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1.  Successful management of severe intrahepatic cholestasis of pregnancy: report of a first Japanese case 
BMC Gastroenterology  2014;14(1):160.
Background
Intrahepatic cholestasis of pregnancy (ICP) is a cholestasis condition caused by elevated levels of serum bile acids that mainly occurs in the third trimester of pregnancy. Maternal symptoms include pruritus; elevation of transaminases, biliary enzymes, and bilirubin levels; and abnormal liver function tests. Fetal symptoms include spontaneous preterm labor, fetal distress, and intrauterine death. It is more prevalent in the Caucasians and is rarely found in Asian countries, including Japan. The etiology of ICP has been reported as involving various factors such as, environmental factors, hormone balance, and genetic components. The genetic factors include single-nucleotide polymorphisms (SNPs) in the genes of canalicular transporters, including ABCB4 and ABCB11. It has also been reported that the combination of these SNPs induces severe cholestasis and liver dysfunction.
Case presentation
Here, we report for the first time a 24-year Japanese case of severe ICP diagnosed by typical symptoms, serum biochemical analysis, and treated with the administration of ursodeoxycholic acid which improved cholestasis and liver injury and prevented fetal death. The sequence analysis showed SNPs reported their association with ICP in the ABCB11 (rs2287622, V444A) and ABCB4 (rs1202283, N168N) loci.
Conclusion
The risk of ICP has been reported to be population-specific, and it is rare in the Japanese population. Our case was successfully treated with ursodeoxycholic acid and the genetic sequence analysis has supported the diagnosis. Because genetic variation in ABCB4 and ABCB11 has also been reported in the Japanese population, we need to be aware of potential ICP cases in pregnant Japanese women although further studies are necessary.
doi:10.1186/1471-230X-14-160
PMCID: PMC4175624  PMID: 25218883
Intrahepatic cholestasis of pregnancy; Bile acid; Ursodeoxycholic acid; Single-nucleotide polymorphism; ABCB11; ABCB4
2.  Impaired fetal adrenal function in intrahepatic cholestasis of pregnancy 
Summary
Background
Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-associated liver disease of unknown etiology. The aim of this study was to investigate the change in maternal and fetal adrenal function in clinical and experimental ICP.
Material/Methods
The maternal and fetal serum levels of cortisol and dehydroepiandrosterone sulfate (DHEAS) were determined in 14 women with ICP and in pregnant rats with estrogen-induced intrahepatic cholestasis.
Results
In women with ICP, the fetal serum cortisol and DHEAS levels were significantly higher than those in women with normal pregnancy, after correcting the impact of gestational age at delivery. The relationship between fetal cortisol and maternal cholic acid levels was bidirectional; the fetal cortisol tended to increase in mild ICP, while it decreased in severe ICP. In pregnant rats with estrogen-induced cholestasis, the fetal cortisol level was significantly lower in the group with oxytocin injection, compared with the group without oxytocin injection (191.92±18.86 vs. 272.71±31.83 ng/ml, P<0.05). In contrast, the fetal cortisol concentration was increased after oxytocin injection in normal control rats.
Conclusions
The data indicate that fetal stress-responsive system is stimulated in mild ICP, but it is suppressed in severe ICP, which might contribute to the occurrence of unpredictable sudden fetal death. Further studies are warranted to explore the role of impaired fetal adrenal function in the pathogenesis of ICP and the clinical implications.
doi:10.12659/MSM.881766
PMCID: PMC3539589  PMID: 21525808
cortisol; dehydroepiandrosterone sulfate; intrahepatic cholestasis of pregnancy; fetal death; cholic acid; human; rat
3.  The Reversed Feto-Maternal Bile Acid Gradient in Intrahepatic Cholestasis of Pregnancy Is Corrected by Ursodeoxycholic Acid 
PLoS ONE  2014;9(1):e83828.
Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disorder associated with an increased risk of adverse fetal outcomes. It is characterised by raised maternal serum bile acids, which are believed to cause the adverse outcomes. ICP is commonly treated with ursodeoxycholic acid (UDCA). This study aimed to determine the fetal and maternal bile acid profiles in normal and ICP pregnancies, and to examine the effect of UDCA treatment. Matched maternal and umbilical cord serum samples were collected from untreated ICP (n = 18), UDCA-treated ICP (n = 46) and uncomplicated pregnancy (n = 15) cases at the time of delivery. Nineteen individual bile acids were measured using HPLC-MS/MS. Maternal and fetal serum bile acids are significantly raised in ICP compared with normal pregnancy (p = <0.0001 and <0.05, respectively), predominantly due to increased levels of conjugated cholic and chenodeoxycholic acid. There are no differences between the umbilical cord artery and cord vein levels of the major bile acid species. The feto-maternal gradient of bile acids is reversed in ICP. Treatment with UDCA significantly reduces serum bile acids in the maternal compartment (p = <0.0001), thereby reducing the feto-maternal transplacental gradient. UDCA-treatment does not cause a clinically important increase in lithocholic acid (LCA) concentrations. ICP is associated with significant quantitative and qualitative changes in the maternal and fetal bile acid pools. Treatment with UDCA reduces the level of bile acids in both compartments and reverses the qualitative changes. We have not found evidence to support the suggestion that UDCA treatment increases fetal LCA concentrations to deleterious levels.
doi:10.1371/journal.pone.0083828
PMCID: PMC3885440  PMID: 24421907
4.  Intrahepatic cholestasis of pregnancy 
Intrahepatic cholestasis of pregnancy (ICP) is a cholestatic disorder characterized by (i) pruritus with onset in the second or third trimester of pregnancy, (ii) elevated serum aminotransferases and bile acid levels, and (iii) spontaneous relief of signs and symptoms within two to three weeks after delivery. ICP is observed in 0.4–1% of pregnancies in most areas of Central and Western Europe and North America, while in Chile and Bolivia as well as Scandinavia and the Baltic states roughly 5–15% and 1–2%, respectively, of pregnancies are associated with ICP. Genetic and hormonal factors, but also environmental factors may contribute to the pathogenesis of ICP. Intrahepatic cholestasis of pregnancy increases the risk of preterm delivery (19–60%), meconium staining of amniotic fluid (27%), fetal bradycardia (14%), fetal distress (22–41%), and fetal loss (0.4–4.1%), particularly when associated with fasting serum bile acid levels > 40 μmol/L. The hydrophilic bile acid ursodeoxycholic acid (10–20 mg/kg/d) is today regarded as the first line treatment for intrahepatic cholestasis of pregnancy. Delivery has been recommended in the 38th week when lung maturity has been established.
doi:10.1186/1750-1172-2-26
PMCID: PMC1891276  PMID: 17535422
5.  Effect of Bile Acid on Fetal Lung in Rat Model of Intrahepatic Cholestasis of Pregnancy 
Objective. To determine the correlation between maternal bile acid (BA) level and fetal pulmonary surfactant in rats and study the effects of BA on fetal lung in rat model of intrahepatic cholestasis of pregnancy. Methods. Forty pregnant rats were treated with (A) 5.5 mg/kg BA, (B) 1.4 mg/kg BA, and (C) 1 ml physiological saline. Levels of total bile acid (TBA), ALT, AST, TBIL, DBIL, and SP-A were determined and the lungs of fetal rats were analyzed for pathological changes. Results. Groups A and B intervened with BA showed significant higher level of TBA in both maternal and fetal serum, more mortality rate of fetal rats, more concentration of SP-A in fetal serum, and wider alveolus mesenchyme of fetal rats than the control Group C. Higher level of BA associated with increased fetal risk and lower numerical density of mitochondria in type II alveolar epithelial cells. The levels of TBA in maternal serum were found to have significant positive correlation with those in fetal serum and SP-A level but negatively with the area of alveolus and the numerical density of lamellar body. Conclusions. The TBA level in maternal serum showed significant association with lung pathological changes in fetal rats.
doi:10.1155/2014/308274
PMCID: PMC3980923  PMID: 24778648
6.  Comparative Proteomics Analysis of Placenta from Pregnant Women with Intrahepatic Cholestasis of Pregnancy 
PLoS ONE  2013;8(12):e83281.
