women had an EMCS and 58 (3.2%) children were born with birth asphyxia. Vitamin D deficiency was only associated with higher odds of EMCS in women without epidural anaesthesia (AOR = 2.01, p = 0.044). Vitamin D deficiency was also associated with higher odds of birth asphyxia (AOR = 2.22, p = 0.044). CONCLUSIONS FOR PRACTICE: In this Swedish prospective population-based cohort study, vitamin D deficiency in late pregnancy was associated with doubled odds of birth asphyxia and with EMCS in deliveries not aided by epidural anaesthesia. Prevention of vitamin D deficiency among pregnant women may reduce the incidence of EMCS and birth asphyxia. The mechanism behind the findings require further investigation.

Trajectory of vitamin D status during pregnancy in relation to neonatal birth size and fetal survival: a prospective cohort study.

BACKGROUND: We investigated the associations between vitamin D status in early and late pregnancy with neonatal small for gestational age (SGA), low birth weight (LBW) and preterm delivery. Furthermore, associations between vitamin D status and pregnancy loss were studied. METHODS: Serum 25-hydroxyvitamin D (25OHD) was sampled in gestational week ≤ 16 (trimester 1 (T1), N = 2046) and > 31 (trimester 3 (T3), N = 1816) and analysed using liquid chromatography tandem mass spectrometry. Pregnant women were recruited at antenatal clinics in south-west Sweden at latitude 57-58°N. Gestational and neonatal data were retrieved from medical records. Multiple gestations and terminated pregnancies were excluded from the analyses. SGA was defined as weight and/or length at birth < 2 SD of the population mean and LBW as < 2500 g. Preterm delivery was defined as delivery < 37 + 0 gestational weeks and pregnancy loss as spontaneous abortion or intrauterine fetal death. Associations between neonatal outcomes and 25OHD at T1, T3 and change in 25OHD (T3-T1) were studied using logistic regression. RESULTS: T1 25OHD was negatively associated with pregnancy loss and 1 nmol/L increase in 25OHD was associated with 1% lower odds of pregnancy loss (OR 0.99, p = 0.046). T3 25OHD ≥ 100 nmol/L (equal to 40 ng/ml) was associated with lower odds of SGA (OR 0.3, p = 0.031) and LBW (OR 0.2, p = 0.046), compared to vitamin D deficiency (25OHD < 30 nmol/L, or 12 ng/ml). Women with a ≥ 30 nmol/L increment in 25OHD from T1 to T3 had the lowest odds of SGA, LBW and preterm delivery. CONCLUSIONS: Vitamin D deficiency in late pregnancy was associated with higher odds of SGA and LBW. Lower 25OHD in early pregnancy was only associated with pregnancy loss. Vitamin D status trajectory from early to late pregnancy was inversely associated with SGA, LBW and preterm delivery with the lowest odds among women with the highest increment in 25OHD. Thus, both higher vitamin D status in late pregnancy and gestational vitamin D status trajectory can be suspected to play a role in healthy pregnancy.

Sociodemographic factors associated with dietary supplement use in early pregnancy in a Swedish cohort.

Sociodemographic factors have been associated with dietary supplement use among pregnant women but few data exist in a Swedish population. This study aimed to identify factors associated with overall supplement use as well as use of folic acid, vitamin D and n-3 in early pregnancy. Women in the first trimester of pregnancy were included at registration to the antenatal care in 2013-2014 (n 2109). Information regarding supplement use as well as sociodemographic and anthropometric data were obtained from questionnaires and medical records. Multivariable logistic regression analysis was performed to determine the relationship between sociodemographic variables and supplement use. A total of 78 % of the participants reported using at least one dietary supplement in the first trimester. Folic acid supplement use was reported by 74 %, vitamin D supplement use by 43 % and n-3 supplement use by <5 %. Use of any type of supplement in early pregnancy was related to gestational age, parity, birthplace, education and employment. Folic acid supplement use was related to gestational age, parity, birthplace, income, education and employment. Vitamin D supplement use was related to gestational age, birthplace and education. In conclusion, in the first trimester of pregnancy, folic acid supplements were used by three in four women, while vitamin D supplements were used by less than half of the women. The results of this study show a socioeconomic disparity between supplement users and non-users which may have a negative impact on the health of future generations.

