Bile Acid Effects in Fetal Arrhythmia Study

Brief Title

Bile Acid Effects in Fetal Arrhythmia Study

Official Title

Investigation of the Effect of Elevated Serum Bile Acids in Intrahepatic Cholestasis of Pregnancy (ICP) on the Fetal Cardiac Rhythm and on Myometrial Contractility: a Prospective Case-control Pilot Study

Brief Summary

      Intrahepatic cholestasis of pregnancy (ICP) is a liver disorder of pregnancy that typically
      presents in late pregnancy with generalised itching. ICP is associated with an increased risk
      of pregnancy complications, including premature labour, fetal distress, and stillbirth.
      Models of the fetal heart (using cells from rodents) have shown that high bile acids levels
      cause an abnormal heart rhythm (arrhythmia), which may be the cause of stillbirth. High
      levels of bile acids also cause preterm labour in animal models.

      This pilot study aims to assess whether severe ICP, defined as maternal serum bile acid
      levels ≥40μmol/L, is associated with abnormal fetal heart rhythms and abnormal myometrial
      contractility, which may lead to preterm birth.

      Fetal heart rhythms and myometrial contractility will be recorded using a portable
      electrocardiogram (ECG) device, the Monica AN24. This monitors the fetal heart and myometrial
      activity via stickers applied to the mother's abdomen. It also records the maternal ECG. It
      will also study women with uncomplicated pregnancy, in order to make comparisons.

      The importance of maternal position during sleep has also more recently been established,
      with some studies demonstrating an association between the risk of stillbirth and the
      position the mother was sleeping in. Work by Stone et al published this year has shown that
      the maternal sleep position has a significant impact on the fetal sleep state and fetal heart
      rate, (in particular something called the fetal RMSSD value). The researchers therefore wish
      to identify any potential correlation between fetal heart arrhythmia and maternal sleep
      position. To do this they will use a Zephyr BioPatchTM which provides a clear indication of
      whether the patient was in left lateral, right lateral or supine position.
    

Detailed Description

      Intrahepatic cholestasis of pregnancy (ICP) also known as obstetric cholestasis (OC) is a
      liver disorder unique to pregnancy that affects 0.5-1% of women in the UK. It typically
      presents in the third trimester of pregnancy with pruritus that can affect any part of the
      body, but is most commonly experienced on the palms and soles. Biochemically, it is
      characterised by liver dysfunction with raised serum bile acids, and clinically, by a
      significantly increased incidence of fetal complications, including spontaneous preterm
      labour, fetal distress, meconium staining of the amniotic fluid and sudden fetal death

      The aetiology of ICP is complex and incompletely understood although the maternal disease is
      likely to be caused by interaction between sex hormone metabolites and bile acids in
      genetically susceptible women . To date, genetic variation in several biliary transporters
      have been identified that predispose women to the disease. The aetiology of the adverse
      perinatal outcomes is also not fully understood.

      ICP is associated with an increased risk of adverse perinatal outcomes, including spontaneous
      preterm delivery, meconium staining of the amniotic fluid, admission to the neonatal unit and
      sudden intrauterine death. As with the maternal disease, the aetiology for the perinatal
      complications is not fully understood, but evidence from animal and in vitro studies suggests
      a role for bile acids. This hypothesis is supported by the finding that the risk of adverse
      perinatal outcomes is directly associated with the level of maternal serum bile acids, and
      specifically with maternal serum bile acids exceeding 40 μmol /L, i.e. severe ICP.

      Of the adverse perinatal outcomes associated with ICP, the most severe is sudden intrauterine
      death, which is reported to affect between 2 and 4% of ICP pregnancies. The mechanism for
      fetal demise is unclear, but is appears to be a sudden event as there are several case
      reports of normal fetal movements and CTG recordings in the hours preceding fetal demise.
      Furthermore, at post-mortem there is typically no evidence of preceding uteroplacental
      insufficiency, and the babies are appropriately grown. One possible explanation for the
      sudden intrauterine death is an acute cardiac arrhythmia leading to fetal cardiac arrest.
      This hypothesis is supported by evidence from in vitro studies of cultured neonatal rat
      cardiomyocytes which demonstrate the development of arrhythmias following the addition of
      bile acids to the culture (Williamson et al., 2001). Further studies have shown that this
      effect is dose dependent and reversed by the addition of ursodeoxycholic acid (UDCA), the
      drug commonly used to treat ICP. However, there are very few case reports in the literature
      of fetal heart abnormalities in women with ICP, but studies have reported bradycardias,
      tachycardias and atrial flutter. Prolongation of the PR interval in the fetal echocardiogram
      has also been reported; this clinical feature has been known to predispose the heart to
      arrhythmias. A recent study using the same technique has also reported fetal diastolic
      dysfunction in patients with severe ICP. Given the paucity of human clinical data regarding
      the fetal heart rhythm in ICP, the researchers propose to undertake this study to investigate
      whether ICP is associated with fetal arrhythmias and the influence of bile acid levels on
      fetal heart rhythm. In parallel they will evaluate whether there is fetal ventricular
      dysfunction.

