Letter: E

Etanercept is a human tumour necrosis factor (TNF) receptor p75 Fc fusion protein monoclonal antibody. It is used in the treatment of rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, non-radiographic axial spondyloarthritis, and plaque psoriasis where other systemic therapies are ineffective or unsuitable.

Maternal autoimmune/inflammatory conditions are known to increase the risk of certain adverse pregnancy outcomes, including miscarriage, preterm delivery and low infant birth weight, particularly where the maternal condition is poorly controlled either around the time of conception and/or during pregnancy. Studies that have included disease-matched control groups suggest no additional increased risks relating to use of anti-TNFα therapies.

Studies that provide data on the safety of etanercept use in pregnancy collectively describe more than 1,200 exposed pregnancies, with first trimester exposure confirmed in 389. These data do not indicate that etanercept use in pregnancy increases the overall risk of congenital malformation, or any of specific malformation/pattern of malformations. The available evidence also does not suggest that increased risks of miscarriage, intrauterine death, preterm delivery or impaired fetal growth exist following etanercept use in pregnancy. A small number of uncontrolled case reports have described normal childhood development up to 3 years of age.

Use of immunosuppressant antibodies that actively cross the placenta during pregnancy could result in immunosuppression in the neonate and increase the risk of infection. Rare cases of fatal infection following BCG vaccination after in utero anti-TNFα exposure have been described in the literature. General guidance has been provided from a number of authorities around avoiding/deferring live vaccine use in infants exposed to etanercept in utero. These recommendations vary depending on both the circumstances of etanercept exposure and infant infection risk. UKTIS recommend a case-specific risk assessment approach when considering the use of live vaccines following in utero etanercept exposure. Discussion with UKTIS is recommended in all cases where use of a live vaccine is being considered in an infant <12 months of age where there has been in utero exposure to etanercept.

Pregnant women treated with etanercept are likely to be offered additional fetal growth monitoring due to their underlying medical condition; no additional fetal monitoring is required as a result of etanercept exposure specifically. 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.

Ethylene glycol is an odourless, colourless, sweet-tasting liquid used as a coolant in brake fluid and antifreeze, and a precursor in polymer manufacture.

As with all chemicals, unnecessary exposure to ethylene glycol should be avoided during pregnancy. However, where occupational exposure is unavoidable, precautions should be taken to ensure that exposure is well within the recommended exposure limits and not associated with toxic symptoms.

The available data relating to occupational and acute ethylene glycol exposure in pregnancy are highly limited, consisting of a small number of exposed pregnancies detailed in descriptive studies.

Maternal toxicity associated with ethylene glycol exposure is likely to be a major determinant of risk to the fetus. However, due to the limited available data regarding the teratogenicity of ethylene glycol, it is not currently possible to state that an absence of maternal toxicity excludes the possibility of adverse events occurring in the developing fetus.

As ethylene glycol is highly toxic, where cases of poisoning occur in pregnancy, treatment should be as for the non-pregnant patient and should not be withheld on account of pregnancy. There are very limited data available concerning the use of the antidotes fomepizole and ethanol in pregnancy. However, when indicated, the maternal and fetal benefits of antidote treatment will outweigh the risks associated with untreated ethylene glycol poisoning. If treatment with an antidote is required, then fomepizole is preferred at all stages of pregnancy as ethanol can cause harmful fetal effects. However, where fomepizole is either unavailable or not considered appropriate, ethanol should not be withheld on account of pregnancy.

Exposure to ethylene glycol alone 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. In all cases of ethylene glycol exposure in pregnancy, extended maternal and fetal monitoring may be warranted. Discussion with UKTIS is recommended in all cases.

Everolimus is a tyrosine kinase inhibitor indicated (by specific brand) for: (i) the treatment of advanced renal cell carcinoma, neuroendocrine tumours of pancreatic, gastrointestinal or lung origin, and hormone receptor-positive advanced breast cancer; (ii) the prevention of graft rejection following renal, liver or heart transplantation; (iii) the treatment of subependymal giant cell astrocytoma, renal angiomyolipoma, and refractory seizures associated with tuberous sclerosis complex.