Vitamin D Status during Pregnancy in a Multi-Ethnic Population-Representative Swedish Cohort.

There is currently little information on changes in vitamin D status during pregnancy and its predictors. The aim was to study the determinants of change in vitamin D status during pregnancy and of vitamin D deficiency (<30 nmol/L) in early pregnancy. Blood was drawn in the first (T1) and third trimester (T3). Serum 25-hydroxyvitamin D (25(OH)D) (N = 1985) was analysed by liquid chromatography tandem-mass spectrometry. Season-corrected 25(OH)D was calculated by fitting cosine functions to the data. Mean (standard deviation) 25(OH)D was 64.5(24.5) nmol/L at T1 and 74.6(34.4) at T3. Mean age was 31.3(4.9) years, mean body mass index (BMI) was 24.5(4.2) kg/m² and 74% of the women were born in Sweden. Vitamin D deficiency was common among women born in Africa (51%) and Asia (46%) and prevalent in 10% of the whole cohort. Determinants of vitamin D deficiency at T1 were of non-North European origin, and had less sun exposure, lower vitamin D intake and lower age. Season-corrected 25(OH)D increased by 11(23) nmol/L from T1 to T3. The determinants of season-corrected change in 25(OH)D were origin, sun-seeking behaviour, clothing style, dietary vitamin D intake, vitamin D supplementation and recent travel <35° N. In conclusion, season-corrected 25(OH)D concentration increased during pregnancy and depended partly on lifestyle factors. The overall prevalence of vitamin D deficiency was low but common among women born in Africa and Asia. Among them, the determinants of both vitamin D deficiency and change in season-corrected vitamin D status were fewer, indicating a smaller effect of sun exposure.

Adopting a healthy lifestyle when pregnant and obese - an interview study three years after childbirth.

BACKGROUND: Obesity during pregnancy is increasing and is related to life-threatening and ill-health conditions in both mother and child. Initiating and maintaining a healthy lifestyle when pregnant with body mass index (BMI) ≥ 30 kg/m(2) can improve health and decrease risks during pregnancy and of long-term illness for the mother and the child. To minimise gestational weight gain women with BMI ≥ 30 kg/m(2) in early pregnancy were invited to a lifestyle intervention including advice and support on diet and physical activity in Gothenburg, Sweden. The aim of this study was to explore the experiences of women with BMI ≥ 30 kg/m(2) regarding minimising their gestational weight gain, and to assess how health professionals' care approaches are reflected in the women's narratives. METHODS: Semi-structured interviews were conducted with 17 women who had participated in a lifestyle intervention for women with BMI ≥ 30 kg/m(2) during pregnancy 3 years earlier. The interviews were digitally recorded and transcribed in full. Thematic analysis was used. RESULTS: The meaning of changing lifestyle for minimising weight gain and of the professional's care approaches is described in four themes: the child as the main motivation for making healthy changes; a need to be seen and supported on own terms to establish healthy routines; being able to manage healthy activities and own weight; and need for additional support to maintain a healthy lifestyle. CONCLUSIONS: To support women with BMI ≥ 30 kg/m(2) to make healthy lifestyle changes and limit weight gain during pregnancy antenatal health care providers should 1) address women's weight in a non-judgmental way using BMI, and provide accurate and appropriate information about the benefits of limited gestational weight gain; 2) support the woman on her own terms in a collaborative relationship with the midwife; 3) work in partnership to give the woman the tools to self-manage healthy activities and 4) give continued personal support and monitoring to maintain healthy eating and regular physical activity habits after childbirth involving also the partner and family.

