USE OF ATROPINE IN PREGNANCY

Atropine is a tropane alkaloid with antimuscarinic effects. It is used in the treatment of symptomatic bradycardia, as an antisialagogue, as an antidote, and topically as a mydriatic and cycloplegic.

Data on the use of atropine in pregnancy are extremely limited, but do not currently indicate an increased risk of fetal malformation. Information on other adverse pregnancy outcomes is too limited to permit an evidence-based assessment of any risk.

Atropine should not be withheld in a pregnant patient if there is a compelling clinical indication for use. Enhanced antenatal surveillance may be warranted following maternal atropine exposure and should be decided on a case-by-case basis. Discussion with UKTIS is recommended in all cases of exposure to atropine at any stage of pregnancy.

USE OF AZATHIOPRINE OR MERCAPTOPURINE IN PREGNANCY

Azathioprine is a prodrug and is rapidly metabolised to its active metabolite mercaptopurine (6-MP). Mercaptopurine is a purine analogue which interferes with the synthesis of DNA and RNA and has immunosuppressant properties. Azathioprine is licensed to treat various auto-immune disorders such as inflammatory bowel disease, rheumatoid arthritis and psoriasis, and for the prevention of allograft rejection. It is also used off-licence to treat severe refractory eczema. Mercaptopurine is licensed to treat acute and chronic leukaemia, as maintenance therapy in acute lymphoblastic and myelogenous leukaemia, and is used off-license to treat severe ulcerative colitis and Crohn’s disease.

The available data do not demonstrate that azathioprine/mercaptopurine exposure during early pregnancy increases the risk of congenital malformation, preterm delivery, or adversely affects fetal growth. There is also no robust evidence of increased risks of intrauterine death, miscarriage, or altered neurodevelopment following gestational azathioprine exposure. However, as the available data for many of these outcomes are limited in quantity and sometimes also methodologically, more robust epidemiological data are ideally required.

Neonatal leucopoenia and thrombocytopenia have been reported in a number of case reports following azathioprine exposure in utero but no epidemiological studies quantifying these risks are available. There is therefore a theoretical concern that the use of azathioprine/mercaptopurine during pregnancy could result in immunosuppression in the neonate, leading to an increased risk of infection and adverse effects following administration of live vaccines. Advice from the MHRA states that infants exposed in utero to certain immunosuppressive medications should not receive live vaccines until they are least 6 months old, although no specific advice relating to azathioprine exposure was issued.

USE OF ARTEMISININ & ARTEMISININ DERIVATIVES IN PREGNANCY

Artemisinin and its derivatives (artesunate, artemether, dihydroartemisinin) are used in the treatment of malaria, usually in combination with other antimalarials, which is termed artemisinin-based combination therapy (ACT). In the UK the only licensed artemisinin derivative is artemether (in combination with lumefantrine).

Artemisinins have been associated with embryolethality in animal studies, therefore theoretical concerns regarding use in humans exist. However, human data do not provide evidence of an increased risk of miscarriage following exposure to artemisinin and its derivatives during pregnancy. 

The available human data do not currently provide any reliable evidence indicating that first trimester artemisinin use is associated with an increased risk of malformation. However, the data are highly limited which precludes the ability to provide an informed assessment of the risk. A large number of second and third trimester pregnancy exposures have been documented which do not signal that gestational exposure to artemisinin or its derivatives is associated with increased rates of stillbirth, low birth weight or preterm delivery above those observed in women treated with other antimalarials.

Untreated or inadequately treated maternal malaria infection poses a serious risk to both the mother and the fetus, therefore treatment with artemisinin or artemisinin derivatives should not be withheld at any stage of pregnancy if considered essential for maternal treatment. The UK malaria treatment guidelines (2016) and WHO guidelines for the treatment of malaria (2015) state that uncomplicated falciparum malaria should be treated with artemether-lumefantrine in the second and third trimester, and with quinine and clindamycin in the first trimester. Women with severe malaria in any trimester of pregnancy should be treated the same as non-pregnant patients, with artesunate preferred over quinine. Specialist advice should be sought regarding treatment of malaria during pregnancy.

