Letter: M

Monkeypox belongs to the Orthopoxvirus genus in the Poxviridae family. Monkeypox infection produces a disease which clinically resembles smallpox. Monkeypox has two known distinct genetic clades, central African (Congo Basin) clade and the West African clade. Historically, the Congo Basin clade has caused more severe disease and is thought to be more transmissible. In the 2022 UK outbreak, all reported cases have been identified as the West African clade.

Data regarding monkeypox infection during pregnancy are highly limited, consisting of a single case report and a small case series (n=4). All reported cases were therefore likely infected with the Congo Basin clade. All but one of the reports describe an adverse outcome, including miscarriage (n=3), and a neonatal death with features suggestive of vertical transmission. There is an absence of information relating to birth outcomes following infection with the West African clade which is circulating in the UK. Therefore, due to the lack of data and the clinical similarity between monkeypox and smallpox infection, a significant risk of adverse maternal and pregnancy outcomes cannot be excluded following infection with either clade.

A non-replicating smallpox vaccine, Modified Vaccinia Ankara – Bavarian Nordic (MVA-BN) is effective against monkeypox infection. The manufacturer of MVA-BN does not report associations with adverse pregnancy outcomes in the product literature. However, data are limited to animal studies (three pregnant rat models) and spontaneous reports of fewer than 300 exposed human pregnancies. Potential maternal adverse effects following administration of MVA-BN are expected to be similar to those in the non-pregnant population. Any theoretical risk from vaccination needs to be weighed against the maternal risk of more severe disease from viral infections in the third trimester, and the fetal risks of infection: fetal demise, preterm delivery, and vertical transmission. The UK Health Security Agency (UKHSA) therefore conclude that pregnancy is NOT a contraindication for MVA-BN vaccine.

No human pregnancy data are available for the two antiviral medications (cidofovir and tecovirimat) suggested as possible treatment options by the UKHSA. Animal data and in vitro mutagenicity assays have raised some potential concerns with regards to cidofovir and its use in pregnancy is therefore not recommended. Pregnancy outcome data from animals following tecovirimat exposure is more reassuring, and it may be preferred for use in pregnant women with monkeypox. The decision to use either treatment should be made on a case-by-case basis.

Due to the potential risk of more severe disease from viral infections occurring during the third trimester, and the potentially increased risk of adverse fetal effects, additional monitoring may be required. Discussion with UKTIS and a regional fetal medicine unit is advised.

Mycophenolate mofetil (MMF) is the pro-drug of mycophenolic acid (MPA), an antiproliferative agent that interferes with purine synthesis, thereby suppressing the immune response. MMF/MPA are indicated for the prophylaxis of organ rejection in transplant recipients and are generally used concomitantly with other immunosuppressant medications, including ciclosporin and corticosteroids. MMF/MPA are also used off-license to control autoimmune conditions such as psoriasis and lupus nephritis.

MMF/MPA are contraindicated during pregnancy unless there is no possible alternative to prevent rejection of a transplanted organ. This is due to an increased risk of first trimester pregnancy loss and confirmed human teratogenic effects, including craniofacial anomalies (cleft lip and/or palate, microtia, external auditory canal atresia, micrognathia); microphthalmia, coloboma of iris and retina, and hypertelorism; complex congenital cardiac anomalies, including septal defects, conotruncal and outflow tract anomalies; oesophageal atresia, diaphragmatic hernia, and various vertebral and skeletal anomalies. The two largest cohort studies carried out to date report malformation rates of 11.6% and 26% among offspring exposed to MMF in the first trimester.

The UK Medicines and Healthcare products Regulatory Agency (MHRA) guidelines state that females of reproductive potential who are prescribed MMF or MPA should use at least one form of reliable contraception during treatment and for six weeks after cessation. Male patients or their untreated female partner should use reliable contraception during treatment and for at least 90 days after cessation. Readers are advised to consult the most up-to-date version of these guidelines before prescribing MMF or MPA.

Women taking MMF or MPA who are planning a pregnancy should be reviewed by a specialist so that, if possible, a suitable alternative medication regime can be implemented prior to conception. Women taking these drugs who report an unplanned pregnancy should be offered urgent review, either in clinic or by telephone, within one or two working days.

Women exposed to MMF or MPA during early pregnancy should be counselled about the risks to the fetus and offered detailed anomaly scans focussing on the craniofacial structures, the heart, abdomen and skeletal system. Clinicians should also be aware that case-specific assessment of risk could also be affected by other factors that may independently increase the risk of adverse pregnancy outcome. Please report all cases of MMF/MPA exposure to UKTIS.