Hemodynamic responses to single sessions of aerobic exercise and resistance exercise in pregnancy.

INTRODUCTION: Previous research on maternal hemodynamic responses to a single exercise session during pregnancy is sparse, especially considering immediate responses to resistance exercise. The aim of the study was to examine blood pressure, heart rate, body temperature, and Rating of Perceived Exertion in healthy pregnant women during single sessions of continuous submaximal exercise in pregnancy week 21. MATERIAL AND METHODS: A cross-over design was used. Twenty healthy pregnant women from four prenatal clinics in Gothenburg, Sweden, were included. On day 1, the women did 30 min of aerobic exercise and on day 3 they did 30 min of resistance exercise. Blood pressure, heart rate, and Rating of Perceived Exertion were measured after 15 and 30 min of exercise. RESULTS: After 15 and 30 min of exercise, there was a significant increase in systolic blood pressure and heart rate (p < 0.001). Diastolic blood pressure increased slightly more after 15 and 30 min of aerobic exercise (p = 0.01) than resistance exercise (p = 0.03). Resistance exercise was perceived as more intense than aerobic exercise after 15 min (p = 0.02) and 30 min (p = 0.001) of exercise. Five minutes after completing the exercise, blood pressure quickly reverted to normal although heart rate was still increased (p = 0.001). There was no correlation between heart rate and Rating of Perceived Exertion (rs  = 0.05-0.43). CONCLUSIONS: Maternal hemodynamic responses were essentially the same, regardless of whether the exercise was submaximal aerobic or resistance exercise, although resistance exercise was perceived as more intense. Aerobic and resistance exercise corresponding to "somewhat hard" seems to have no adverse effect with regard to maternal hemodynamic responses in healthy pregnancy.

Preeclampsia and Blood Pressure Trajectory during Pregnancy in Relation to Vitamin D Status.

Every tenth pregnancy is affected by hypertension, one of the most common complications and leading causes of maternal death worldwide. Hypertensive disorders in pregnancy include pregnancy-induced hypertension and preeclampsia. The pathophysiology of the development of hypertension in pregnancy is unknown, but studies suggest an association with vitamin D status, measured as 25-hydroxyvitamin D (25(OH)D). The aim of this study was to investigate the association between gestational 25(OH)D concentration and preeclampsia, pregnancy-induced hypertension and blood pressure trajectory. This cohort study included 2000 women. Blood was collected at the first (T1) and third (T3) trimester (mean gestational weeks 10.8 and 33.4). Blood pressure at gestational weeks 10, 25, 32 and 37 as well as symptoms of preeclampsia and pregnancy-induced hypertension were retrieved from medical records. Serum 25(OH)D concentrations (LC-MS/MS) in T1 was not significantly associated with preeclampsia. However, both 25(OH)D in T3 and change in 25(OH)D from T1 to T3 were significantly and negatively associated with preeclampsia. Women with a change in 25(OH)D concentration of ≥30 nmol/L had an odds ratio of 0.22 (p = 0.002) for preeclampsia. T1 25(OH)D was positively related to T1 systolic (ß = 0.03, p = 0.022) and T1 diastolic blood pressure (ß = 0.02, p = 0.016), and to systolic (ß = 0.02, p = 0.02) blood pressure trajectory during pregnancy, in adjusted analyses. There was no association between 25(OH)D and pregnancy-induced hypertension in adjusted analysis. In conclusion, an increase in 25(OH)D concentration during pregnancy of at least 30 nmol/L, regardless of vitamin D status in T1, was associated with a lower odds ratio for preeclampsia. Vitamin D status was significantly and positively associated with T1 blood pressure and gestational systolic blood pressure trajectory but not with pregnancy-induced hypertension.

Mighty Mums - An antenatal health care intervention can reduce gestational weight gain in women with obesity.