The data relating to human gestational everolimus exposure are extremely limited, consisting of case reports of eight pregnancies. While all reported pregnancies resulted in live-born, non-malformed infants, in the absence of controlled studies it is not currently possible to quantify the risk of adverse pregnancy outcome following gestational everolimus exposure. Pregnant women or those planning a pregnancy using everolimus should be offered specialist review so that an individualised assessment of the possible risks and benefits of switching or continuing their medication can be discussed.

Due to the unknown effects of everolimus on a developing fetus, gestational exposure may be regarded as medical grounds for additional fetal monitoring, including regular assessment of fetal growth and wellbeing. In pregnant women in whom use of everolimus is indicated, other factors, including the effects of the underlying maternal condition, 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.

Eye drops are used to administer medication to the eye and, depending on the condition being treated, may contain steroids, antibiotics, antihistamines, sympathomimetics, prostaglandins, beta-blockers, parasympathomimetics, parasympatholytics, non-steroidal anti-inflammatory drugs (NSAIDs) or topical anaesthetics.

There are few published data on the potential fetotoxic effects of topical ophthalmic medications in human pregnancy. Pharmacokinetic data on the systemic absorption of individual preparations are also lacking. However, many of the drugs found in eye drops are administered systemically in pregnancy without conclusive evidence of an increased risk of congenital malformation or other adverse pregnancy outcome in the offspring. Although it is therefore unlikely that ocular administration of such drugs will be associated with an increased risk of fetal toxicity if the dose used does not exceed that of systemic regimes, medications which have known fetal effects following systemic use should be used with caution as some systemic absorption of ocular preparations is possible. Where ocular use of a potentially teratogenic preparation is considered necessary in pregnancy, discussion with the patient should include both the risks of not treating the condition as well as any known or theoretical risks to the fetus.

Exposure to topical ophthalmic medications at any stage in pregnancy would not usually be regarded as medical grounds for termination of pregnancy. The need for additional fetal monitoring should be assessed based on the specific medication. Other risk factors which independently increase the risk of adverse pregnancy outcome may also be present in individual cases. Clinicians are reminded of the importance of consideration of such factors when performing case-specific risk assessments.

Please refer to the UKTIS monograph for each specific medication where available.

Escitalopram is a selective serotonin reuptake inhibitor (SSRI) used in the treatment of depression, panic disorder, with or without agoraphobia, generalised and social anxiety disorder, and obsessive-compulsive disorder.

Although limited, data on the risk of congenital malformation following escitalopram use in early pregnancy are generally reassuring. The available studies, including two meta-analyses, provide no evidence of an increased rate of overall congenital malformation or overall cardiovascular malformation, and the majority of studies investigating specific cardiovascular malformations have not identified increased risks for escitalopram-exposed infants. However, two studies have associated escitalopram use in early pregnancy with possible increased risks of atrioventricular septal defects, with an increased risk of Ebstein’s anomaly also identified in one. These findings, which may be confounded, require confirmation in future studies.

The incidence of miscarriage, preterm delivery or intrauterine death has not been shown to be increased following escitalopram exposure in a small number of studies. However, a single study has provided evidence of a possible increase in the risk of low birth weight. As the available data are limited, the possibility of an increased risk for any of the above outcomes cannot be excluded, although the data are likely confounded.

In utero exposure to SSRIs in the weeks prior to delivery confers a risk of transient neonatal withdrawal syndrome and infants should be delivered in hospital and monitored for central nervous system, motor, respiratory and gastrointestinal symptoms.

An increased risk of persistent pulmonary hypertension of the newborn (PPHN) has been reported following exposure to SSRIs as a class beyond 20 weeks of gestation. The current estimate of the absolute risk of PPHN following SSRI exposure is <0.4% (background rate 0.1 to 0.2%), suggesting that it remains uncommon following exposure. However, as PPHN is potentially serious, this should be discussed with women considering SSRI use in pregnancy.