Metoprolol 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 metoprolol use in pregnancy. Single case-control studies found no associations between first trimester metoprolol exposure and hypospadias and posterior cleft palate respectively. Further studies are required to corroborate these findings.

The limited available data currently provide no convincing evidence that exposure to metoprolol in utero has clinically relevant effects on fetal growth or increases the risk of preterm delivery. However, reduced fetal growth has been observed following gestational exposure to other beta blockers. Ongoing data collection is therefore required to fully assess this risk.

There are no controlled data comparing rates of miscarriage, stillbirth or neurodevelopmental outcomes following gestational metoprolol exposure. As such, it is not possible to predict the risks for these outcomes.

Use of beta blockers near term may result in beta-adrenoceptor blockade, leading to neonatal bradycardia, hypotension and hypoglycaemia. However, there are limited data on rates of these neonatal complications in metoprolol-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 metoprolol at any stage of pregnancy would not usually be regarded as medical grounds for termination. In pregnancies complicated by maternal hypertension and/or where metoprolol 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

Metronidazole is an antimicrobial agent that is used for prophylaxis and treatment of anaerobic, protozoal, Helicobacter pylori and skin infections. It is commonly prescribed orally or as a gel for treatment of bacterial vaginosis and trichomonal infections. Where oral treatment is deemed appropriate, the manufacturer advises against a single high-dose regimen during pregnancy.

Metronidazole was teratogenic in some early animal studies, but this has proved difficult to reproduce. The available human data, which are almost exclusively based on oral exposure, do not, overall, indicate an increased risk of congenital malformation. There is also no indication of increased risks of preterm delivery, low infant birth weight, intrauterine death, or neonatal complications following metronidazole exposure in pregnancy. Metronidazole exposure in early pregnancy has been associated with miscarriage; however, it is possible that underlying maternal infection may play an independent role in increasing miscarriage risk.

Where possible, the results of culture and sensitivity tests should be available before making a treatment choice in accordance with local prescribing guidelines.

Exposure to metronidazole 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.

Mirtazapine is a benzazepine tetracyclic antidepressant licensed for use in the treatment of depression and mood disorders. It is also used off-licence in the treatment of anxiety and as an antiemetic. Its mechanism of action is related to that of selective-serotonin reuptake inhibitors (SSRIs).

The data regarding exposure to mirtazapine in human pregnancy comprise around 1,300 exposures derived from case reports, case series and observational cohort studies.

The available data, although limited and conflicting for some outcomes, do not currently indicate that mirtazapine use in pregnancy increases the risk of malformation, preterm delivery, or an impact upon fetal growth. The available data regarding miscarriage, intrauterine death, neonatal complications and neurodevelopmental impairment risks do not currently provide evidence of an association with mirtazapine use in pregnancy, but are too limited to allow definitive conclusions to be drawn.

In utero SSRI exposure has been associated with a small increase in the occurrence of persistent pulmonary hypertension of the newborn (PPHN) and neonatal withdrawal. No epidemiological studies have investigated the risk of PPHN for mirtazapine specifically. Owing to the pharmacological similarities between mirtazapine and SSRI antidepressants, and given that cases of poor neonatal adaptation syndrome, neonatal withdrawal features and PPHN have been described in uncontrolled case reports/series, neonatal monitoring is recommended following mirtazapine exposure in the later stages of pregnancy.

Infants exposed to antidepressants in utero should ideally be delivered in a unit with adequate neonatal support and the delivery team made aware of the exposure. In non-pregnant adults, mirtazapine has an elimination half-life of 20 to 40 hours which is extended in cases of liver or renal impairment.[SmPC] Due to immature metabolic capabilities, neonatal clearance of mirtazapine following in utero exposure may also be prolonged, and as such neonatal effects may be delayed.

It is important to ensure that maternal mental health is treated appropriately. As such, mirtazapine use in pregnancy may be clinically indicated, but the risks and benefits must be carefully considered on a case-by-case basis. Where possible, non-pharmaceutical management of depression and/or anxiety is preferable in pregnancy. Where a patient is stabilised on mirtazapine, either prior to conception or during pregnancy, any perceived benefits of altering the treatment should be carefully weighed against the risk of maternal relapse either during pregnancy or post-partum. In cases where treatment with mirtazapine is continued in pregnancy, the lowest effective dose should be used.

Exposure to mirtazapine 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.