BACKGROUND: overweight and obesity are growing public health problems and around 13% of women assigned to antenatal health care (AHC) in Sweden have obesity (Body Mass Index, BMI ≥30). The risk of complications during pregnancy and childbirth increase with increasing BMI. Excessive gestational weight gain (GWG) among obese women further increases the risks of adverse pregnancy outcomes. In this pilot-study from AHC in Gothenburg, a co-ordinated project with standardised care, given by midwives and supported by dietitian and aiming at reducing weight gain in obese pregnant women, is evaluated. OBJECTIVE: to evaluate the effects of a behavioural intervention programme for women with BMI ≥30, with emphasis on nutrition and physical activity, with regards to GWG and effect on weight at the post partum check-up. METHODS: in the pilot study, the intervention group consisted of the first 50 enrolled obese pregnant women in a large life style project within the AHC in Gothenburg. The control group consisted of 50 obese pregnant women in the same city. The intervention included 60 minutes extra time with the midwife and also offered food discussion group, walking poles and pedometers. The intervention group was prescribed physical activity and could choose from food advice with different content. If needed, the woman was offered referral to the dietitian for a personal meeting. A network was formed with the surrounding community. Outcome measures were GWG, weight change at the postnatal check-up compared with when signing in to antenatal health care, and change in BMI during the same period. FINDINGS: women in the intervention group had a significantly lower GWG (8.6 ± 4.9 kg versus 12.5 ± 5.1 kg; p=0.001) and a significantly lower weight at the postnatal check up versus the first contact with AHC (-0.2 ± 5.7 kg versus +2.0 ± 4.5 kg; p=0.032), as well as a decrease in BMI (-0.04 ± 2.1 versus +0.77 ± 2.0; p=0.037). More women in the intervention than in the control group managed GWG <7 kg [18 (36%) versus 8 (16%); p=0.039]. CONCLUSION: obese pregnant women adhering to a standardised life style project in primary care using restricted resources can limit their weight gain during pregnancy, and show less weight retention after pregnancy compared to controls.

The efficacy of moderate-to-vigorous resistance exercise during pregnancy: a randomized controlled trial.

OBJECTIVES: To assess the effect and safety of moderate-to-vigorous resistance exercise during pregnancy. DESIGN: Randomized controlled study. SETTING: Two antenatal clinics in Gothenburg, Sweden. POPULATION: Ninety-two healthy pregnant women. METHODS: The intervention was administered during gestational weeks 14-25. The intervention group received supervised resistance exercise twice a week, performed at an activity level equivalent to within moderate-to-vigorous (n = 51). The control group received generalized exercise recommendation, a home-based training program and a telephone follow up (n = 41). MAIN OUTCOME MEASURES: Health-related quality of life, physical strength, pain, weight, blood pressure, functional status, activity level, and perinatal data. RESULTS: Functional status deteriorated during the intervention in both groups and pain increased. Significant differences between the groups were obtained only for birthweight. Newborns delivered by women who underwent resistance exercise during pregnancy were significantly heavier than those born to control women; 3561 (±452) g vs. 3251 (±437) g (p = 0.02), a difference that disappeared when adjustment was made for gestational age (p = 0.059). Both groups showed normal health-related quality of life, blood pressure, and perinatal data. CONCLUSIONS: These findings indicate that supervised, moderate-to-vigorous resistance exercise does not jeopardize the health status of healthy pregnant women or the fetus during pregnancy, but instead appears to be an appropriate form of exercise in healthy pregnancy.

Experiences of exercise during pregnancy among women who perform regular resistance training: a qualitative study.

