TREATMENT OF INTRAHEPATIC CHOLESTASIS OF PREGNANCY (OBSTETRIC CHOLESTASIS)

Intrahepatic cholestasis of pregnancy (ICP), also known as obstetric cholestasis, is a pregnancy-specific liver condition with onset most commonly in the third trimester.

Maternal signs and symptoms of ICP include pruritus and raised serum bile acids; abnormal liver function (ALT/AST) is also a common feature. The pruritus can cause sleep disturbance and can adversely affect quality of life, but ICP is otherwise not detrimental to maternal health. ICP is, however, associated with serious risks to the fetus, including stillbirth, rates of which are thought to be particularly elevated with maternal serum bile acid concentrations >100 µmol/L. Other adverse outcomes associated with ICP include neonatal respiratory distress secondary to meconium aspiration, preterm delivery (spontaneous and iatrogenic) and the potential for fetal and neonatal bleeding disorders. Fetal monitoring has not been shown to predict or to reduce the risk of adverse perinatal outcomes in pregnancies affected by ICP, but may be offered to provide reassurance. Regular monitoring of maternal serum bile acid levels and liver function is routine; serum bile acid levels may predict the risk of stillbirth and the requirement for delivery. All women with ICP should be offered consultant-led care and delivery at a hospital unit.

Symptomatic treatments to reduce the sensation of itch include topical emollients (with or without menthol) and sedating antihistamines. The most widely used pharmacological treatment to reduce bile acid concentrations in ICP is ursodeoxycholic acid (UDCA). Rifampicin is also occasionally used on a case-by-case basis as an adjunct to UDCA if bile acid levels are extremely high.

ICP is associated with an increased risk of vitamin K deficiency due to reduced enterohepatic recirculation of bile acids and resultant malabsorption of fats and fat-soluble vitamins. Although there are no randomised controlled clinical trials that support or refute the use of vitamin K, the Royal College of Obstetricians and Gynaecologists (RCOG) guidelines recommend maternal and neonatal vitamin K supplementation.

Exposure to the medications included in this monograph at any stage in pregnancy would not usually be regarded as medical grounds for termination of pregnancy or any additional fetal monitoring. However, other risk factors may be present in individual cases which may independently increase the risk of adverse pregnancy outcome. Clinicians are reminded of the importance of consideration of such factors when performing case-specific risk assessments.

USE OF ONDANSETRON IN PREGNANCY

Ondansetron is a selective 5-HT3 serotonin antagonist used in the treatment of chemotherapy-induced and post-operative nausea and vomiting, and off-licence for nausea and vomiting in pregnancy (NVP) and hyperemesis gravidarum (HG).

The currently available data do not provide evidence that ondansetron use in the first trimester of pregnancy is associated with an increase in the overall malformation rate.

Although small numbers of studies have described statistically significant increased risks of both overall and specific cardiac malformations, namely septal defects, these data are conflicting. Furthermore, most of these studies did not utilise disease-matched ondansetron unexposed control groups, therefore the possibility of confounding cannot be excluded.

Several studies have suggested that associations may exist between maternal ondansetron use and fetal orofacial clefts, specifically cleft palate alone. Whilst the available data are conflicting, should a true association exist, the absolute risk is likely to remain small (background rate ~0.11% vs. ondansetron-exposed rate ~0.14%).

Four studies which utilised data from three unique datasets have also suggested possible associations with overall or specific renal malformations. These observations require further investigation before more definitive conclusions can be drawn.

Studies investigating miscarriage, intrauterine death/stillbirth, low birth weight, preterm delivery and neurodevelopmental impairment risks are more limited than those investigating malformation risks, but do not currently provide evidence suggestive of an increased risk of these outcomes following maternal ondansetron use in pregnancy.

Ondansetron should only be used during pregnancy where the benefits of treatment are considered to outweigh any potential fetal risks. Exposure to ondansetron at any stage in pregnancy would not usually be regarded as medical grounds for termination of pregnancy or any additional fetal monitoring. However, other risk factors may be present in individual cases which may independently increase the risk of adverse pregnancy outcome. Clinicians are reminded of the importance of consideration of such factors when performing case-specific risk assessments.

USE OF ORLISTAT IN PREGNANCY

Orlistat is an orally administered gastric and pancreatic lipase inhibitor which reduces the absorption of dietary fat. It is used in conjunction with dietary measures to enhance weight loss in adults who are overweight (BMI ≥25). Systemic absorption of orlistat is expected to be negligible.

The limited data on the use of orlistat in pregnancy do not suggest an increased risk of fetal congenital malformation or miscarriage but are too limited to exclude such risks. There are no data available regarding intrauterine death, preterm delivery, low birth weight or neonatal complication risks.