Introduction
Intrahepatic cholestasis of pregnancy (ICP) usually occurs in the third trimester and associated with increased risks in fetal complications. Currently, the exact cause of this disease is unknown. In this study we aim to investigate the potential proteins in placenta, which may participate in the molecular mechanisms of ICP-related fetal complications using iTRAQ-based proteomics approach.
Methods
The iTRAQ analysis combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS) was performed to separate differentially expressed placental proteins from 4 pregnant women with ICP and 4 healthy pregnant women. Bioinformatics analysis was used to find the relative processes that these differentially expressed proteins were involved in. Three apoptosis related proteins ERp29, PRDX6 and MPO that resulted from iTRAQ-based proteomics were further verified in placenta by Western blotting and immunohistochemistry. Placental apoptosis was also detected by TUNEL assay.
Results
Proteomics results showed there were 38 differentially expressed proteins from pregnant women with ICP and healthy pregnant women, 29 were upregulated and 9 were downregulated in placenta from pregnant women with ICP. Bioinformatics analysis showed most of the identified proteins was functionally related to specific cell processes, including apoptosis, oxidative stress, lipid metabolism. The expression levels of ERp29, PRDX6 and MPO were consistent with the proteomics data. The apoptosis index in placenta from ICP patients was significantly increased.
Conclusion
This preliminary work provides a better understanding of the proteomic alterations of placenta from pregnant women with ICP and may provide us some new insights into the pathophysiology and potential novel treatment targets for ICP.
doi:10.1371/journal.pone.0083281
PMCID: PMC3877025  PMID: 24391750
7.  The impact of intrahepatic cholestasis of pregnancy with hepatitis B virus infection on perinatal outcomes 
Introduction
To investigate the impact of intrahepatic cholestasis of pregnancy (ICP) with hepatitis B virus (HBV) infection on perinatal outcomes.
Methods
In the study, 200 pregnant women were divided into four groups, including 50 cases with ICP and HBV infection, 50 cases with ICP, 50 cases with HBV infection, and 50 healthy pregnancies. The delivery process and perinatal outcomes were analyzed among different groups.
Results
When compared to the healthy pregnancy group, significantly increased rates of premature rupture of membranes, meconium-stained amniotic fluid, and cesarean section were observed in cases of ICP, HBV infection, or ICP patients with HBV (P<0.05). Specifically, the rates of HBV infection in the newborn, fetal distress, neonatal asphyxia, and birth defects in the newborn, and infant Apgar scores were higher in ICP pregnancies with HBV (56%, 48%, 16%, and 48%, respectively) than in the other groups (P<0.05).
Conclusion
ICP combined with HBV infection has a clear influence on perinatal infant outcomes.
doi:10.2147/TCRM.S61530
PMCID: PMC4043812  PMID: 24920912
premature rupture of membranes; meconium-stained amniotic fluid; cesarean section; fetal distress; neonatal asphyxia; birth defects; Apgar scores
8.  Intrahepatic cholestasis of pregnancy-current achievements and unsolved problems 
Intrahepatic cholestasis of pregnancy (ICP) is the most common pregnancy-related liver disorder. Maternal effects of ICP are mild; however, there is a clear association between ICP and higher frequency of fetal distress, preterm delivery, and sudden intrauterine fetal death. The cause of ICP remains elusive, but there is evidence that mutations in genes encoding hepatobiliary transport proteins can predispose for the development of ICP. Recent data suggest that ursodeoxycholic acid is currently the most effective pharmacologic treatment, whereas obstetric management is still debated. Clinical trials are required to identify the most suitable monitoring modalities that can specifically predict poor perinatal outcome. This article aims to review current achievements and unsolved problems of ICP.
doi:10.3748/wjg.14.5781
PMCID: PMC2751886  PMID: 18855975
Cholestasis of pregnancy; Canalicular ABC transporters; Pruritus; Fetal outcome; Ursodeoxycholic acid
9.  Human leukocyte antigen G and miR-148a are associated with the pathogenesis of intrahepatic cholestasis of pregnancy 
Intrahepatic cholestasis of pregnancy (ICP) occurs mainly during the third trimester of gestation and is characterized by pruritus and elevated serum bile acid levels. The pathogenesis of this disease has yet to be elucidated. The nonclassical human leukocyte antigen G (HLA-G) is a trophoblast-specific molecule and is involved in the regulation of maternal immune response at the maternal-fetal interface. MicroRNAs (miRNAs) have an important role in a number of physiological and pathological processes. However, the roles of HLA-G and miRNAs in immune response in the pathogenesis of ICP have yet to be elucidated. In the present study, the expression of HLA-G and miR-148a in the placenta of patients with ICP was investigated. The mRNA and protein expression levels of HLA-G were markedly reduced in the placenta of patients with ICP compared with the levels in healthy pregnant females, and were negatively correlated with serum total bile acid (TBA) levels. It was also observed that miR-148a levels were markedly upregulated in the placenta and peripheral blood of patients with ICP. Furthermore, the mRNA and protein expression levels of HLA-G in the placenta were negatively correlated with the miR-148 levels in the placenta, but not in the peripheral blood, while the miR-148a levels in the placenta were positively correlated with serum TBA levels. These results suggest that the downregulation of HLA-G is probably caused by the upregulation of miR-148a in the placenta, and miR-148a in the placenta may contribute to the pathogenesis of ICP via the inhibition of HLA-G expression.
doi:10.3892/etm.2014.1986
PMCID: PMC4218636  PMID: 25371718
human leukocyte antigen G; miR-148a; intrahepatic cholestasis of pregnancy; placenta
10.  ATP8B1 mutations in British cases with intrahepatic cholestasis of pregnancy 
Gut  2005;54(6):829-834.
Background: Intrahepatic cholestasis of pregnancy (ICP) affects approximately 0.7% of pregnancies in the UK and is associated with prematurity, fetal distress, and intrauterine death. Homozygous mutations in the ATP8B1 gene cause cholestasis with a normal serum gamma-glutamyl transpeptidase (γ-GT), and have been reported in two forms of cholestasis: progressive familial intrahepatic cholestasis type 1 (PFIC1) and benign recurrent intrahepatic cholestasis (BRIC).
Aims: To establish whether mutations in ATP8B1 are associated with ICP in British cases
Patients: Sixteen well phenotyped women with ICP without raised γ-GT were selected for sequence analysis. Subsequently, 182 patients and 120 controls were examined for the presence of the variants detected.
Methods: All coding exons were sequenced in 16 cases. Eight ICP cases, including two women carrying a mutation, were investigated using in vivo hepatic 31P magnetic resonance spectroscopy (MRS)
Results: Two heterozygous ATP8B1 transitions (208G>A and 2599C>T) that resulted in amino acid substitutions were identified; 208G>A was identified in three cases. MRS revealed an increased phosphodiester signal (Mann-Whitney U test, p = 0.03) and a decreased phosphomonoester/phosphodiester ratio (p = 0.04) in ICP cases compared with controls.