SUMMARY: Modafinil is a psychostimulant medication used to improve wakefulness in adults with narcolepsy, for fatigue related to multiple sclerosis, and for the treatment of attention deficit hyperactivity disorder (ADHD). Armodafinil is the R-enantiomer of modafinil and possesses the same pharmacodynamic effects; although this medication is not licensed for clinical use in the UK, some of the available pregnancy data are provided from studies using this medication.

Published data regarding maternal modafinil/armodafinil use in pregnancy are limited, consisting of a small number of uncontrolled case reports/series and two population-based cohort studies. Together these studies describe approximately 290 exposed pregnancies, of which 230 were in the first trimester.

The available data, although limited and conflicting, provide evidence that modafinil/armodafinil use in pregnancy may increase the risk of congenital malformation. Of the three largest studies currently available (each describing <100 first trimester-exposed pregnancies), two identified increased risks, with the controlled study indicating an approximate 3-fold increased risk attributable to modafinil exposure. The remaining study found no increase in the rate of malformation following first trimester modafinil exposure. Due to the limited and conflicting nature of the available evidence, it is currently unclear if first trimester modafinil exposure truly increases the risk of fetal malformation. If the evidence indicating an increased risk of malformation is accurate, the data suggest that approximately 4 to 6 additional malformed infants could be expected for every 100 modafinil-exposed pregnancies (relative to an expected background rate of 2 to 3 per 100). A single uncontrolled study described a rate of miscarriage consistent with the expected background rate following maternal modafinil/armodafinil use in early pregnancy. However, the available data are provided by a single uncontrolled case series and therefore additional studies are required.

No studies have investigated the risk of stillbirth, preterm delivery, growth restriction, neurodevelopmental impairment or neonatal complications following modafinil use in pregnancy. Although the risk of neonatal withdrawal has not been formally studied, as modafinil is a centrally acting medication, symptoms of withdrawal may be experienced following its use in the latter stages of pregnancy.

It is important to ensure that the maternal condition for which modafinil is prescribed is appropriately treated during pregnancy. It is strongly recommended that the potential risks and benefits of continued use, as well as any potential alternatives, are discussed with UKTIS.

Detailed anomaly scans are recommended following first trimester modafinil exposure. The anomalies described in the literature include congenital torticollis, unspecified cardiac defects and hypospadias, which may not always be detectable by prenatal ultrasound. Exposure to modafinil at any stage in pregnancy would not 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.

Molnupiravir is an antiviral pro-drug that inhibits viral replication through the active metabolite being incorporated into the viral RNA, resulting in an accumulation of errors in the viral genome. In the UK, it is licensed as a five-day course for the treatment of mild to moderate COVID-19 in adults with a positive SARS-COV-2 diagnostic test, who have at least one risk factor for developing severe illness.

Preclinical animal reproductive toxicity data are conflicting, with high maternal doses administered in the rat model demonstrating possible teratogenic effects, but no evidence of similar effects observed in the rabbit model. There are currently no human data regarding the safety of molnupiravir in pregnancy. UKTIS are collecting outcome data for all pregnancies with maternal or paternal exposure to molnupiravir (more information can be found here).

Although COVID-19 in pregnancy presents a significant risk to both the woman and her baby, both the mechanism of action of molnupiravir and the preclinical animal data warrant a cautious approach towards its use in pregnancy. Molnupiravir is not to be routinely recommended in pregnancy until further studies have established its effectiveness and safety. The manufacturer of molnupiravir recommends that women of childbearing potential should use effective contraception for the duration of treatment and for four days after the final dose. Pregnant women who have received molnupiravir at any stage in pregnancy should be referred to UKTIS for further counselling and follow-up of the pregnancy outcome.

In circumstances where the woman is experiencing severe symptoms of COVID-19, and where other more established treatments have failed, the risks and benefits of molnupiravir may need to be considered and discussed on an individual patient basis. However, the efficacy of molnupiravir has not been proven in such clinical scenarios, and alternative early treatment options that do not pose theoretical risks of fetal harm, such as casirivimab/imdevimab (Ronapreve) monoclonal antibodies, may be preferred for pregnant women. Discussion with UKTIS is recommended in all cases where molnupiravir treatment is being considered in pregnancy.

Owing to the lack of data regarding malformation risks, routine detailed fetal anomaly scans are recommended for all pregnancies with exposure to molnupiravir in the first trimester, or where there was paternal exposure to molnupiravir around the time of conception. Exposure to molnupiravir 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.