As orlistat may impair the absorption of fat soluble vitamins (A, D, E and K), there are theoretical concerns that its use during pregnancy may restrict nutrient availability to the fetus. Given that the available fetal safety data are too limited to provide robust evidence-based recommendations regarding use in pregnancy, routine use in pregnancy is not recommended.

Maternal obesity is associated with an increased risk of congenital malformations and adverse maternal and fetal outcomes; weight loss preconception is therefore recommended. Pregnant women with a BMI>30 should be advised to take 5mg folic acid supplementation one month before conception up until the end of the first trimester. Dieting or use of products to lose weight during pregnancy is not recommended.

Experience of orlistat use in pregnancy is limited. Where exposure in the first trimester has occurred, a detailed fetal anomaly scan should be considered in addition to any other antenatal investigations relating to the maternal obesity, and the drug discontinued as soon as pregnancy is diagnosed. Women and health professionals should be aware that antenatal detection of fetal anomalies is compromised with increasing BMI, and that a normal scan is not informative with respect to neurodevelopmental outcomes. Other risk factors which independently increase the risk of adverse pregnancy outcome may be present in individual cases. Clinicians are reminded of the importance of consideration of such factors when performing case-specific risk assessments.                        

USE OF OSELTAMIVIR IN PREGNANCY

Oseltamivir is an oral neuraminidase inhibitor (NI) used in the treatment of influenza infection (licensed for use within 48 hours of the first symptoms), for post-exposure prophylaxis in at-risk groups when influenza is circulating in the community, and to prevent influenza in exceptional circumstances, such as during a pandemic. Oseltamivir is not currently recommended for seasonal prophylaxis against influenza.

Oseltamivir was the NI of choice for use in pregnancy in most countries other than the UK during the 2009 H1N1 pandemic, and as a result is the NI for which there is the most experience of use in pregnancy. In the UK, oseltamivir is therefore currently recommended over zanamivir for the treatment/prophylaxis in pregnant women, except in cases of known or suspected oseltamivir resistance. UK guidelines may, however, change and readers are advised to consult Public Health England guidance directly or to contact UKTIS for current recommendations.

Human data relating to oseltamivir use in pregnancy are, however, still limited. There is currently no signal of a teratogenic effect, or increased risk of other adverse fetal effects, but data for some outcomes are too limited to exclude an increased risk to the fetus. Evidence from the H1N1 pandemic demonstrated that prompt treatment of influenza in pregnancy with neuraminidase inhibitors improves maternal outcomes. The maternal and fetal risks of untreated influenza infection in pregnancy may be significant and the benefits of treatment with oseltamivir are therefore likely to outweigh any theoretical risks to the fetus.

Exposure to oseltamivir at any stage in pregnancy would not usually be regarded as medical grounds for termination of pregnancy or any additional fetal monitoring. However, other risk factors may be present in individual cases which may independently increase the risk of adverse pregnancy outcome. Clinicians are reminded of the importance of consideration of such factors when performing case-specific risk assessments.

USE OF OXPRENOLOL IN PREGNANCY

Oxprenolol is a cardioselective beta blocker licensed for the treatment of hypertension, angina pectoris, cardiac arrhythmias, myocardial infarction, adjunctive management of thyrotoxicosis, and prophylaxis of migraine.

There are no published data on overall rates of congenital malformation following oxprenolol use in pregnancy. A single case-control study found a possible association between first trimester oxprenolol exposure and cleft lip and/or palate. A further case-control study found no association between gestational oxprenolol use and neural tube defects. Both of these findings require ongoing research for confirmation. Limited data do not suggest that exposure to oxprenolol in utero adversely affects fetal growth or gestational length; however further studies are required as reduced fetal growth has been observed following gestational exposure to other beta blockers. Data are too limited to permit an evidence-based assessment of the risks of miscarriage, stillbirth, preterm delivery and adverse neurodevelopmental effects following gestational oxprenolol exposure.

Use of beta blockers near term may result in beta-adrenoceptor blockade, leading to neonatal bradycardia, hypotension and hypoglycaemia. However, there are no data on rates of these neonatal complications in oxprenolol-exposed infants and the absolute risk therefore remains unquantified. Assessment of the neonate for these effects is advised until more robust data become available.

Exposure to oxprenolol at any stage of pregnancy would not usually be regarded as medical grounds for termination. In pregnancies complicated by maternal hypertension and/or where oxprenolol has been administered, careful monitoring of fetal growth is advised. Other risk factors may also be present in individual cases which may independently increase the risk of adverse pregnancy outcome. Clinicians are reminded of the importance of considering such factors when performing case-specific risk assessments.

Related document: Use of beta blockers in pregnancy

USE OF OXYCODONE IN PREGNANCY

Oxycodone is a semisynthetic opioid analgesic administered orally, intramuscularly or intravenously for the treatment of moderate to severe pain.