BACKGROUND: Women who are pregnant and healthy are recommended to do 30 minutes or more of light to moderate exercise a day on most, if not all, days of the week. However, only 1 of 6 pregnant women in the United States and northern Europe follows these recommendations. Little attention has been given to the experience of exercise in pregnancy. OBJECTIVES: The aim of the study was to describe experiences of exercise during pregnancy among women who performed regular resistance training. DESIGN: This was a qualitative, inductive content analysis study. METHODS: Seventeen pregnant women who exercised on a regular basis participated in individual semistructured, face-to-face interviews that were recorded, transcribed, coded, and condensed into subcategories and categories. RESULTS: Four categories emerged (subcategories within parentheses): (1) positive impact on body and mind (reduced pregnancy-related problems, increased self-confidence and sense of control, immediate positive feedback, and effects on lifestyle and quality of life); (2) expected benefits and facilitators (knowledge of health benefits, part of one's lifestyle, preventing pregnancy-related problems, social support, staying in good shape, and healthy living with regard to the fetus); (3) new exercise barriers (physical limitations, taking care not to harm oneself or the fetus, uncertainty or lack of knowledge, sense of exclusion at the fitness center, lack of understanding on the part of others, and the pregnancy itself provided an easy excuse); and (4) overcoming exercise barriers (lowering the intensity of exercise, modifying the type of exercise, changing exercise goals, and being extra attentive during exercise). CONCLUSION: Pregnant women strived to exercise if the exercise facilitators outweighed the barriers. As the study described facilitators, barriers, and strategies for how to overcome exercise barriers, the results can be useful in exercise promotion in healthy pregnancy.

A comprehensive analysis of common genetic variation around six candidate loci for intrahepatic cholestasis of pregnancy.

OBJECTIVES: Intrahepatic cholestasis of pregnancy (ICP) has a complex etiology with a significant genetic component. Heterozygous mutations of canalicular transporters occur in a subset of ICP cases and a population susceptibility allele (p.444A) has been identified in ABCB11. We sought to expand our knowledge of the detailed genetic contribution to ICP by investigation of common variation around candidate loci with biological plausibility for a role in ICP (ABCB4, ABCB11, ABCC2, ATP8B1, NR1H4, and FGF19). METHODS: ICP patients (n=563) of white western European origin and controls (n=642) were analyzed in a case-control design. Single-nucleotide polymorphism (SNP) markers (n=83) were selected from the HapMap data set (Tagger, Haploview 4.1 (build 22)). Genotyping was performed by allelic discrimination assay on a robotic platform. Following quality control, SNP data were analyzed by Armitage's trend test. RESULTS: Cochran-Armitage trend testing identified six SNPs in ABCB11 together with six SNPs in ABCB4 that showed significant evidence of association. The minimum Bonferroni corrected P value for trend testing ABCB11 was 5.81×10(-4) (rs3815676) and for ABCB4 it was 4.6×10(-7)(rs2109505). Conditional analysis of the two clusters of association signals suggested a single signal in ABCB4 but evidence for two independent signals in ABCB11. To confirm these findings, a second study was performed in a further 227 cases, which confirmed and strengthened the original findings. CONCLUSIONS: Our analysis of a large cohort of ICP cases has identified a key role for common variation around the ABCB4 and ABCB11 loci, identified the core associations, and expanded our knowledge of ICP susceptibility.

Effects of craniosacral therapy as adjunct to standard treatment for pelvic girdle pain in pregnant women: a multicenter, single blind, randomized controlled trial.