Conclusions: We were able to demonstrate ATP8B1 mutations in ICP. MRS studies suggest that susceptibility to ICP is associated with a relative rise in biliary phospholipid. These data also suggest that MRS may be used for non-invasive assessment of the liver and biliary constituents in cholestasis.
doi:10.1136/gut.2004.058115
PMCID: PMC1774530  PMID: 15888793
bile; liver; magnetic resonance spectroscopy; intrahepatic cholestasis of pregnancy
11.  Intrahepatic cholestasis of pregnancy: the severe form is associated with common variants of the hepatobiliary phospholipid transporter ABCB4 gene 
Gut  2006;56(2):265-270.
Background
Intrahepatic cholestasis of pregnancy (ICP) is characterised by troublesome maternal pruritus, raised serum bile acid levels and increased fetal risk. Mutations of the ABCB4 gene encoding the hepatobiliary phospholipid transporter have been identified in a small proportion of patients with cholestasis of pregnancy. In a recent prospective study on 693 patients with cholestasis of pregnancy, a cut‐off level for serum bile acid (⩾40 μmol/l) was determined for increased risk of fetal complications.
Objectives
To investigate whether common combinations of polymorphic alleles (haplotypes) of the genes encoding the hepatobiliary ATP‐binding cassette (ABC) transporters for phospholipids (ABCB4) and bile acids (ABCB11) were associated with this severe form of cholestasis of pregnancy.
Methods
For genetic analysis, 52 women with bile acid levels ⩾40 μmol/l (called cases) and 52 unaffected women (called controls) matched for age, parity and geographical residence were studied. Gene variants tagging common ABCB4 and ABCB11 haplotypes were genotyped and haplotype distributions were compared between cases and controls by permutation testing.
Results
In contrast with ABCB11 haplotypes, ABCB4 haplotypes differed between the two groups (p = 0.019), showing that the severe form of cholestasis of pregnancy is associated with the ABCB4 gene variants. Specifically, haplotype ABCB4_5 occurred more often in cases, whereas haplotypes ABCB4_3 and ABCB4_7 were more common in controls. These associations were reflected by different frequencies of at‐risk alleles of the two tagging polymorphisms (c.711A: odds ratio (OR) 2.27, p = 0.04; deletion intron 5: OR 14.68, p = 0.012).
Conclusion
Variants of ABCB4 represent genetic risk factors for the severe form of ICP in Sweden.
doi:10.1136/gut.2006.092742
PMCID: PMC1856745  PMID: 16891356
12.  Bile acid patterns in meconium are influenced by cholestasis of pregnancy and not altered by ursodeoxycholic acid treatment 
Gut  1999;45(3):446-452.
BACKGROUND—Data on meconium bile acid composition in newborn babies of patients with intrahepatic cholestasis of pregnancy (ICP) are relatively scant, and changes that occur on ursodeoxycholic acid (UDCA) administration have not been evaluated.
AIMS—To investigate bile acid profiles in meconium of neonates from untreated and UDCA treated patients with ICP. Maternal serum bile acid composition was also analysed both at diagnosis and delivery to determine whether this influences the concentration and proportion of bile acids in the meconium.
PATIENTS/METHODS—The population included eight healthy pregnant women and 16 patients with ICP, nine of which received UDCA (12.5-15.0 mg/kg body weight/day) for 15±4 days until parturition. Bile acids were assessed in the meconium by gas chromatography-mass spectrometry and in maternal serum by high performance liquid chromatography.
RESULTS—Total bile acid and cholic acid concentrations in the meconium were increased (p<0.01) in newborns from patients with ICP (13.5 (5.1) and 8.4 (4.1) µmol/g respectively; mean (SEM)) as compared with controls (2.0 (0.5) and 0.8 (0.3) µmol/g respectively), reflecting the total bile acid and cholic acid levels in the maternal serum (r = 0.85 and r = 0.84, p<0.01). After UDCA administration, total bile acid concentrations decreased in the mother (~3-fold, p<0.05) but not in the meconium. UDCA concentration in the meconium showed only a 2-fold increase after treatment, despite the much greater increase in the maternal serum (p<0.01). Lithocholic acid concentration in the meconium was not increased by UDCA treatment.
CONCLUSIONS—UDCA administration does not influence the concentration and proportion of bile acids in the meconium, which in turn are altered by ICP. Moreover, this beneficial treatment for the mother does not increase meconium levels of potentially toxic metabolites of UDCA such as lithocholic acid.


Keywords: bile acids; cholestasis; pregnancy; cholic acid; meconium; ursodeoxycholic acid therapy
PMCID: PMC1727639  PMID: 10446117
13.  Predictors of premature delivery in patients with intrahepatic cholestasis of pregnancy 
AIM: To evaluate the predictive value of clinical symptoms and biochemical parameters for prematurity in intrahepatic cholestasis of pregnancy (ICP).
METHODS: Sixty symptomatic patients with ICP were included in this retrospective analysis. Preterm delivery was defined as delivery before 37 wk gestation. Predictors of preterm delivery were disclosed by binary multivariate logistic regression analysis.
RESULTS: Mean time of delivery was 38.1 ± 1.7 wk. No stillbirths occurred. Premature delivery was observed in eight (13.3%) patients. Total fasting serum bile acids were higher (47.8 ± 15.2 vs 41.0 ± 10.0 μmol/L, P < 0.05), and pruritus tended to start earlier (29.0 ± 3.9 vs 31.6 ± 3.3 wk, P = 0.057) in patients with premature delivery when compared to those with term delivery. Binary multivariate logistic regression analysis revealed that early onset of pruritus (OR 1.70, 95% CI 1.23-2.95, P = 0.038) and serum bile acid (OR 2.13, 95% CI 1.13-3.25, P = 0.013) were independent predictors of preterm delivery.
CONCLUSION: Early onset of pruritus and high levels of serum bile acids predict preterm delivery in ICP, and define a subgroup of patients at risk for poor neonatal outcome.
doi:10.3748/wjg.v13.i46.6226
PMCID: PMC4171234  PMID: 18069764
Intrahepatic cholestasis; Delivery; Pregnancy
14.  Planned Vaginal Birth or Elective Repeat Caesarean: Patient Preference Restricted Cohort with Nested Randomised Trial 
PLoS Medicine  2012;9(3):e1001192.
A study conducted in Australia provides new data on the outcomes for mother and baby associated with either planned vaginal birth, or elective repeat caesarean section following a previous caesarean section.
Background
Uncertainty exists about benefits and harms of a planned vaginal birth after caesarean (VBAC) compared with elective repeat caesarean (ERC). We conducted a prospective restricted cohort study consisting of a patient preference cohort study, and a small nested randomised trial to compare benefits and risks of a planned ERC with planned VBAC.
Methods and findings
2,345 women with one prior caesarean, eligible for VBAC at term, were recruited from 14 Australian maternity hospitals. Women were assigned by patient preference (n = 2,323) or randomisation (n = 22) to planned VBAC (1,225 patient preference, 12 randomised) or planned ERC (1,098 patient preference, ten randomised). The primary outcome was risk of fetal death or death of liveborn infant before discharge or serious infant outcome. Data were analysed for the 2,345 women (100%) and infants enrolled.