There is no indication that maternal therapeutic use of oxycodone in early pregnancy increases overall congenital malformation rates in exposed offspring, but the available data are not sufficient to exclude an increase in risk. One small study assessed the risk of miscarriage and found no evidence of an association with maternal therapeutic oxycodone exposure. One study, with at least 2,000 exposed pregnancies assessed for each outcome, found that oxycodone exposure in the first and second, but not the third trimester, was associated with a small increased risk of preterm delivery (absolute risk ~10% vs. background risk ~7%). However, it is unclear whether residual data confounding may have contributed to this finding, particularly as later pregnancy exposures are generally thought more likely to influence preterm delivery risk. In the same study, exposure in any trimester was not associated with either stillbirth or SGA infants. No studies have assessed neurodevelopmental outcomes or rates of childhood cancer in the offspring following maternal use of oxycodone.

Use of any opioid during pregnancy, particularly around the time of delivery, confers a risk of neonatal respiratory depression and neonatal withdrawal, both of which have been described following in utero oxycodone exposure. Exposed infants should be delivered in a hospital setting and monitored for these effects.

Where oxycodone poisoning occurs in pregnancy, maternal toxicity is likely to be a major factor in determining any risk to the fetus. However, due to a lack of sufficient poisoning in pregnancy exposure data, an increased risk of adverse outcomes in the absence of maternal toxicity cannot currently be excluded. If use of an antidote (e.g. naloxone) is required in the management of maternal toxicity it should not be withheld on account of pregnancy.

Exposure to oxycodone at any stage in pregnancy would not usually be regarded as medical grounds for termination of pregnancy. However, other risk factors may be present in individual cases which may independently increase the risk of adverse pregnancy outcome. Clinicians are reminded of the importance of consideration of such factors when performing case-specific risk assessments. Enhanced fetal monitoring may be warranted during instances of maternal toxicity

USE OF OLANZAPINE IN PREGNANCY

Olanzapine is an atypical antipsychotic (AAP) used in the treatment of schizophrenia, manic episodes and recurrence in bipolar disorder. 

Congenital malformation rates specifically following olanzapine exposure have been statistically analysed in a collective total of ~2,500 pregnancies. There is currently no indication of an increased risk of major congenital malformation or of heart defects specifically. Rates of other specific malformation subtypes have not been statistically assessed. Miscarriage rates following first trimester olanzapine exposure have been quantified in a collective total of just 223 women. While there is currently no evidence of an association with olanzapine exposure, larger studies are required to confirm this finding. Data relating to other pregnancy outcomes following maternal olanzapine exposure are either extremely limited or are absent, thus precluding evidence-based risk assessments.

Studies of antipsychotics (APs)/AAPs as therapeutic classes that include a collective total of >13,600 exposures do not raise concerns of adverse pregnancy outcomes directly related to use. Although findings relating to stillbirth and preterm delivery rates are conflicting, the studies reporting positive findings for these outcomes were not adequately controlled and further research is therefore required to confirm or refute these associations. Neurodevelopmental outcomes following in utero exposure to APs have not been sufficiently studied to permit any assessment of risk.

In the non-pregnant population, use of AAPs (particularly olanzapine and clozapine) is a risk factor for impaired glucose homeostasis and type 2 diabetes. There are therefore concerns of an increased risk of maternal gestational diabetes mellitus (GDM) and its sequelae following gestational olanzapine use, and the two studies that assessed GDM rates following specific olanzapine exposure suggest a possible association. An increased risk of fetal macrosomia following gestational exposure to olanzapine is therefore also possible.

Use of olanzapine and other APs throughout pregnancy or near delivery has been associated with withdrawal symptoms in the neonate and/or poor neonatal adaptation syndrome (PNAS). These symptoms are likely to be more severe in infants exposed in utero to more than one CNS acting drug. Delivery should therefore be planned in a unit with neonatal intensive care facilities.

It is important to ensure that maternal mental health conditions are treated appropriately. Where a woman’s illness is well-controlled on olanzapine, either prior to conception or during pregnancy, the risk of discontinuing or changing medication, or reducing the dose, should be carefully weighed against the risk of relapse. Where clinically appropriate, clinicians are encouraged to discuss the advantages and disadvantages of continued olanzapine use during pregnancy with the patient. Where the benefit of continued treatment is considered to outweigh any potential or known risks, olanzapine may be prescribed for use in pregnancy.

ORGANOPHOSPHATE POISONING IN PREGNANCY

Organophosphates (OPs) are esters of phosphoric acid widely used as domestic and industrial insecticides and pesticides. OPs are also used in chemical warfare as nerve agents. OPs are often diluted in an organic solvent and exposure can occur from ingestion, inhalation, dermal, and ocular exposure.

