Letter: M

Mesalazine is an active metabolite of sulfasalazine.

Six biologic monoclonal antibody (mAb) therapies are licensed for the management of severe asthma: mepolizumab, reslizumab, benralizumab, omalizumab, dupilumab, and tezepelumab. This monograph summarises the available data for mepolizumab, benralizumab, tezepelumab, and reslizumab. For further information on omalizumab and dupilumab, please see the separate UKTIS monographs.

There are limited published human pregnancy data relating to mepolizumab and benralizumab. Data regarding reslizumab are very limited. No published human pregnancy exposures to tezepelumab have been identified. Data are derived from case reports (mepolizumab-exposed n=3; benralizumab-exposed n=6) and a pharmacovigilance analysis including 154 mepolizumab exposed, 774 benralizumab exposed, and 25 reslizumab-exposed pregnancies. The nature and size of these datasets limit the assessment of the risk of adverse pregnancy outcomes. mAbs do not actively cross the placenta in the first trimester and are therefore not expected to result in direct fetal exposure; this may lead to a lower risk of teratogenic/embryotoxic effects.

It is critically important to ensure that maternal asthma is well-controlled in pregnancy. Where a woman’s asthma is well-controlled with a mAb, particularly when conventional treatments have been ineffective, the risks and benefits of continuing treatment during pregnancy should be assessed on a case-by-case basis and discussed with the patient as part of a shared decision-making process.

Guidance from the UK Health Security Agency (UKHSA) [issued 2017] advises that live vaccines should be avoided until the infant is at least 6 months of age following in utero exposure to biologic immunosuppressant therapies. While mAbs used to treat asthma are not broadly immunosuppressant, the effects of in utero exposure on the neonatal or infant immune system are largely unknown. Please contact UKTIS for an individualised risk assessment where BCG vaccination is indicated in an infant under 6 months of age with prenatal asthma mAb exposure.

Exposure to asthma mAbs 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 which could independently increase the risk of adverse pregnancy outcome may be present in individual cases. Such factors are important to consider when performing case-specific risk assessments.

Urinary incontinence, defined as the involuntary leakage of urine, has multiple causes which may require different management strategies. Stress incontinence is common during pregnancy, caused by the hormonal changes of pregnancy and pressure on the bladder from the expanding uterus. Pharmacological treatment is not routinely indicated for urinary stress incontinence that has occurred due to pregnancy.

Women with pre-existing conditions that cause urinary frequency, enuresis and incontinence may require ongoing treatment during pregnancy under specialist supervision. Human pregnancy safety data is limited or lacking for most of the drug options, and the risks and benefits should therefore be considered on a case-by-case basis, taking into account the severity of the woman’s condition and likely effects on her health and quality of life if an established medication regimen is altered.

Oxybutynin is the best studied treatment for urinary frequency during pregnancy, although data are still very limited. Neither of two studies nor a handful of case reports raise concern that oxybutynin exposure is associated with infant congenital malformation. Increased risks of preterm delivery and low infant birth weight were noted in one of the studies but may be related to the underlying maternal condition. These findings require confirmation.

There are no further published human pregnancy exposure data for drugs to treat urinary frequency, enuresis and/or incontinence. A small number of pregnancy outcomes have been reported to UKTIS following prenatal exposure to oxybutynin, solifenacin, tolterodine, fesoterodine, mirabegron, propantheline, and trospium, with no major congenital malformations described. Data are absent for darifenacin, flavoxate, and propiverine.

Adverse fetal effects have been observed in preclinical (animal) studies of darifenacin, propiverine, fesoterodine, mirabegron, oxybutynin, and tolterodine; however, some exposures were at maternally toxic doses.

Exposure to drugs used to reduce symptoms of urinary frequency, enuresis and incontinence at any stage in pregnancy would not usually be regarded as medical grounds for termination of pregnancy; however, due to the lack of data, additional fetal monitoring may be warranted. 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.

Mpox, formerly monkeypox, belongs to the Orthopoxvirus genus in the Poxviridae family. Mpox infection produces a disease which clinically resembles smallpox. Mpox has two known distinct genetic clades, Clade I (formerly central African or Congo Basin clade) and Clade II (formerly the West African clade). Historically, Clade I has caused more severe disease and is thought to be more transmissible. In the 2022 outbreak, all reported UK cases were identified as Clade II. An emerging 2024 outbreak is caused by a Clade I variant known as Clade IB.

Data regarding mpox infection during pregnancy are highly limited, consisting of case reports and small case series. Although a small number of healthy pregnancies have been reported following mpox infection during pregnancy, the limited available data suggest the possibility of fetal demise and vertical transmission-associated poor neonatal outcomes. Due to the clinical similarity between mpox and smallpox infection, a significant risk of adverse maternal and pregnancy outcomes cannot be excluded following infection with either mpox clade.

A non-replicating smallpox vaccine, Modified Vaccinia Ankara – Bavarian Nordic (MVA-BN) is effective against mpox infection. The manufacturer of MVA-BN does not report associations between vaccination and 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. There is no robust evidence to suggest that any non-live vaccine used in pregnancy increases the risk of adverse fetal outcomes. 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.