The risk of fetal death or liveborn infant death prior to discharge or serious infant outcome was significantly lower for infants born in the planned ERC group compared with infants in the planned VBAC group (0.9% versus 2.4%; relative risk [RR] 0.39; 95% CI 0.19–0.80; number needed to treat to benefit 66; 95% CI 40–200). Fewer women in the planned ERC group compared with women in the planned VBAC had a major haemorrhage (blood loss ≥1,500 ml and/or blood transfusion), (0.8% [9/1,108] versus 2.3% [29/1,237]; RR 0.37; 95% CI 0.17–0.80).
Conclusions
Among women with one prior caesarean, planned ERC compared with planned VBAC was associated with a lower risk of fetal and infant death or serious infant outcome. The risk of major maternal haemorrhage was reduced with no increase in maternal or perinatal complications to time of hospital discharge. Women, clinicians, and policy makers can use this information to develop health advice and make decisions about care for women who have had a previous caesarean.
Trial registration
Current Controlled Trials ISRCTN53974531
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Rates of caesarean section are rising around the world, particularly in high- and middle-income countries, where most women have a choice of how their baby is delivered. Historically, the obstetrician in charge of the woman's care made the decision on whether to perform an elective (planned) caesarean section based on medical criteria. For women who have had a previous caesarean section, typically, their options for mode of childbirth are either a trial of vaginal birth or an elective repeat caesarean section. The proportion of women attempting a vaginal birth after a previous caesarean section has been declining in many countries partly due to the variable chance of achieving a successful vaginal birth (reported between 56% and 80%) and partly because of negative reports of the risk of complications, both to the mother and the baby, of a having a vaginal delivery following a caesarean section. Consequently, the rates of repeat caesarean section have risen sharply, for example, currently 83% in Australia and almost 90% in the US.
Why Was This Study Done?
Both elective repeat caesarean section and subsequent vaginal delivery after a previous caesarean section have clinical risks and benefits. Most obviously, having a surgical procedure puts the woman having the repeat caesarean section at risk of surgical complications, especially if performed under a general anesthetic, and her baby may be at risk of respiratory complications. However, subsequent vaginal delivery following a previous caesarean section may put the mother at risk of bleeding severely enough to need a blood transfusion (more than 1,500 ml blood loss) and she may also be at increased risk of rupturing her uterus; and her baby may have an increased risk of dying or of becoming brain damaged due to lack of oxygen.
However, to date there have been no randomized controlled trials of elective repeat caesarean section versus vaginal delivery following a previous caesarean section to compare the health outcomes of mother and baby and a recent systematic review could draw no conclusions. So the researchers conducted this prospective cohort study based on patient preference (with a few women agreeing to be randomized to mode of delivery), to compare the health outcomes for mother and baby for elective repeat caesarean section versus vaginal delivery in women following a previous caesarean section.
What Did the Researchers Do and Find?
Between 2002 and 2007, the researchers recruited 2,345 suitable women (that is, women who had one previous caesarean section, were currently 37 weeks pregnant with a single baby, and who were clinically able to have a vaginal delivery) from 14 maternity hospitals throughout Australia. A few women (22) agreed to be randomized to either mode of delivery but most women chose her preferred option. Then, depending on the woman's preferences for mode of birth, participating obstetricians either scheduled a date for an elective caesarean section (1,098 women) or assessed on-going suitability for the woman to have a planned vaginal delivery (1,225 women). However only 535 (43.2%) women who chose to have a vaginal birth were able to deliver this way because of failure to progress in labor or fetal distress: 334 of these women (27.0%) had to have an elective caesarean section and 368 women had to have an emergency caesarean section.
Although no women died, women who had a planned caesarean section experienced less severe bleeding than women who delivered vaginally. There were no infant deaths in those born by elective caesarean section but two unexplained stillbirths in the planned vaginal delivery group. There was also a reduced risk of nonfatal serious outcome before discharge from hospital for infants delivered by in the elective caesarean section. The researchers calculated that one infant death or near death would be prevented for every 66 elective caesarean sections performed in women who had a previous caesarean section.
What Do These Findings Mean?
These findings show that in women who had delivered by a previous caesarean section delivering their next baby by planned caesarean section was associated with less infant death and better health outcomes for the mother before she was discharged from the hospital compared to women who had a subsequent vaginal delivery. This information can be used by women, clinicians, and policy makers in helping to make decisions about the mode of subsequent deliveries and best care for women who have had a previous caesarean section.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001192.
This study is linked to a PLoS Medicine Research Article by Fitzpatrick and colleagues and a PLoS Medicine Perspective by Catherine Spong
The American Congress of Obstetricians and Gynecologists has information sheets for patients on caesarean sections and on vaginal birth after caesarean delivery
Childbirth Connection, a US-based not-for-profit organization, provides information about caesarean sections and about vaginal birth after caesarean
The National Childbirth Trust, a UK charity, provides information for parents on all aspects of pregnancy and birth, including caesarean sections and vaginal birth after caesarean delivery
The UK charity Healthtalkonline has personal stories from women making decisions about birth after a caesarean section
doi:10.1371/journal.pmed.1001192
PMCID: PMC3302845  PMID: 22427749
15.  Uterine Rupture by Intended Mode of Delivery in the UK: A National Case-Control Study 
PLoS Medicine  2012;9(3):e1001184.
A case-control study using UK data estimates the risk of uterine rupture in subsequent deliveries amongst women who have had a previous caesarean section.
Background
Recent reports of the risk of morbidity due to uterine rupture are thought to have contributed in some countries to a decrease in the number of women attempting a vaginal birth after caesarean section. The aims of this study were to estimate the incidence of true uterine rupture in the UK and to investigate and quantify the associated risk factors and outcomes, on the basis of intended mode of delivery.
Methods and Findings
A UK national case-control study was undertaken between April 2009 and April 2010. The participants comprised 159 women with uterine rupture and 448 control women with a previous caesarean delivery. The estimated incidence of uterine rupture was 0.2 per 1,000 maternities overall; 2.1 and 0.3 per 1,000 maternities in women with a previous caesarean delivery planning vaginal or elective caesarean delivery, respectively. Amongst women with a previous caesarean delivery, odds of rupture were also increased in women who had ≥ two previous caesarean deliveries (adjusted odds ratio [aOR] 3.02, 95% CI 1.16–7.85) and <12 months since their last caesarean delivery (aOR 3.12, 95% CI 1.62–6.02). A higher risk of rupture with labour induction and oxytocin use was apparent (aOR 3.92, 95% CI 1.00–15.33). Two women with uterine rupture died (case fatality 1.3%, 95% CI 0.2–4.5%). There were 18 perinatal deaths associated with uterine rupture among 145 infants (perinatal mortality 124 per 1,000 total births, 95% CI 75–189).
Conclusions
Although uterine rupture is associated with significant mortality and morbidity, even amongst women with a previous caesarean section planning a vaginal delivery, it is a rare occurrence. For women with a previous caesarean section, risk of uterine rupture increases with number of previous caesarean deliveries, a short interval since the last caesarean section, and labour induction and/or augmentation. These factors should be considered when counselling and managing the labour of women with a previous caesarean section.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Uterine rupture is a serious complication of pregnancy in which the wall of the uterus (womb) tears during pregnancy or early labor. Signs and symptoms of uterine rupture include fetal heart rate abnormalities, abdominal pain, and vaginal bleeding. If uterine rupture happens during labor, the woman must have an immediate caesarean section (surgical delivery of her baby) to save both her life and that of her baby. The woman's womb and nearby organs can be damaged at rupture or removed during surgery and she may need a blood transfusion because of severe bleeding. Moreover, her baby may develop respiratory distress syndrome and other life-threatening complications. In high income countries, uterine rupture most commonly occurs in women who have delivered a previous pregnancy by caesarean section. In a caesarean section, the baby is delivered through a cut made through the abdominal wall and the uterine wall. The stretching that occurs during pregnancy or the strong contractions of labor can tear the scar left by this cut, resulting in uterine rupture.