Numerous studies have raised concerns about possible adverse effects on pregnancy outcome following chronic low dose OP pesticide exposure due to residential or occupational proximity to agricultural areas.

Data on acute OP exposure/poisoning in pregnancy are limited to case reports. Due to the lack of data and the possible adverse associations reported with chronic, low dose exposure to pesticides in general, an increase in risk cannot be ruled out. Where maternal toxicity is present, particularly when exposure occurs close to term or delivery, there may be a risk of neonatal toxicity.

There are no guidelines regarding the treatment of OP poisoning during pregnancy. Maternal toxicity following OP exposure is likely to be a major determinant of risk to the fetus. Management of the pregnant patient should be the same as for the non-pregnant patient. Where a specific antidote is clinically indicated this should not be withheld on account of pregnancy.

Where exposure to OPs has occurred in pregnancy, enhanced maternal and fetal monitoring may be warranted. Discussion with UKTIS is recommended.

OCCUPATIONAL CYTOTOXIC MEDICATION EXPOSURE IN PREGNANCY

Cytotoxic medications are generally used in the chemotherapeutic management of cancer and some autoimmune conditions. These medications act through a variety of pharmacological mechanisms which can include the inhibition of cell division and/or induction of cellular apoptosis.

As studies have shown that occupational exposure to some cytotoxic agents can result in systemic absorption, such exposure during pregnancy could theoretically result in fetal exposure. The available data concerning occupational cytotoxic medication exposure in human pregnancy currently consists of 15 controlled studies and two meta-analyses which collectively provide the outcomes of more than 9,000 unique exposed pregnancies. Much of these data are provided from studies of occupational exposure undertaken prior to current workplace health and safety legislation relating to handling of cytotoxic medication. As such, the available data may serve as a poor predictor of fetal exposure risks when current legislation regarding appropriate precautionary measures is adhered to.

Although some studies have described increased risks of congenital malformation, spontaneous abortion, ectopic pregnancy, preterm delivery and low birth weight, the data are conflicting and often confounded. As such, the available data are not considered to provide sufficient evidence of an increased risk of adverse pregnancy outcomes following occupational exposure.

Due to a lack of evidence indicating that occupational exposure to cytotoxic medication during pregnancy is without risk, caution is advised where possible or continued exposure during pregnancy may occur. In such cases use of personal protective equipment and adherence to standard handling precautions is advised.

Inadvertent occupational exposure to cytotoxic medication at any stage in pregnancy would not usually be regarded as medical grounds for termination of pregnancy or additional monitoring where PPE has been used and procedures to limit exposure have been followed. However, other risk factors may be present in individual cases which may independently increase the risk of adverse pregnancy outcome. Clinicians are reminded of the importance of consideration of such factors when performing case-specific risk assessments. Where systemic maternal absorption is thought likely, an individual case assessment by UKTIS is advised.

OCCUPATIONAL EXPOSURE TO CHEMICALS IN PREGNANCY

For the majority of chemicals used in the workplace, although there is knowledge of general toxicity, there are no robust data quantifying fetal outcomes following exposure in human pregnancy.

In most cases of chemical exposure in a pregnant woman, maternal toxicity is likely to be a major determinant of risk to the fetus. However, due to a lack of data relating to the potential teratogenicity of most chemicals, it is not possible to state that an absence of maternal toxicity excludes the possibility of adverse fetal effects.

It is therefore important to read product labels and safety data sheets before using chemicals and to use chemicals in the recommended way.

If a pregnant woman is likely to come into contact with chemicals at work, an occupational health assessment is recommended as early in pregnancy as possible.

General recommendations:

1. Exposure to chemicals should be kept to a minimum; certainly within the occupational exposure standards (OESs) and maximum exposure limits (MELs) recommended by the Control of Substances Hazardous to Health (COSHH) Regulations 2002.

2.  Exposure should not be associated with symptoms suggestive of toxicity.

3. The work area should be well ventilated.

4.  Personal protective equipment (PPE) such as protective clothing, masks, and gloves should be utilised if appropriate, and good working practices maintained.

5.  If maternal toxicity occurs, further exposure to the chemical should be ceased immediately and a full occupational health assessment undertaken.

6.  If toxic symptoms occur the exposed party should attend A&E and/or advice should be sought from the national poisons information service (NPIS).

7.  Where maternal toxicity has occurred, additional fetal monitoring or intervention may be indicated, taking into account the stage of pregnancy at which the exposure occurred.

Where advice is required regarding exposure during pregnancy to a specific chemical please refer to the individual UKTIS monograph if available, or contact UKTIS for more information. The full list of available monographs is at uktis.org