OBJECTIVE: Pelvic girdle pain (PGP) is a disabling condition affecting 30% of pregnant women. The aim of this study was to investigate the efficacy of craniosacral therapy as an adjunct to standard treatment compared with standard treatment alone for PGP during pregnancy. DESIGN: Randomized, multicenter, single blind, controlled trial. SETTING: University hospital, a private clinic and 26 maternity care centers in Gothenburg, Sweden. POPULATION: A total of 123 pregnant women with PGP. METHODS: Participants were randomly assigned to standard treatment (control group, n = 60) or standard treatment plus craniosacral therapy (intervention group, n = 63). PRIMARY OUTCOME MEASURES: pain intensity (visual analog scale 0-100 mm) and sick leave. SECONDARY OUTCOMES: function (Oswestry Disability Index), health-related quality of life (European Quality of Life measure), unpleasantness of pain (visual analog scale), and assessment of the severity of PGP by an independent examiner. RESULTS: Between-group differences for morning pain, symptom-free women and function in the last treatment week were in favor of the intervention group. Visual analog scale median was 27 mm (95% confidence interval 24.6-35.9) vs. 35 mm (95% confidence interval 33.5-45.7) (p = 0.017) and the function disability index was 40 (range 34-46) vs. 48 (range 40-56) (p = 0.016). CONCLUSIONS: Lower morning pain intensity and less deteriorated function was seen after craniosacral therapy in conjunction with standard treatment compared with standard treatment alone, but no effects regarding evening pain and sick-leave. Treatment effects were small and clinically questionable and conclusions should be drawn carefully. Further studies are warranted before recommending craniosacral therapy for PGP.

Increasing participation in cervical cancer screening: telephone contact with long-term non-attendees in Sweden. Results from RACOMIP, a randomized controlled trial.

Non-participation is the foremost screening-related risk factor for cervical cancer. We studied the effectiveness and cost-effectiveness of an intervention to increase participation in the context of a well-run screening program. Telephone contact with non-attendees, offering an appointment to take a smear, was compared with a control group in a population-based randomized trial in western Sweden. Of 8,800 randomly selected women aged 30-62, without a registered Pap smear in the two latest screening rounds, 4,000 were randomized to a telephone arm, another 800 were offered a high-risk human papillomavirus (HPV) self-test by mail (not reported in this article) and 4,000 constituted a control group. Endpoints were frequency of testing, frequency of abnormal smears and further assessment of abnormal tests. Participation during the following 12 months was significantly higher in the telephone arm than in the control group, 718 (18.0%) versus 422 (10.6%) [RR: 1.70, 95% confidence interval (CI): 1.52-1.90]. The number of detected abnormal smears was 39 and 19, respectively (RR: 2.05, 95% CI: 1.19-3.55). The respective numbers of further assessed abnormalities were 34 and 18 (RR: 1.89, 95% CI: 1.07-3.34). Twice as many high-grade intraepithelial neoplasia (CIN2+) were detected and treated in the telephone arm: 14 and 7, respectively. Telephone contact with women who have abstained from cervical cancer screening for long time increases participation and leads to a significant increase in detection of atypical smears. Cost calculations indicate that this intervention is unlikely to be cost-generating and this strategy is feasible in the context of a screening program.

Efficacy of ursodeoxycholic acid in treating intrahepatic cholestasis of pregnancy: a meta-analysis.