Why Was This Study Done?
Women who have had a caesarean delivery are generally encouraged to try to deliver subsequent babies vaginally. However, recent reports of an increased risk of complications (morbidity) and death (mortality) due to uterine rupture are thought to reduce women's willingness to attempt vaginal birth after caesarean (VBAC) in some countries. In the UK, for example, where one in four babies is delivered by caesarean section, a previous caesarean delivery is one of commonest reasons for a repeat section. Obstetricians (doctors who care for women during child birth) need to know as much as possible about the incidence of uterine rupture and about the risk factors for it so that they can advise women who have had a previous caesarean section about their delivery options. In this national case-control study (a study that compares the characteristics of people with and without a specific condition), the researchers estimate the incidence of uterine rupture in the UK by intended mode of delivery and investigate and quantify the risk factors for and outcomes of uterine rupture.
What Did the Researchers Do and Find?
The researchers used the UK Obstetric Surveillance System (UKOSS) to identify all the women in the UK who had a uterine rupture over a 13-month period (159 women, 139 of whom had had a previous caesarean delivery). Controls for the study were women who had not had a uterine rupture but who had previously delivered by caesarean section. Overall, the incidence of uterine rupture was 0.2 per 1,000 maternities. In women with a previous caesarean delivery, 2.1 and 0.3 per 1,000 maternities ended in uterine rupture in women planning vaginal delivery and caesarean delivery, respectively. Amongst women who had had a previous caesarean delivery, the risk of uterine rupture was greater among those who had had two or more previous caesarean deliveries or a caesarean delivery less than 12 months previously, or whose labor was induced. Two women died following uterine rupture (a case fatality of 1.3%) and 18 babies died around the time of birth (a perinatal mortality rate of 124 per 1,000 live births; the UK perinatal mortality rate is 7.5 per 1,000 live births). 15 of the women who had a uterine rupture had their womb removed, 10 had other organs damaged, and nearly half had other complications; 19 of the surviving babies had health problems.
What Do These Findings Mean?
These findings indicate that, in the UK, although uterine rupture is associated with significant mortality and morbidity, it is a rare occurrence even among women who have had a previous caesarean delivery and are planning a vaginal delivery. They also indicate that, for women who have previously had a caesarean section, the risk of rupture increases with the number of previous caesarean deliveries, with a short interval since the last caesarean section, and with labor induction. Although the researchers may not have identified all the women who had a uterine rupture during the study period or may have identified only the worst cases, these findings provide valuable information about the factors that obstetricians need to consider when advising women who have previously had a caesarean section and when managing their labor.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001184.
This study is linked to a PLoS Medicine Research Article by Caroline Crowther and a PLoS Medicine Perspective by Catherine Spong
Wikipedia has a page on uterine rupture (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
The American Congress of Obstetricians and Gynecologists has information sheets for patients on caesarean sections and on vaginal birth after caesarean delivery
The Royal College of Obstetricians and Gynaecologists in the UK has information for women on birth after previous caesarean
Childbirth Connection, a US-based not-for-profit organization, provides information about caesarean sections and about vaginal birth after caesarean
The National Childbirth Trust, a UK charity, provides information for parents on all aspects of pregnancy and birth, including caesarean sections and vaginal birth after caesarean delivery
The UK charity Healthtalkonline has personal stories from women making decisions about birth after a caesarean section
A personal story of uterine rupture during an attempted VBAC is available
The UK Obstetric Surveillance System studies rare disorders of pregnancy in the UK
doi:10.1371/journal.pmed.1001184
PMCID: PMC3302846  PMID: 22427745
16.  Roles of PPARγ/NF-κB Signaling Pathway in the Pathogenesis of Intrahepatic Cholestasis of Pregnancy 
PLoS ONE  2014;9(1):e87343.
Background
Intrahepatic cholestasis of pregnancy (ICP) is the most prevalent pregnancy specific liver disease. However, the pathogenesis and etiology of ICP is poorly understood.
Aim
To assess the expression of peroxisome proliferator-activated receptorγ (PPARγ) and nuclear factor kappa B (NF-κB) in placenta and HTR-8/SVneo cell, and evaluate the serum levels of cytokines, bile acids, hepatic function and lipids in control and ICP patients and the fetal outcome, in order to explore the role of PPARγ/NF-κB signaling pathway in the possible mechanism of ICP.
Methods
Clinical data of the pregnant women were collected and serum levels of cytokines, bile acids, hepatic function and lipids were measured. Expressions of PPARγ and NF-κB in placenta and HTR-8/SVneo cell were determined. The new-born information was collected to demonstrate the relationship between PPARγ/NF-κB signaling pathway and ICP.
Results
The serum levels of bile acids, hepatic function, triglycerides (TG), total cholesterol (TC), IL-6, IL-12 and TNF-α in ICP group were significantly increased (P<0.01), and serum level of IL-4 was significantly decreased (P<0.01). PPARγ and NF-κB staining were found in the membrane and cytoplasm of placental trophoblast cell. The expression of PPARγ and NF-κB were significantly higher in ICP group and taurocholate acid (TCA) treated HTR-8/SVneo cell (P<0.01). The new-born information in severe ICP group were significantly different as compared to that in control group (P<0.05), and part of information in mild ICP group were also difference to that in control group (P<0.05).
Conclusions
The higher expressions of PPARγ and NF-κB in ICP placenta and TCA treated HTR-8/SVneo cell, together with the abnormal serum levels of cytokines, might induced by the imbalance of inflammatory and immune reaction, and then disturb placental bile acid and serum lipids transportation, finally result in fatal cholestasis which probably be one of the mechanism of ICP.
doi:10.1371/journal.pone.0087343
PMCID: PMC3906154  PMID: 24489901
17.  Placental gene-expression profiles of intrahepatic cholestasis of pregnancy reveal involvement of multiple molecular pathways in blood vessel formation and inflammation 
BMC Medical Genomics  2014;7:42.
Background
Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-associated liver disease with potentially deleterious consequences for the fetus, particularly when maternal serum bile-acid concentration >40 μM. However, the etiology and pathogenesis of ICP remain elusive. To reveal the underlying molecular mechanisms for the association of maternal serum bile-acid level and fetal outcome in ICP patients, DNA microarray was applied to characterize the whole-genome expression profiles of placentas from healthy women and women diagnosed with ICP.
Methods
Thirty pregnant women recruited in this study were categorized evenly into three groups: healthy group; mild ICP, with serum bile-acid concentration ranging from 10–40 μM; and severe ICP, with bile-acid concentration >40 μM. Gene Ontology analysis in combination with construction of gene-interaction and gene co-expression networks were applied to identify the core regulatory genes associated with ICP pathogenesis, which were further validated by quantitative real-time PCR and histological staining.
Results
The core regulatory genes were mainly involved in immune response, VEGF signaling pathway and G-protein-coupled receptor signaling, implying essential roles of immune response, vasculogenesis and angiogenesis in ICP pathogenesis. This implication was supported by the observed aggregated immune-cell infiltration and deficient blood vessel formation in ICP placentas.