Montelukast is a cysteinyl leukotriene type-1 receptor antagonist used in the treatment of asthma as an ‘add-on’ therapy where symptoms are inadequately controlled with use of an inhaled corticosteroid and a short acting β-agonist. Montelukast is also licensed as an alternative treatment to low-dose inhaled corticosteroids for people with mild persistent asthma and no recent history of serious asthma attacks requiring oral corticosteroid use, or who cannot use inhaled corticosteroids; for the prophylaxis of asthma in which the predominant component is exercise-induced bronchoconstriction; and for symptomatic relief of seasonal allergic rhinitis in people with asthma.

There is no good evidence that montelukast exposure during pregnancy is associated with an increased risk of infant congenital malformation. A possible association between montelukast exposure and limb reduction defects identified from early spontaneous reports provided to the manufacturer of montelukast was not reproduced in a subsequent study. The data relating to risks of miscarriage, stillbirth, low infant birth weight and premature delivery are limited, and although there is currently no reliable evidence of any increased risks, further studies are required to confirm these findings.

Uncontrolled maternal asthma has been associated with a number of adverse pregnancy outcomes, including fetal loss, preterm birth and low infant birth weight, as well as adverse maternal events such as preeclampsia. Where clinically indicated, continued maternal treatment with montelukast in pregnancy is likely to outweigh any theoretical risk posed to the fetus. Montelukast therapy should not be discontinued on account of pregnancy without careful consideration of the risk to both mother and fetus of uncontrolled maternal asthma.

Exposure to montelukast 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.

Morphine is an opioid analgesic most commonly administered orally, intravenously or rectally for the treatment of severe or intractable pain.

Data relating specifically to morphine exposure in human pregnancy are extremely limited. It is not currently possible to exclude a teratogenic effect.

There are no controlled studies of the effect of morphine exposure on the incidence of miscarriage and no robust evidence of an increased malformation risk. Increased rates of specific malformations have been observed in some studies analysing opioids as a class, but the data are conflicting and the studies confounded. Data are extremely limited in relation to low birth weight, preterm delivery, stillbirth and neurodevelopmental outcomes, but a possible association with altered fetal growth in utero and visual defects (strabismus) have been reported, the clinical significance of which is unclear. Codeine, another opioid analgesic, is metabolised to morphine. Data are similarly limited and are reviewed in a separate UKTIS monograph. 

Owing to the lack of data regarding malformation risks, women who have been exposed to morphine in the first trimester are particularly encouraged to attend their routine detailed fetal anomaly scan, which is generally conducted at around 18 to 20 weeks of pregnancy. Use of any opioid during pregnancy, particularly around the time of delivery, confers a risk of neonatal respiratory depression and neonatal withdrawal. Delivery in a hospital setting is therefore advisable.

Where morphine poisoning or overdose occurs in pregnancy, maternal toxicity is likely to be a major factor in determining risk to the fetus. 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 morphine 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.

Summary: Methylphenidate is a central nervous system stimulant used in the management of attention deficit hyperactivity disorder (ADHD). It is also used off-license in the treatment of narcolepsy.

The data regarding therapeutic use of methylphenidate do not suggest a significant increase in overall congenital malformation rates. There may be a non-causal association between methylphenidate use in pregnancy and fetal cardiac malformation. Two studies which utilised an overlapping dataset have described increased risks of some specific cardiac defects (conotruncal and major arch anomalies in one and ventricular septal defects (VSD) in the other). However, the data regarding VSD risks were conflicting between the two studies, the risk estimates were imprecise, and the findings may have been produced through statistical chance. Methylphenidate use in early pregnancy should be considered a prognostic risk factor for fetal cardiac malformation, and a fetal echocardiogram could be considered at 18 to 22 weeks gestational age.

Up to two-fold increased risks of miscarriage with methylphenidate use in early pregnancy and low Apgar score with use in later pregnancy have also been identified. Rates of intrauterine death, small for gestational age or preterm delivery have not been shown to be increased following pregnancy exposure; however, the data are too limited to exclude increased risks. As with other CNS-acting drugs, neonatal withdrawal symptoms may be expected following the use of methylphenidate during pregnancy. A single study investigating the long-term effects of antenatal ADHD medication exposure (mainly exposed to methylphenidate) did not indicate associations with increased risks of neurodevelopmental impairments.

Growth restriction and preterm delivery have been reported following abuse of methylphenidate in pregnancy. However, the data are too limited to confirm an association and concurrent risk factors for adverse pregnancy outcomes were present in most cases.

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 methylphenidate to another medication(s).

Exposure to methylphenidate at any stage of pregnancy would not usually be regarded as medical grounds for termination of pregnancy. However, 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.