BACKGROUND & AIMS: We performed a meta-analysis to evaluate the effects of ursodeoxycholic acid (UDCA) on pruritus, liver test results, and outcomes of babies born to women with intrahepatic cholestasis of pregnancy (ICP). METHODS: We performed a systematic review of 9 published, randomized controlled trials (3 double blinded) that compared the effects of UDCA to other drugs, placebo, or no specific treatment (controls) in patients with ICP. We analyzed data from 454 patients: 207 received only UDCA, 70 received only placebo, 42 received cholestyramine, 36 received dexamethasone for 1 week and then placebo for 2 weeks, 65 received S-adenosyl-methionine, and 34 received no specific treatment. To achieve consistency among end points, a standard questionnaire was sent to all corresponding authors. For each end point, we performed pooled analysis that compared the effects of UDCA with those of all controls and UDCA with those of placebos. RESULTS: In pooled analyses that compared UDCA with all controls, UDCA was associated with total resolution of pruritus (odds ratio [OR], 0.23; 95% confidence interval [CI], 0.07-0.74; P < .01), reduced pruritis (OR, 0.27; 95% CI, 0.13-0.55; P < .0001), normalization of serum levels of alanine aminotransferase (ALT) (OR, 0.23; 95% CI, 0.10-0.50; P < .001), decreased serum level of ALT (OR, 0.24; 95% CI, 0.11-0.52; P < .0001), reduced serum levels of bile acids (OR, 0.37; 95% CI, 0.19-0.75; P < .001), fewer premature births (OR, 0.44; 95% CI, 0.24-0.79; P < .01), reduced fetal distress (OR, 0.46; 95% CI, 0.25-0.86; P < .01), less frequent respiratory distress syndrome (OR, 0.30; 95% CI, 0.12-0.74; P < .01), and fewer neonates in the intensive care unit (OR, 0.49; 95% CI, 0.25-0.98; P = .046). In pooled analyses that compared the effects of UDCA with placebo, UDCA reduced pruritus (OR, 0.21; 95% CI, 0.07-0.62; P < .01), normalized (OR, 0.18; 95% CI, 0.06-0.52; P < .001) or decreased serum levels of ALT (OR, 0.12; 95% CI, 0.05-0.31; P < .0001), and reduced serum levels of bile acids (OR, 0.30; 95% CI, 0.12-0.73; P < .01). CONCLUSIONS: Based on a meta-analysis, UDCA is effective in reducing pruritus and improving liver test results in patients with ICP; UDCA therapy might also benefit fetal outcomes.

Intrahepatic cholestasis of pregnancy: Amelioration of pruritus by UDCA is associated with decreased progesterone disulphates in urine.

UNLABELLED: Intrahepatic cholestasis of pregnancy (ICP) is characterized by pruritus, elevated bile acids, and, specifically, elevated disulphated progesterone metabolites. We aimed to study changes in these parameters during treatment with dexamethasone or ursodeoxycholic acid (UDCA) in 40 out of 130 women included in the Swedish ICP intervention trial (26 randomized to placebo or UDCA, 14 randomized to dexamethasone). Serum bile acid profiles and urinary steroid hormone metabolites were analyzed using isotope-dilution gas chromatography-mass spectrometry and electrospray-mass spectrometry. We found that all patients displayed ICP-typical serum bile acid profiles with >50% cholic acid at baseline but almost 80% UDCA upon treatment with this bile acid. In UDCA-treated patients, relative amounts of disulphated progesterone metabolites in urine decreased by 34%, 48% (P < 0.05), and 55% (P < 0.05) after 1, 2, and 3 weeks of treatment, respectively, which was significantly correlated to improvements of pruritus scores but not to serum bile acid levels. In contrast, in patients randomized to dexamethasone or placebo, no changes in steroid metabolites or pruritus scores were observed. CONCLUSION: UDCA treatment in ICP decreased urinary excretion of disulphated progesterone metabolites, suggesting that amelioration of pruritus is connected to stimulation of hepatobiliary excretion of progesterone disulphates.

Functional variants of the central bile acid sensor FXR identified in intrahepatic cholestasis of pregnancy.

BACKGROUND AND AIMS: Intrahepatic cholestasis of pregnancy (ICP) is characterized by liver impairment, pruritus, and elevated maternal serum bile acids. It can cause premature delivery and intrauterine death. Bile acid synthesis, metabolism, and transport are regulated by the bile acid sensor FXR, and we hypothesized that genetic variation in FXR confers susceptibility to ICP. METHODS: The coding regions and intron/exon boundaries of FXR were sequenced in 92 British ICP cases of mixed ethnicity. Subsequently, a case-control study of allele frequencies of these variants in 2 independent cohorts of Caucasian ICP patients and controls was performed. Variants were cloned into an FXR expression plasmid and tested in functional assays. RESULTS: We identified 4 novel heterozygous FXR variants (-1g>t, M1V, W80R, M173T) in ICP. W80R was not present in Caucasians and M1V was detected uniquely in 1 British case. M173T and -1g>t occur both in Caucasian cases and controls, and we found a significant association of M173T with ICP (OR, 3.2; 95% confidence interval, 1.1-11.2; P = .02) when the allele frequencies of both Caucasian cohorts were analyzed together. We demonstrate functional defects in either translation efficiency or activity for 3 of the 4 variants (-1g>t, M1V, M173T). CONCLUSIONS: This is the first report of functional variants in FXR. We propose that these variants may predispose to ICP, and because FXR has a central role in regulating bile and lipid homeostasis they may be associated with other cholestatic and dyslipidemic disorders.