The Medicines and Healthcare products Regulatory Authority (MHRA) has advised that there is a small overall increased risk of postpartum haemorrhage (PPH) attributable to SSRI/SNRI use in the month prior to delivery, but this risk may be higher in women with other risk factors for abnormal bleeding. Studies have identified up to a 1.3-fold increased risk following gestational use of an SSRI; should this prove accurate, the absolute risk of PPH among SSRI-exposed women would range from 13 to 20% (background 10 to 15%). Careful assessment of the risk of PPH versus the risk of maternal relapse, should the medication be discontinued, is advised when considering continued SSRI/SNRI antidepressant use in late pregnancy. Prescribers are also encouraged to ensure maternal compliance with heparin self-administration in all pregnant women with risk factors for venous thromboembolism.

It is important to ensure that mental health conditions are treated appropriately. As such, escitalopram may be suitable for use in pregnancy following an individualised assessment of the risks and benefits. Where clinically appropriate, non-pharmaceutical management of depression and/or anxiety could be considered during pregnancy. However, where a patient is stabilised on escitalopram, either prior to conception or during pregnancy, the risk of discontinuing treatment, changing the medication or reducing the dose, should be carefully weighed against the risk of maternal relapse. In cases where treatment with escitalopram is continued in pregnancy, the lowest effective dose should be used.

Exposure to escitalopram at any stage in pregnancy would not usually be regarded as medical grounds for termination of pregnancy, or any additional fetal monitoring. 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.

Esmolol is a cardioselective beta blocker used in the short-term treatment of supraventricular arrhythmias, tachycardia, and hypertension in the perioperative period.

There are no studies of rates of specific pregnancy outcomes following gestational exposure to esmolol. An evidence-based assessment of the potential risks of congenital malformation, miscarriage, stillbirth, intrauterine growth restriction (IUGR), preterm delivery and adverse neurodevelopmental effects following in utero exposure is therefore not possible.

Studies of beta blockers as a class do not show that use during pregnancy is associated with fetal structural malformation. Use of beta blockers in pregnancy has been associated with adverse effects on fetal growth, although because maternal hypertension is linked to intrauterine growth restriction, the relative contribution of beta blocker exposure to this outcome remains unquantified. Overall, data do not suggest that gestational beta blocker exposure increases the risk of preterm delivery. Data on rates of miscarriage, stillbirth and neurodevelopmental outcomes are too limited to permit a risk assessment.

Use of beta blockers near term may result in neonatal beta-adrenoceptor blockade, leading to neonatal bradycardia, hypotension and hypoglycaemia. Respiratory distress has also been reported. Assessment of the neonate for these effects is advised.

Exposure to esmolol at any stage in pregnancy would not be regarded as medical grounds for termination of pregnancy. Additional fetal monitoring is generally indicated in pregnancies complicated by maternal cardiac disease, regardless of pharmacotherapy. Additional growth scans should be offered following gestational exposure to beta blockers. 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.

Related document: Use of beta blockers in pregnancy

Essential oils are scented volatile aromatic compounds extracted from plants. They are used in perfumes, cosmetics, flavourings, and in aromatherapy. There are no epidemiological or evidence-based studies on the safety of essential oils during pregnancy. The only available published data are a small number of anecdotal case reports, and opinion on essential oil safety in pregnancy has historically been based on unpublished experience.

Commercially available toiletry products usually contain a low concentration of essential oils (typically <0.01%) and use according to the manufacturer’s instructions is not thought to increase the risk of adverse pregnancy outcomes.

Although no specific adverse effects on the fetus have been documented, topical exposure to higher concentrations of oils (e.g. during a massage) may be associated with a theoretical risk  as a number of oils are thought to have abortifacient properties when ingested and pregnancy outcomes following use have not been studied.

Ingestion of essential oils in pregnancy confers a risk of maternal and therefore fetal toxicity. Case reports have documented onset of intrauterine contractions and spontaneous abortion following maternal ingestion, however a causal relationship to the essential oil remains unproven and these outcomes may reflect secondary effects of maternal toxicity.

Women who have ingested an essential oil in pregnancy should be managed as for the non-pregnant patient. For current guidelines on the management of essential oil poisoning the reader should consult TOXBASE or contact UKTIS. If maternal toxicity occurs, enhanced fetal monitoring may be warranted.

Inadvertent topical exposure to an essential oil during pregnancy would not usually be regarded as medical grounds for termination of pregnancy or 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.