Conclusions
Our study provides a system-level insight into the placental gene-expression profiles of women with mild or severe ICP, and reveals multiple molecular pathways in immune response and blood vessel formation that might contribute to ICP pathogenesis.
doi:10.1186/1755-8794-7-42
PMCID: PMC4105836  PMID: 25001852
Microarray; Intrahepatic cholestasis of pregnancy; Placenta; Genome-wide; Immune response
18.  Fetal Growth and Risk of Stillbirth: A Population-Based Case–Control Study 
PLoS Medicine  2014;11(4):e1001633.
Radek Bukowski and colleagues conducted a case control study in 59 US hospitals to determine the relationship between fetal growth and stillbirth, and find that both restrictive and excessive growth could play a role.
Please see later in the article for the Editors' Summary
Background
Stillbirth is strongly related to impaired fetal growth. However, the relationship between fetal growth and stillbirth is difficult to determine because of uncertainty in the timing of death and confounding characteristics affecting normal fetal growth.
Methods and Findings
We conducted a population-based case–control study of all stillbirths and a representative sample of live births in 59 hospitals in five geographic areas in the US. Fetal growth abnormalities were categorized as small for gestational age (SGA) (<10th percentile) or large for gestational age (LGA) (>90th percentile) at death (stillbirth) or delivery (live birth) using population, ultrasound, and individualized norms. Gestational age at death was determined using an algorithm that considered the time-of-death interval, postmortem examination, and reliability of the gestational age estimate. Data were weighted to account for the sampling design and differential participation rates in various subgroups. Among 527 singleton stillbirths and 1,821 singleton live births studied, stillbirth was associated with SGA based on population, ultrasound, and individualized norms (odds ratio [OR] [95% CI]: 3.0 [2.2 to 4.0]; 4.7 [3.7 to 5.9]; 4.6 [3.6 to 5.9], respectively). LGA was also associated with increased risk of stillbirth using ultrasound and individualized norms (OR [95% CI]: 3.5 [2.4 to 5.0]; 2.3 [1.7 to 3.1], respectively), but not population norms (OR [95% CI]: 0.6 [0.4 to 1.0]). The associations were stronger with more severe SGA and LGA (<5th and >95th percentile). Analyses adjusted for stillbirth risk factors, subset analyses excluding potential confounders, and analyses in preterm and term pregnancies showed similar patterns of association. In this study 70% of cases and 63% of controls agreed to participate. Analysis weights accounted for differences between consenting and non-consenting women. Some of the characteristics used for individualized fetal growth estimates were missing and were replaced with reference values. However, a sensitivity analysis using individualized norms based on the subset of stillbirths and live births with non-missing variables showed similar findings.
Conclusions
Stillbirth is associated with both growth restriction and excessive fetal growth. These findings suggest that, contrary to current practices and recommendations, stillbirth prevention strategies should focus on both severe SGA and severe LGA pregnancies.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Pregnancy is usually a happy time, when the parents-to-be anticipate the arrival of a new baby. But, sadly, about 20% of pregnancies end in miscarriage—the early loss of a fetus (developing baby) that is unable to survive independently. Other pregnancies end in stillbirth—fetal death after 20 weeks of pregnancy (in the US; after 24 weeks in the UK). Stillbirths, like miscarriages, are common. In the US, for example, one in every 160 pregnancies ends in stillbirth. How women discover that their unborn baby has died varies. Some women simply know something is wrong and go to hospital to have their fears confirmed. Others find out when a routine check-up detects no fetal heartbeat. Most women give birth naturally after their baby has died, but if the mother's health is at risk, labor may be induced. Common causes of stillbirth include birth defects and infections. Risk factors for stillbirth include being overweight and smoking during pregnancy.
Why Was This Study Done?
Stillbirths are often associated with having a “small for gestational age” (SGA) fetus. Gestation is the period during which a baby develops in its mother's womb. Gestational age is estimated from the date of the woman's last menstrual period and/or from ultrasound scans. An SGA fetus is lighter than expected for its age based on observed distributions (norms) of fetal weights for gestational age. Although stillbirth is clearly associated with impaired fetal growth, the exact relationship between fetal growth and stillbirth remains unclear for two reasons. First, studies investigating this relationship have used gestational age at delivery rather than gestational age at death as an estimate of fetal age, which overestimates the gestational age of stillbirths and leads to errors in estimates of the proportions of SGA and “large for gestational age” (LGA) stillbirths. Second, many characteristics that affect normal fetal growth are also associated with the risk of stillbirth, and this has not been allowed for in previous studies. In this population-based case–control study, the researchers investigate the fetal growth abnormalities associated with stillbirth using a new approach to estimate gestational age and accounting for the effect of characteristics that affect both fetal growth and stillbirth. A population-based case–control study compares the characteristics of patients with a condition in a population with those of unaffected people in the same population.
What Did the Researchers Do and Find?
The researchers investigated all the stillbirths and a sample of live births that occurred over 2.5 years at 59 hospitals in five US regions. They used a formula developed by the Stillbirth Collaborative Research Network to calculate the gestational age at death of the stillbirths. They categorized fetuses as SGA if they had a weight for gestational age within the bottom 10% (below the 10th percentile) of the population and as LGA if they had a weight for gestational age above the 90th percentile at death (stillbirth) or delivery (live birth) using population, ultrasound, and individualized norms of fetal weight for gestational age. Population norms incorporate weights for gestational age from normal pregnancies and from pregnancies complicated by growth abnormalities, whereas the other two norms include weights for gestational age from normal pregnancies only. Having an SGA fetus was associated with a 3- to 4-fold increased risk of stillbirth compared to having a fetus with “appropriate” weight for gestational age based on all three norms. LGA was associated with an increased risk of stillbirth based on the ultrasound and individualized norms but not the population norms. Being more severely SGA or LGA (below the 5th percentile or above the 95th percentile) was associated with an increased risk of stillbirth.
What Do These Findings Mean?
These findings indicate that, when the time of death is accounted for and norms for weight for gestational age only from uncomplicated pregnancies are used, stillbirth is associated with both restricted and excessive fetal growth. Overall, abnormal fetal growth was identified in 25% of stillbirths using population norms and in about 50% of stillbirths using ultrasound or individualized norms. Although the accuracy of these findings is likely to be affected by aspects of the study design, these findings suggest that, contrary to current practices, strategies designed to prevent stillbirth should focus on identifying both severely SGA and severely LGA fetuses and should use norms for the calculation of weight for gestational age based on normal pregnancies only. Such an approach has the potential to identify almost half of the pregnancies likely to result in stillbirth.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001633.
The March of Dimes, a nonprofit organization for pregnancy and baby health, provides information on stillbirth
Tommy's, a UK nonprofit organization that funds research into stillbirth, premature birth, and miscarriage and provides information for parents-to-be, also provides information on stillbirth (including personal stories)
The UK National Health Service Choices website provides information about stillbirth (including a video about dealing with grief after a stillbirth)
MedlinePlus provides links to other resources about stillbirth (in English and Spanish)
Information about the Stillbirth Collaborative Research Network is available
doi:10.1371/journal.pmed.1001633
PMCID: PMC3995658  PMID: 24755550
19.  Predictors of Poor Perinatal Outcome following Maternal Perception of Reduced Fetal Movements – A Prospective Cohort Study 
PLoS ONE  2012;7(7):e39784.
Background
Maternal perception of reduced fetal movement (RFM) is associated with increased risk of stillbirth and fetal growth restriction (FGR). RFM is thought to represent fetal compensation to conserve energy due to insufficient oxygen and nutrient transfer resulting from placental insufficiency.
Objective
To identify predictors of poor perinatal outcome after maternal perception of reduced fetal movements (RFM).
Design
Prospective cohort study.