      Recent studies have shown that maternal lie has an association with stillbirth; an increased
      risk of stillbirth was observed when women slept in a supine or right lateral position. Stone
      et al published data from a study where the Monica AN24, a transabdominal fetal
      electrocardiogram (fECG) monitor, was used on mothers lying in supine, left and right lateral
      positions. They found that the fetal short-term heart rate variability (RMSSD) changed
      depending on the position the mother was lying in. Unpublished data also using the Monica
      AN24 has demonstrated an association between maternal lie and maternal RMSSD (Fifer et al,
      personal communication). As the RMSSD is one of the principal measures the research team will
      be using to detect arrhythmogenic activity, analysis will include the detection of maternal
      lie in order to accurately determine short-term heart rate variability.

      There is limited evidence that the maternal heart is affected by ICP to cause maternal rhythm
      disturbance, although there is one report of prolonged maternal QT interval. The fetal heart
      develops in an environment of relative hypoxia and this is associated with the transformation
      of human fetal cardiac fibroblasts into myofibroblasts, which subsequently disappear
      post-natally. Myofibroblasts may re-appear in the diseased adult heart during the process of
      remodelling following infarction, and have been shown to act as an arrhythmogenic focus in
      these circumstances. Interestingly, in vitro data have demonstrated that the myofibroblasts
      also act as the arrhythmogenic focus in bile acid induced arrhythmia in the neonatal heart.
      UDCA has also been demonstrated to protect against bile acid-induced arrhythmias in
      myofibroblasts.

      ICP is also associated with an increased risk of spontaneous preterm labour. Again, the
      reasons for this are unclear, but evidence from animal studies suggests that bile acids may
      be involved. Bile acid infusions cause spontaneous preterm labour in sheep and in vitro
      studies have shown that they increase the sensitivity of the myometrium to the hormone
      oxytocin which is central to the process of labour. Human data regarding myometrial
      contractility are lacking. As a secondary aim of this study, the research team also propose
      to investigate whether ICP is associated with abnormal myometrial contractility.

      Data regarding fetal cardiac rhythms and myometrial contractility collected from women with
      ICP will be compared to data collected from women with uncomplicated pregnancy. The inclusion
      of women with uncomplicated pregnancies will ensure that any variation identified in the
      fetal cardiac rhythms or myometrial contractility in women with ICP is attributable to the
      condition, rather than a variant of normal. The parallel recording of the maternal ECG in
      both women with ICP and women with uncomplicated pregnancy will enable the research team to
      ensure that any abnormal fetal cardiac rhythms are not due to an inherited arrhythmia.

      Fetal and maternal ECG, and myometrial contractility data will be collected using the Monica
      AN24 device. This is a small wearable monitor that continuously records maternal and fetal
      ECG's, and myometrial activity data via electrodes placed on the maternal abdomen. Maternal
      lie will be detected using the Zephyr BioPatchTM. This wearable monitor is much smaller than
      the Monica AN24 and also functions via adhesive electrodes. It is placed at the base of the
      breastbone of the participant.
    


Study Type

Observational


Primary Outcome

Measurement of the influence of maternal bile acids levels on fetal ECG

Secondary Outcome

 Measurement of the influence of fetal bile acids levels on fetal ECG

Condition

Cholestasis of Pregnancy

Intervention

Monica AN24

Study Arms / Comparison Groups

 Cases and Controls
Description:  Cases - Pregnant women with ICP defined as pruritus in pregnancy in association with raised serum bile acids (using hospital threshold for diagnosis), and in the absence of an alternative cause.
Controls - Pregnant women not affected by ICP, or other liver, cardiac or hypertensive disorders.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Device

Estimated Enrollment

400

Start Date

February 27, 2015

Completion Date

March 31, 2020

Primary Completion Date

March 31, 2020

Eligibility Criteria

        Inclusion Criteria:

          -  CASES - Pregnant women with ICP defined as pruritus in pregnancy in association with
             raised serum bile acids (using hospital threshold for diagnosis), and in the absence
             of an alternative cause.

          -  CONTROLS - Pregnant women not affected by ICP, or other liver, cardiac or hypertensive
             disorders.

          -  Pregnant women who are willing and able to give consent.

          -  Pregnant women ≥ 18 years of age.

        Exclusion Criteria:

          -  Non-pregnant women.

          -  Pregnant women with medical disorders that can cause liver impairment in pregnancy
             e.g. pre-eclampsia, acute fatty liver of pregnancy, diabetes mellitus.

          -  Pregnant women with a history of pre-existing liver or cardiac

          -  Pregnant women with current hypertensive disease (this would include women taking
             drugs such as methyldopa, labetolol, atenolol, bisoprolol, nifedipine, amlodipine)

          -  Pregnant women who are expecting more than one baby.

          -  Pregnant women with blood-borne viruses e.g. HIV and hepatitis.

          -  Women ≤ 18 years of age.

          -  Pregnant women expecting a baby with a structural heart abnormality identified

          -  Women unable or unwilling to give informed consent.
      

Gender

Female

Ages

18 Years - N/A

Accepts Healthy Volunteers

Accepts Healthy Volunteers

Contacts

Catherine Williamson, 0207 848 6202, [email protected]

Location Countries

United Kingdom

Location Countries

United Kingdom

Administrative Informations


NCT ID

NCT03519399

Organization ID

RJ115/N071


Responsible Party

Sponsor

Study Sponsor

Guy's and St Thomas' NHS Foundation Trust

Collaborators

 King's College London

Study Sponsor

Catherine Williamson, Principal Investigator, King's College London


Verification Date

July 2019