Exposure to artemisinin and derivatives of the compound at any stage in pregnancy in the absence of maternal malaria infection would not usually be regarded as medical grounds for 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. Discussion with UKTIS is recommended in all cases.

USE OF ASPIRIN AND ASPIRIN OVERDOSE IN PREGNANCY

Aspirin is an acetylated salicylate with analgesic, antipyretic, anti-inflammatory and antiplatelet properties. Low-dose aspirin (75-300mg/day) is used as an antiplatelet medication in the prophylaxis of thromboembolic cerebrovascular disease and myocardial infarction. Higher doses of aspirin (up to 4g/day) are used in the control of mild-to-moderate pain and pyrexia. 

The National Institute for Health and Care Excellence (NICE) guidelines state that pregnant women at high risk of pre-eclampsia should be offered low-dose aspirin from 12 gestational weeks. Low-dose aspirin is sometimes used from conception for women undergoing fertility treatment and those with a history of recurrent miscarriage or conditions such as antiphospholipid syndrome, as some studies have suggested an improvement in live birth rates.

There is no specific information on malformation rates following use of low-dose aspirin in pregnancy but in most cases this treatment is initiated after 12 weeks of pregnancy when fetal organogenesis is complete and there is little risk of medication-induced structural malformation. Increased risks of gastroschisis, cleft lip and palate, and neural tube defects have been reported following maternal use of aspirin during pregnancy (mainly at analgesic doses), however data are conflicting and may also be confounded, and a causal association with aspirin has not been proven. Data relating to risk of cardiac malformations are reassuring.

The majority of evidence suggests that there is no association between the use of low-dose aspirin and miscarriage, fetal growth restriction, or preterm delivery. Stillbirth data are limited to one small randomised-controlled trial that found no increased risk following exposure to low-dose aspirin. No data are available on pregnancy outcomes following aspirin use at analgesic doses, and data on neurodevelopmental outcomes following in utero aspirin exposure at any dose are too limited to facilitate an evidence-based assessment of risk.

Chronic exposure to analgesic doses of aspirin >300mg/day from 30 weeks of pregnancy may be associated with neonatal bleeding complications and premature closure of the ductus arteriosus (DA), resulting in pulmonary vasculature abnormalities and persistent pulmonary hypertension of the newborn (PPHN). These effects have not been reported with low-dose aspirin use.

Regular use of analgesic doses of aspirin in the third trimester should be avoided if possible. In circumstances where the maternal clinical condition requires treatment with analgesic doses of aspirin during the third trimester, fetal monitoring for oligohydramnios and ductus arteriosus patency is recommended. Exposure to analgesic doses of aspirin prior to the third trimester would not be considered an indication for any additional fetal monitoring. 

Aspirin overdose can result in severe maternal toxicity and consequently adverse fetal effects.  Pregnant women who have overdosed on aspirin should be managed as for the non-pregnant patient and may require additional interventions and/or fetal monitoring. Discussion with UKTIS and NPIS is recommended in all such cases.

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.

USE OF ATENOLOL IN PREGNANCY

Atenolol is a cardioselective beta-blocker licensed for the treatment of hypertension, angina pectoris, cardiac arrhythmias, for secondary prevention after acute myocardial infarction, and also off-license for migraine prophylaxis.

Data on overall rates of fetal structural malformations, or of specific malformations following first trimester use of atenolol, are too limited to permit an evidence-based risk assessment. There are also insufficient data to assess the risk of miscarriage, stillbirth, and adverse neurodevelopmental outcomes following gestational atenolol exposure.

It is currently unclear whether gestational use of atenolol increases the risk of preterm delivery. Although the currently available limited data do not suggest that this is the case, further research is required to confirm this finding.

There is some evidence that atenolol exposure in pregnancy may adversely affect fetal growth, although data are conflicting. Some studies suggest that the risk of adverse effects on fetal growth may be higher when exposure commences prior to 20 gestational weeks but the possibility of a maternal disease effect cannot be excluded.