Intrahepatic cholestasis of pregnancy: a randomized controlled trial comparing dexamethasone and ursodeoxycholic acid.

Intrahepatic cholestasis of pregnancy (ICP) is characterized by troublesome maternal pruritus, elevated serum bile acids (> or =10 micromol/L) and increased fetal risk. Recently we determined a cutoff level of serum bile acids, > or =40 micromol/L, to be associated with impaired fetal outcome. We have now studied the effects of ursodeoxycholic acid (UDCA) and dexamethasone on pruritus, biochemical markers of cholestasis, and fetal complication rates in a double-blind, placebo-controlled trial. For this purpose, 130 women with ICP were randomly allocated to UDCA (1 g/day for three weeks), or dexamethasone (12 mg/day for 1 week and placebo during weeks 2 and 3), or placebo for 3 weeks. Pruritus and biochemical markers of cholestasis were analyzed at inclusion and after 3 weeks of treatment. Fetal complications (spontaneous preterm delivery; asphyxial events; and meconium staining of amniotic fluid, placenta, and membranes) were registered at delivery. An intention-to-treat analysis showed significant reduction of alanine aminotransferase (ALT) (P = .01) and bilirubin (P = .002) in the UDCA group only. In a subgroup analysis of ICP women with serum bile acids > or =40 micromol/L at inclusion (n = 34), UDCA had significant effects on pruritus (-75%), bile acids (-79%), ALT (-80%), and bilirubin (-50%) as well, but not on fetal complication rates. Dexamethasone yielded no alleviation of pruritus or reduction of ALT and was less effective than UDCA at reducing bile acids and bilirubin. In conclusion, 3 weeks of UDCA treatment improved some biochemical markers of ICP irrespective of disease severity, whereas significant relief from pruritus and marked reduction of serum bile acids were only found in patients with severe ICP.

Intrahepatic cholestasis of pregnancy: Relationships between bile acid levels and fetal complication rates.

Intrahepatic cholestasis of pregnancy (ICP), characterized by pruritus in the second half of pregnancy, entails an increased risk to the fetus. This study was designed to determine the incidence and fetal complication rates in ICP, and to define groups at increased risk. In an prospective cohort study conducted between February 1, 1999, and January 31, 2002, all 45,485 pregnancies in a defined region of Sweden (Västra Götaland) were screened for ICP, defined as otherwise unexplained pruritus of pregnancy in combination with fasting serum bile acid levels > or = 10 micromol/L. Pruritus was reported by 937 (2.1%) women, and ICP was diagnosed in 693 (1.5%). Simple logistic regression analyses showed that the probability of fetal complications (spontaneous preterm deliveries, asphyxial events, and meconium staining of amniotic fluid, placenta, and membranes) increased by 1%-2% per additional micromol/L of serum bile acids. Complementary analyses showed that fetal complications did not arise until bile acid levels were > or = 40 micromol/L. Gallstone disease and a family history of ICP were significantly (P < .001) more prevalent in the group of ICP patients with higher bile acid levels. In conclusion, we found an incidence of ICP in our population of 1.5%. From complication rates recorded prospectively, we could define a mild (81%) and a severe (19%) form of ICP, the latter with bile acid levels > or = 40 micromol/L. No increase in fetal risk was detected in ICP patients with bile acid levels < 40 micromol/L, and we propose that these women be managed expectantly, which would significantly reduce the costs of medical care.