Letter: E

Direct oral anticoagulants (DOACs) include Factor Xa inhibitors (apixaban, rivaroxaban, edoxaban) and the direct thrombin inhibitor (dabigatran). These drugs act on specific components of the coagulation cascade, resulting in reduced thrombin generation and inhibition of fibrin clot formation. They are widely used for stroke prevention in atrial fibrillation, and the treatment and prevention of venous thromboembolism.

Elexacaftor is a Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) modulator licensed for the treatment of cystic fibrosis.

Erythromycin is a macrolide antibiotic, indications include sinusitis, laryngitis, pharyngitis, tonsillitis, bronchitis, pneumonia, otitis media, otitis externa, skin and soft tissue infections, and gastrointestinal infections.

Most studies investigating malformation risk following erythromycin use in pregnancy do not provide evidence of an association. A single study has described an association with specific malformations, including anencephaly and transverse limb defects; however, these findings may have been impacted by methodological biases and/or confounding by indication, and therefore do not provide compelling evidence of a causal association and require further investigation.

The limited data available do not suggest an increased risk of miscarriage, intrauterine death, low birth weight, preterm delivery or neonatal complications following gestational exposure to erythromycin. Results from studies which investigated offspring neurodevelopment and cerebral palsy risk following antibiotic use in the management of spontaneous preterm labour (SPL) or premature rupture of membranes (PROM) are conflicting but likely heavily influenced by the high incidence of preterm delivery.

At the time of writing, the Royal College of Obstetricians and Gynaecologists (RCOG) advise routine intrapartum antibiotic prophylaxis (IAP) for all women in preterm labour, with or without PROM. Benzylpenicillin should be used preferentially but substituted for a cephalosporin in patients with a non-severe penicillin allergy, or vancomycin where the allergy is severe. The National Institute for Health and Care Excellence (NICE) guidelines also state that women with pre-labour PROM should be offered oral erythromycin (250mg, 4 times a day) for a maximum of 10 days or until the woman is in established labour (whichever is sooner), with oral penicillin offered to women who cannot tolerate erythromycin.

It is important to effectively treat infections in pregnancy as adverse maternal and fetal effects may result from uncontrolled infection or pyrexia.

Where possible, the results of culture and sensitivity tests should guide treatment choice in accordance with local prescribing guidelines. If a macrolide is indicated, erythromycin has historically been preferred during pregnancy because there is more documented experience of its use than for other macrolides. However, treatment choices should be made on a case-by-case basis accounting for likely efficacy and tolerability, as well as possible fetal effects.

Exposure to erythromycin 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.

Ethosuximide is an anti-seizure medication (ASM) indicated (often in polytherapy) for the treatment of absence seizures, atypical absence seizures, and myoclonic seizures.

Ethosuximide use has been described in ~225 human pregnancies, mainly in case reports/series. Numerous congenital anomalies have been noted, including patent ductus arteriosus, cleft lip and palate, talipes, and dysmorphic facial features. Many of the infants had been co-exposed to other ASMs. The utility of these reports for assessing the fetal safety profile of ethosuximide is limited by likely reporting bias, study methodology, and the small number of outcomes available. Causality for adverse outcomes cannot be assigned to ethosuximide exposure.

A network meta-analysis that included some of these cases found statistically significant increased risks of overall congenital malformation, as well as cleft lip and palate and talipes following exposure to ethosuximide. The same meta-analysis identified an increased risk of ‘combined fetal loss’ (miscarriage and stillbirth as a composite outcome) but no increased risk of preterm delivery. The findings of this meta-analysis were based on very small numbers of ethosuximide-exposed infants, leading to imprecise risk estimates with very wide confidence intervals, and the data are likely confounded. These data should therefore be interpreted with caution.

There are case reports of neonatal withdrawal following exposure to ethosuximide, mainly in polytherapy. Use of any medication affecting the central nervous system throughout pregnancy or near delivery may be 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. Following ethosuximide exposure in late pregnancy, delivery should be planned in a unit with facilities to monitor and support the neonate.

UK guidelines state that women taking any ASM who are planning a pregnancy, or are pregnant, should take high dose folic acid (5mg/day).

Exposure to ethosuximide at any stage in pregnancy would not usually be regarded as medical grounds for termination of pregnancy. Due to the unknown effects on fetal development, prescribers could consider offering the standard 20-week anomaly scan from 16 weeks onwards. Other risk factors which could independently increase the risk of adverse pregnancy outcome may be present in individual cases and are important to consider in case-specific risk assessments.

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 given intravenously for 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.

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. Additionally, short-term use of esmolol would not be expected to impact upon fetal growth. 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 chronic 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 following topical use of essential oils, risks from exposure to higher concentrations of oils (e.g. during a massage) cannot be ruled out, as pregnancy outcomes following use have not been systematically 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 miscarriage 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.

Topical exposure to an essential oil during pregnancy would not 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.

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. Although the manufacturer of etanercept recommends avoiding live vaccine use until the child is 16 weeks old, other 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 <16 weeks 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 in antifreeze/coolant, windscreen washer fluid, de-icing solutions, hydraulic brake fluid, paints, inks and dyes, and as precursor in polymer manufacture. Ethylene glycol is highly toxic following ingestion, and although ethylene glycol can also be absorbed via inhalation and dermal contact, systemic toxicity is not expected via these routes.

As with all chemicals, unnecessary exposure to ethylene glycol should be avoided during pregnancy. However, where occupational exposure is unavoidable, precautions such as the use of appropriate personal protective equipment 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 ingested 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.