Use of beta-blockers near term may result in neonatal beta-adrenoceptor blockade, leading to neonatal bradycardia, hypotension and hypoglycaemia. Accordingly, some (but not all) studies have reported increased rates of these neonatal complications in atenolol-exposed infants, although the absolute risk remains unquantified. Assessment of the neonate for these effects is thus advised.

Exposure to atenolol at any stage in pregnancy would not usually be regarded as medical grounds for termination of pregnancy. In pregnancies complicated by maternal hypertension and/or where atenolol 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 consideration of such factors when performing case-specific risk assessments.

USE OF ATOMOXETINE IN PREGNANCY

Atomoxetine is a selective noradrenaline reuptake inhibitor (NRI) used in the treatment of attention deficit hyperactivity disorder (ADHD).

The published data regarding atomoxetine use in human pregnancy consist of two case reports and three cohort studies which incorporate a total of 631 atomoxetine-exposed pregnancies, including at least 475 first trimester exposures. In addition, two population-based cohort studies which utilised an overlapping dataset have investigated ADHD medications as a group.

The controlled data for ADHD medicines as a group describe a possible association with miscarriage, preterm delivery, and decreased five-minute Apgar scores. However, data confounding by the underlying maternal condition may have influenced the observations and a separate analysis of the atomoxetine exposures was not undertaken.

The currently available data for atomoxetine do not raise concern of an increased risk of low birth weight and preterm delivery but are too limited to exclude these risks. Data regarding miscarriage, congenital malformation and intrauterine death are limited or absent and therefore it is not currently possible to provide an evidence-based assessment of the risks of these outcomes.

It is important that maternal ADHD is adequately controlled during pregnancy. The risks of destabilisation and maternal relapse must be taken into account when considering dose reduction or switching a patient from atomoxetine to another medication(s).

As with other centrally acting drugs, there is a potential risk of poor neonatal adaptation syndrome (PNAS)/neonatal withdrawal effects and/or persistent pulmonary hypertension of the newborn (PPHN) in the neonate. Infants exposed to atomoxetine in utero should ideally be delivered in a unit with neonatal support and monitored for symptoms of PNAS.

Exposure to atomoxetine 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. Given the lack of sufficient human pregnancy exposure data, the need for additional antenatal anomaly scans and/or fetal monitoring should be considered on a case-by-case basis following maternal atomoxetine use in pregnancy.

USE OF ANGIOTENSIN CONVERTING ENZYME INHIBITORS IN PREGNANCY

Angiotensin converting enzyme (ACE) is an important constituent of the renin angiotensin system (RAS) which regulates fluid volume and controls vascular tone. ACE inhibitors (ACE-I) decrease the activity of ACE to counteract its vasoactive effects, thereby reducing blood pressure. ACE-I are used for the treatment of hypertension, heart failure, nephropathy, and in the prophylaxis of cardiovascular events.

ACE-I fetopathy following exposure to ACE-I in the second and third trimesters of pregnancy is well-described and may include oligohydramnios, renal tubular dysgenesis, neonatal anuria, hypocalvaria, pulmonary hypoplasia, persistent patent ductus arteriosus, mild-to-severe intrauterine growth restriction, and fetal or neonatal death. It is proposed that these effects occur as a result of a direct effect on the fetal RAS which begins to function from approximately 26 weeks gestation. A small prospective case series has suggested that the risk period for ACE-I fetopathy is with exposure beyond 20 weeks gestation. Due to data limitations, the absolute risk of ACE-I fetopathy is unclear.

Due to the risk of ACE-I fetopathy, use of ACE-I in the second and third trimesters is generally contraindicated and should only be reserved for cases of severe maternal illness that cannot be managed using alternative drugs.

There is currently no reliable evidence that exposure to ACE-Is in the first trimester increases the risk of overall infant congenital malformation, or, more specifically, of cardiovascular or CNS malformation. A small number of uncontrolled studies have suggested possible associations with urogenital anomalies, but further research to confirm or refute these observations is required.

Although some studies have described increased risks of miscarriage, preterm delivery and impaired fetal growth following early pregnancy exposure to ACE-I, similar findings have been observed in women taking other antihypertensive medications. As such, these findings are considered confounded by the underlying maternal condition, and there is currently no reliable evidence that first trimester ACE-I exposure directly increases the risk of these outcomes.