Methods
305 women presenting with RFM after 28 weeks of gestation were recruited. Demographic factors and clinical history were recorded and ultrasound performed to assess fetal biometry, liquor volume and umbilical artery Doppler. A maternal serum sample was obtained for measurement of placentally-derived or modified proteins including: alpha fetoprotein (AFP), human chorionic gonadotrophin (hCG), human placental lactogen (hPL), ischaemia-modified albumin (IMA), pregnancy associated plasma protein A (PAPP-A) and progesterone. Factors related to poor perinatal outcome were determined by logistic regression.
Results
22.1% of pregnancies ended in a poor perinatal outcome after RFM. The most common complication was small-for-gestational age infants. Pregnancy outcome after maternal perception of RFM was related to amount of fetal activity while being monitored, abnormal fetal heart rate trace, diastolic blood pressure, estimated fetal weight, liquor volume, serum hCG and hPL. Following multiple logistic regression abnormal fetal heart rate trace (Odds ratio 7.08, 95% Confidence Interval 1.31–38.18), (OR) diastolic blood pressure (OR 1.04 (95% CI 1.01–1.09), estimated fetal weight centile (OR 0.95, 95% CI 0.94–0.97) and log maternal serum hPL (OR 0.13, 95% CI 0.02–0.99) were independently related to pregnancy outcome. hPL was related to placental mass.
Conclusion
Poor perinatal outcome after maternal perception of RFM is closely related to factors which are connected to placental dysfunction. Novel tests of placental function and associated fetal response may provide improved means to detect fetuses at greatest risk of poor perinatal outcome after RFM.
doi:10.1371/journal.pone.0039784
PMCID: PMC3394759  PMID: 22808059
20.  Characterization of the fetal blood transcriptome and proteome in maternal anti-fetal rejection: evidence of a distinct and novel type of human fetal systemic inflammatory response 
Background
The human fetus is able to mount a systemic inflammatory response when exposed to microorganisms. This stereotypic response has been termed the “fetal inflammatory response syndrome” (FIRS), defined as an elevation of fetal plasma interleukin-6 (IL-6). FIRS is frequently observed in patients who delivered preterm associated with intra-amniotic infection (IAI), acute inflammatory lesions in the placenta, and a high rate of neonatal morbidity. Recently, a novel form of fetal systemic inflammation, characterized by an elevation of fetal plasma CXCL10, has been identified in patients with placental lesions suggestive of “maternal anti-fetal rejection”. These lesions include chronic chorioamnionitis, plasma cell deciduitis and villitis of unknown etiology (VUE). In addition, a seropositivity for HLA panel-reactive antibodies (PRA) in maternal sera can also be used as an index of suspicious for “maternal anti-fetal rejection”. The purpose of this study was to determine: 1) the frequency of pathologic evidence of “maternal anti-fetal rejection” in term and spontaneous preterm births; 2) the fetal serum concentration of CXCL10 in patients with and without evidence of maternal anti-fetal rejection; and 3) the fetal blood transcriptome and proteome in pregnancy with evidence of fetal inflammatory response associated with maternal anti-fetal rejection.
Methods
Maternal and fetal sera were obtained from normal term birth (N=150) and spontaneous preterm births (N=150). Fetal inflammatory response associated with maternal anti-fetal rejection was diagnosed when the patients met two or more of the following criteria: 1) presence of chronic placental inflammation; 2) ≥80% of maternal HLA class I panel-reactive antibody (PRA) seropositivity; and 3) fetal serum CXCL10 concentration > 75th percentile of normal. Maternal HLA PRA was analyzed by flow cytometry. The concentration of fetal CXCL10 and IL-6 were determined by ELISA. Transcriptome analysis was undertaken after extraction of total RNA from white blood cells with a whole-genome DASL assay. Proteomic analysis of fetal serum was conducted by two-dimensional difference gel electrophoresis. Differential gene expression was considered significant when there was a p<0.01 and a fold-change >1.5.
Results
1) The frequency of placental lesions consistent with maternal anti-fetal rejection was higher in patients with preterm delivery than in those with term delivery (56% vs. 32%; P<0.001); 2) patients with spontaneous preterm births had a higher rate of maternal HLA PRA class I positivity than those who delivered at term (50% vs. 32%; P=0.002); 3) fetuses who were born to mothers with positive maternal HLA PRA results had a higher median serum CXCL10 concentration than in those with negative HLA PRA results (P<0.001); 4) the median serum CXCL10 concentration (but not IL-6) was higher in fetuses with placental lesions associated with maternal anti-fetal rejection than in those without such lesions (P<0.001); 5) a whole-genome DASL assay of fetal blood RNA demonstrated differential expression of 128 genes between fetuses with and without fetal inflammatory response associated with maternal anti-fetal rejection; and 6) comparison of the fetal serum proteome demonstrated 20 proteins whose abundance differed between fetuses with and without fetal inflammatory response associated with maternal anti-fetal rejection.
Conclusions
We describe systemic inflammatory response in the fetus born to mothers with evidence of maternal anti-fetal rejection. Using high-dimensional biology techniques, the transcriptome and proteome of this novel type of fetal inflammatory response demonstrated the distinct profile from FIRS type I (which is associated with acute infection). This information is crucial to gain a mechanistic understanding of the syndrome as well as to identify biomarkers for this condition.
doi:10.1111/aji.12142
PMCID: PMC3939790  PMID: 23905683
anti-HLA panel-reactive antibody; apolipoprotein C-III; CD34; CXCL10; chronic placental inflammation; pregnancy; proteome; transcriptome
21.  Fetal demise and associated factors following umbilical cord prolapse in Mulago hospital, Uganda: a retrospective study 
Reproductive Health  2014;11:12.
Background
Umbilical cord prolapse is an obstetric complication associated with high perinatal morbidity and mortality. A few interventions may improve fetal outcome. In developed countries these have advanced to giving intrauterine fetal resuscitation. Conditions in low resource settings do not allow for some of these advanced techniques. Putting the mother in knee chest position and immediate delivery may be the only options possible.
We set out to determine the incidence of fetal demise and associated factors following umbilical cord prolapsed (UCP) in Mulago Hospital, Uganda.
Methods
In a retrospective study conducted in Mulago hospital, Uganda, file records of mothers who delivered between 1st January 2000 to 31st December 2009 and had pregnancies complicated by umbilical cord prolapse with live fetus were selected. We collected information on referral status, cord position, cervical dilatation, fetal heart state at the time of diagnosis of UCP, diagnosis to delivery interval, use of knee chest position, mode of delivery, birth weight and fetal outcome.
We computed incidence of fetal demise following UCP and determined factors associated with fetal demise in pregnancies complicated by UCP.
Results
Of 438 cases with prolapsed cord, 101(23%) lost their babies within 24 hours after birth or were delivered dead. This gave annual cumulative incidence of fetal death following UCP of 23/1000 live UCP cases delivered /year.
The major factors associated with fetal outcome in pregnancies complicated by UCP included; diagnosis to delivery interval <30 min, RR 0.79 (CI 0.74-0.85), mode of delivery, RR 1.14 (CI 1.02-1.28), knee chest position, RR 0.81 (CI 0.70-0.95).
Conclusions
The annual cumulative incidence of fetal death in our study was 23/1000 live UCP cases delivery per year for the period of 10 years studied. Cesarean section reduced perinatal mortality by a factor of 2. Diagnosis to delivery interval <30 minutes and putting mother in knee chest position were protective against fetal death.
doi:10.1186/1742-4755-11-12
PMCID: PMC3911795  PMID: 24485199
Fetal demise; Umbilical cord prolapse; Uganda
22.  Genetic evidence of heterogeneity in intrahepatic cholestasis of pregnancy 
Gut  2003;52(7):1025-1029.