Eculizumab is a recombinant humanised monoclonal IgG antibody which inhibits terminal complement activation through binding to the human C5 complement protein. It is licensed for use in patients with paroxysmal nocturnal haemoglobinuria (PNH) and atypical haemolytic-uraemic syndrome (aHUS).

The published data currently consist of 18 case reports and five case series which collectively describe at least 119 unique eculizumab-exposed pregnancies. There is currently only one published case of major congenital malformation among 109 infants born following maternal eculizumab use in the first trimester, however the malformation was attributed to concomitant first trimester warfarin exposure. Preterm delivery and, as a consequence, related anomalies and low infant birth weight have been described in a number of the pregnancies resulting in live birth. However, several of these pregnancies were intentionally delivered early in the medical management of various associated maternal medical conditions. As these data are uncontrolled, it is not possible to evaluate whether treatment with eculizumab impacts on these outcomes. A small number of pregnancies ending in spontaneous abortion and intrauterine death have been reported, as has one intrauterine-exposed infant with neurodevelopmental impairment (speech delay) and another infant with childhood cancer (neuroblastoma).

Both aHUS and PNH during pregnancy are associated with an increased risk of rapidly progressive and severe disease, adverse pregnancy outcome and long term maternal morbidity. The available data do not provide any evidence that eculizumab is a structural teratogen, however experience of eculizumab use in pregnancy remains limited and an increased risk of birth defects, although unlikely, can therefore not be excluded. Other adverse or beneficial fetal effects with use in pregnancy remain unquantified, and theorectial concerns regarding compromised neonatal immune function following prenatal exposure should be noted. However, given the potential severity of the maternal conditions for which eculizumab is indicated, a risk-benefit analysis regarding use in pregnancy should be undertaken on a case-by-case basis and treatment should not be withheld purely on account of pregnancy. Patients should however be made aware of the lack of robust fetal safety data, particularly regarding long term outcomes for exposed offspring, and that research is still needed to evaluate pregnancy and maternal outcome with eculizumab therapy versus regimes such as plasma therapy. 

Exposure to eculizumab at any stage in pregnancy would not usually be regarded as medical grounds for termination of pregnancy. Heightened maternal and fetal monitoring is advised given the severity of the conditions for which treatment with eculizumab is indicated. However, other 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.

Ethylenethiourea (ETU) is used in the rubber industry and in the production of some fungicides. 

Data relating to pregnancy outcomes following ETU exposure are scarce. No increased risk of malformation was observed in a retrospective case-series investigating the offspring of women who worked in the rubber industry and a prospective cohort study found no significant differences in neurodevelopmental outcomes between exposed infants and population norms. However, due to the extremely limited data an evidence-based assessment of fetal risk following either acute or chronic exposure to ethylenethiourea during pregnancy is not possible. 

Teratogenicity has been observed in some (but not all) animal species following in utero ethylenethiourea exposure. Various structural malformations, growth restriction, thyrotoxicity, hepatotoxicity and behavioural abnormalities have been reported in rats. Ethylenethiourea consistently induces anorectal malformations in a high percentage of rat embryos and is therefore used as a positive control for teratogenicity in preclinical studies.  It is not known whether there are similar risks to the human fetus.

As with all chemicals, unnecessary exposure to ethylenethiourea should be avoided during pregnancy. Where occupational exposure is unavoidable, precautions should be taken to ensure that exposure is well within the recommended exposure limits and not associated with toxic symptoms.

Following ethylenethiourea 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 human teratogenicity of ethylenethiourea, it is not currently possible to state that an absence of maternal toxicity excludes the possibility of adverse events occurring in the developing fetus.

There are no published guidelines on the management of poisoning with ethylenethiourea compounds during pregnancy and pregnant patients should be managed as for non-pregnant patients. Thiourea compounds can interfere with thyroid function and maternal thyroid status should be checked following any exposure to ethylenethiourea.

Exposure to ethylenethiourea at any stage in pregnancy may also confer a risk to the fetus. The need for additional fetal monitoring following maternal exposure to ethylenethiourea needs to be assessed on a case-by-case basis. A detailed fetal anomaly scan to include assessment of the fetal thyroid should be considered. Thyroid and liver function should be checked in all exposed neonates at birth. 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 consideration of such factors when performing case-specific risk assessments. Discussion with UKTIS is recommended in all cases.