The National Institute for Health and Care Excellence (NICE) guidelines state that antihypertensive treatment with ACE-I should be stopped upon recognition of pregnancy and alternatives offered.  NICE guidelines identify labetalol as the first-line antihypertensive for use during pregnancy, with nifedipine or methyldopa being possible alternatives, depending on any pre-existing treatment, side effect profiles, risks (including fetal effects), and the woman’s preference. Where prolonged first trimester exposure has occurred, attendance of the routine 20-week anomaly scan is encouraged. Where prolonged second or third trimester exposure has occurred, assessment and management by a specialist in fetal medicine is indicated. Women of childbearing age who are taking an ACE-I should be fully informed of the potential fetal risks and should ideally seek advice before becoming pregnant. Other risk factors may also be present which may increase the risk of adverse pregnancy outcome. Clinicians are reminded to consider these factors when performing risk assessments.

USE OF ANGIOTENSIN II RECEPTOR ANTAGONISTS IN PREGNANCY

Angiotensin-II receptor blockers (ARBs) (azilsartan, candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan, and valsartan) are typically used in the treatment of hypertension, heart failure and diabetic nephropathy.

ARB use during the second or third trimesters of pregnancy has been associated with a potentially severe fetopathy. Features are secondary to oligo-/anhydramnios and include neonatal renal impairment with or without oligo-/anuria, joint contractures, hypocalvaria/widened skull sutures, and pulmonary hypoplasia. Thrombosis of the vena cava may also be a feature. Iatrogenic preterm delivery (and therefore low infant birth weight) are also common. No controlled cohort studies have quantified rates of these outcomes following ARB exposure in later pregnancy, however a small prospective case series cited a fetopathy rate of 29% in fetuses exposed from 20 gestational weeks and stated that this was the specific risk period. ARB exposure appears to be associated with a higher risk of fetopathy than exposure to ACE-inhibitors.

There is currently no convincing evidence that first trimester exposure to ARBs is associated with an increased risk of congenital malformation, neither overall nor for specific anomalies, or other adverse fetal outcomes. However, data relating to first trimester ARB exposure are limited to a collective total of ~420 pregnancies and further information is required.

The National Institute for Health and Care Excellence (NICE) guidelines advise that women taking ARBs who are planning a pregnancy should seek specialist advice regarding alternative therapy. Women who become pregnant while taking an ARB should be advised to switch antihypertensive therapy. NICE guidelines identify labetalol as first-line antihypertensive for use during pregnancy, with nifedipine or methyldopa being possible alternatives depending on any pre-existing treatment, side-effect profiles, risks (including fetal effects) and the woman’s preference.

Where ARB use beyond the first trimester is considered to be unavoidable or has occurred accidentally, strict supervision is required from experts in both maternal and fetal medicine. This may require transfer of the patient to a tertiary referral centre. All pregnant women and those of childbearing potential who are treated with an ARB should be fully informed of the fetal risks. Discussion with UKTIS is recommended. 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.

USE OF ANTHRAX VACCINE IN PREGNANCY

Anthrax vaccine is an inactivated vaccine intended for active immunisation against the disease caused by Bacillus anthracis. The vaccine is not routinely administered in the UK; however vaccination may be required in service personnel or those considered at risk of anthrax due to their occupation. 

Morbidity and mortality following anthrax infection are high and rapid treatment following exposure is therefore required. The benefits of prevention of anthrax infection in pregnancy in certain situations may therefore outweigh any unknown potential risk that anthrax vaccination poses to the fetus.

The available published data regarding exposure to the anthrax vaccine during pregnancy provides no compelling evidence that exposure to anthrax vaccine in pregnancy is teratogenic, however it is recommended that pregnant women ideally defer vaccination unless they are at risk of exposure to Bacillus anthracis.

Inadvertent exposure to the anthrax vaccine at any stage in pregnancy would not usually be regarded as medical grounds for termination of pregnancy or any additional fetal monitoring. Please contact UKTIS or consult TOXBASE for current advice on the management of anthrax in pregnancy.