Background and aims: The aim of this study was to investigate the genetic aetiology of intrahepatic cholestasis of pregnancy (ICP) and the impact of known cholestasis genes (BSEP, FIC1, and MDR3) on the development of this disease.
Patients and methods: Sixty nine Finnish ICP patients were prospectively interviewed for a family history of ICP, and clinical features were compared in patients with familial ICP (patients with a positive family history, n=11) and sporadic patients (patients with no known family history of ICP, n=58). For molecular genetic analysis, 16 individuals from two independently ascertained Finnish ICP families were genotyped for the flanking markers for BSEP, FIC1, and MDR3.
Results: The pedigree structures in 16% (11/69) of patients suggested dominant inheritance. Patients with familial ICP had higher serum aminotransferase levels and a higher recurrence risk (92% v 40%). Both segregation of haplotypes and multipoint linkage analysis excluded BSEP, FIC1, and MDR3 genes in the studied pedigrees. Additionally, the MDR3 gene, previously shown to harbour mutations in ICP patients, was negative for mutations when sequenced in four affected individuals from the two families.
Conclusions: These results support the hypothesis that the aetiology of ICP is heterogeneous and that ICP is due to a genetic predisposition in a proportion of patients. The results of molecular genetic analysis further suggest that the previously identified three cholestasis genes are not likely to be implicated in these Finnish ICP families with dominant inheritance.
PMCID: PMC1773695  PMID: 12801961
intrahepatic cholestasis of pregnancy; obstetric cholestasis; linkage analysis
23.  Effect of Maternal Intrahepatic Cholestasis on Fetal Steroid Metabolism 
Journal of Clinical Investigation  1974;53(6):1709-1715.
Estriol, estriol sulfate, progesterone, and 17 neutral steroid sulfates, including estriol precursors and progesterone metabolites, were determined in 27 cord plasma samples collected after pregnancies complicated by intrahepatic cholestasis of the mother. The levels of these steroids were compared with those in the cord plasma of 42 healthy controls.
In the cord plasma, the steroid profile after pregnancies complicated by maternal intrahepatic cholestasis differed greatly from that seen after uncomplicated pregnancy. Two main differences were found. In the disulfate fraction, the concentrations of two pregnanediol isomers, 5α-pregnane-3α,20α-diol and 5β-pregnane-3α,20α-diol, were high after cholestasis. Other investigators have shown that, as a result of cholestasis, these pregnanediol sulfates circulate in greatly elevated amounts in the maternal plasma. Our results indicate that in cholestasis these steroids cross the placenta into the fetal compartment, where they circulate in elevated amounts as disulfates. Secondly, the concentrations of several steroid sulfates known to be synthesized by the fetus were significantly lower in the cholestasis group than in the healthy controls. This was especially true of 16α-hydroxydehydroepiandrosterone sulfate and 16α-hydroxypregnenolone sulfate. These results suggest that, in pregnancies complicated by maternal intrahepatic cholestasis, impairment of fetal steroid synthesis, and especially of 16α-hydroxylation, occurs in the fetal compartment.
Thus, the changes in maternal steroid metabolism caused by cholestasis are reflected in the steroid profile of the fetoplacental circulation. Furthermore, maternal intrahepatic cholestasis may result in the production of some substance which crosses the placenta and affects fetal steroid metabolism.
PMCID: PMC302667  PMID: 4275337
24.  First description of ABCB4 gene deletions in familial low phospholipid-associated cholelithiasis and oral contraceptives-induced cholestasis 
The wide clinical spectrum of the ABCB4 gene (ATP-binding cassette subfamily B member 4) deficiency syndromes in humans includes low phospholipid-associated cholelithiasis (LPAC), intrahepatic cholestasis of pregnancy (ICP), oral contraceptives-induced cholestasis (CIC), and progressive familial intrahepatic cholestasis type 3 (PFIC3). No ABCB4 mutations are found in a significant proportion of patients with these syndromes. In the present study, 102 unrelated adult patients with LPAC (43 patients) or CIC/ICP (59 patients) were screened for ABCB4 mutations using DNA sequencing. Heterozygous ABCB4 point or short insertion/deletion mutations were found in 37% (16/43) of the LPAC patients and in 27% (16/59) of the ICP/CIC patients. High-resolution gene dosage methodologies were used in the 70 negative patients. Here, we describe for the first time ABCB4 partial or complete heterozygous deletions in 7% (3/43) of the LPAC patients, and in 2% (1/59) of the ICP/CIC patients. Our observations urge to systematically test patients with LPAC, ICP/CIC, and also children with PFIC3 for the presence of ABCB4 deletions using molecular tools allowing detection of gross rearrangements. In clinical practice, a comprehensive ABCB4 alteration-screening algorithm will permit the use of ABCB4 genotyping to confirm the diagnosis of LPAC or ICP/CIC, and allow familial testing. An early diagnosis of these biliary diseases may be beneficial because of the preventive effect of ursodeoxycholic acid on biliary complications. Further comparative studies of patients with well-characterized genotypes (including deletions) and phenotypes will help determine whether ABCB4 mutation types influence clinical outcomes.
doi:10.1038/ejhg.2011.186
PMCID: PMC3283179  PMID: 21989363
ABCB4; deletion; biliary disease; LPAC; MDR3
25.  Intrahepatic Cholestasis of Pregnancy Levels of Sulfated Progesterone Metabolites Inhibit Farnesoid X Receptor Resulting in a Cholestatic Phenotype 
Hepatology (Baltimore, Md.)  2013;57(2):716-726.
Intrahepatic cholestasis of pregnancy (ICP) is the most prevalent pregnancy-specific liver disease and is associated with an increased risk of adverse fetal outcomes, including preterm labor and intrauterine death. The endocrine signals that cause cholestasis are not known but 3α-sulfated progesterone metabolites have been shown to be elevated in ICP, leading us to study the impact of sulfated progesterone metabolites on farnesoid X receptor (FXR)-mediated bile acid homeostasis pathways. Here we report that the 3β-sulfated progesterone metabolite epiallopregnanolone sulfate is supraphysiologically raised in the serum of ICP patients. Mice challenged with cholic acid developed hypercholanemia and a hepatic gene expression profile indicative of FXR activation. However, coadministration of epiallopregnanolone sulfate with cholic acid exacerbated the hypercholanemia and resulted in aberrant gene expression profiles for hepatic bile acid-responsive genes consistent with cholestasis. We demonstrate that levels of epiallopregnanolone sulfate found in ICP can function as a partial agonist for FXR, resulting in the aberrant expression of bile acid homeostasis genes in hepatoma cell lines and primary human hepatocytes. Furthermore, epiallopregnanolone sulfate inhibition of FXR results in reduced FXR-mediated bile acid efflux and secreted FGF19. Using cofactor recruitment assays, we show that epiallopregnanolone sulfate competitively inhibits bile acid-mediated recruitment of cofactor motifs to the FXR-ligand binding domain. Conclusion: Our results reveal a novel molecular interaction between ICP-associated levels of the 3β-sulfated progesterone metabolite epiallopregnanolone sulfate and FXR that couples the endocrine component of pregnancy in ICP to abnormal bile acid homeostasis. (Hepatology 2013;)
doi:10.1002/hep.26055
PMCID: PMC3592994  PMID: 22961653

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