Two antiviral medications (cidofovir and tecovirimat) have been suggested as possible treatment options by the UKHSA. No human pregnancy data are available for cidofovir, but animal data and in vitro assays have indicated a risk of fetal toxicity (at doses less than the therapeutic dose used in humans) and mutagenicity, therefore its use in pregnancy is not recommended. There are limited human data available for tecovirimat, and pregnancy outcome data from animals following tecovirimat exposure is more reassuring. Therefore, tecovirimat may be preferred for use by pregnant women with mpox. 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 among 11.6% and 26% of those 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. Males using MMF/MPA should also discuss their options for treatment with their specialist when considering fathering a pregnancy.

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.

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 tests and experimental in vitro models have demonstrated embryotoxic and teratogenic effects of molnupiravir or its active metabolite. There are currently no data regarding the safety of molnupiravir in human pregnancy. UKTIS is collecting outcome data for all pregnancies with maternal or paternal exposure to molnupiravir (more information can be found here).

Although COVID-19 in pregnancy can present a significant risk to both the woman and her baby, the mechanism of action of molnupiravir and the preclinical animal data warrant a cautious approach towards its use in pregnancy. Molnupiravir is not routinely recommended in pregnancy. 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 of pregnancy should be referred to UKTIS for further counselling and follow-up of the pregnancy outcome.

In circumstances where a 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 are 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 particularly recommended for 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.

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 confirm 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.

There are no controlled data comparing rates of miscarriage, stillbirth or neurodevelopmental outcomes following gestational metoprolol exposure.

Use of beta-blockers near term may result in beta-adrenoceptor blockade, leading to neonatal bradycardia, hypotension, and hypoglycaemia. There are limited data on rates of these neonatal complications in metoprolol-exposed infants and the absolute risk is unquantified. Assessment of the neonate for these effects is advised following gestational metoprolol use.

 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, serial scanning for fetal growth surveillance 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. 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).

Mirtazapine can be used in pregnancy if clinically appropriate. Optimal management of mental health conditions during pregnancy is critical, and minimising risk of relapse should be prioritised when treatment decisions are being made, including consideration of dose changes.

The data regarding exposure to mirtazapine in human pregnancy comprise around 2,000 exposures derived from cohort and case-control studies, as well as case reports and case series.

The available data do not indicate that mirtazapine use in pregnancy increases the risk of miscarriage, congenital malformation, or intrauterine death. While one large study identified increased risks of preterm delivery and infants being born small for gestational age, these data are likely confounded, and a number of smaller studies do not agree with these findings. Data relating to neonatal complications and altered neurodevelopment do not suggest associations with mirtazapine use in pregnancy but ideally require ongoing data collection for confirmation.

In utero SSRI exposure has been associated with a small increase in the prevalence of persistent pulmonary hypertension of the newborn (PPHN). No studies have investigated the risk of PPHN for mirtazapine specifically. Owing to the pharmacological similarities between mirtazapine and SSRIs, and given that there is a case report of PPHN following mirtazapine exposure, neonatal monitoring is recommended.

Centrally acting drugs used around the time of delivery can lead to neonatal withdrawal features. These features have been described in case reports/series following mirtazapine exposure. Infants exposed to mirtazapine should ideally be delivered in a unit able to provide neonatal support. 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. 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.

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.

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. 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 compound.

Due to data suggesting a possible teratogenic effect, the manufacturer advises that modafinil should not be used during pregnancy and that women of reproductive age should use effective contraception during treatment.

Published data regarding maternal modafinil/armodafinil use in pregnancy consist of a small number of uncontrolled case reports/series and two population-based cohort studies. Together, these studies describe approximately 500 pregnancies, of which approximately 400 were exposed in the first trimester.

Although there are concerns that modafinil may be a human teratogen, the available data are limited in methodology and scope, and findings are conflicting. While two studies have described increased malformation risks of similar magnitude (12% and 13%), other studies, including one population-based controlled study, have not confirmed these findings. Additionally, there does not appear to be an established pattern of anomalies. Furthermore, one of the studies indicating increased risks included anomalies typically considered to be minor and therefore presented an inflated major malformation risk estimate. Consequently, the teratogenic potential of modafinil is unclear. If the evidence indicating increased risks was accurate, there could be an additional 4 to 6 malformed infants expected for every 100 modafinil-exposed pregnancies (relative to a background risk of 2 to 3 per 100).

Two uncontrolled case series describe miscarriage risks consistent with the expected background rate following modafinil/armodafinil use in early pregnancy. Additional studies are required to accurately assess miscarriage risk.

The largest available prospective case series (n=173 exposed) reported a possible dose-dependent effect on fetal growth following use of modafinil and a 5.3% incidence of preterm delivery, which is not elevated in comparison with expected background risks. No studies have investigated the risks of stillbirth, 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, withdrawal may be anticipated following its use in later pregnancy.

It is important to consider whether ongoing modafinil treatment is clinically necessary during pregnancy, particularly in the context of potential risk to the fetus, including whether alternative treatment could be offered. It is strongly recommended that the risks and benefits of continued use are discussed with UKTIS.

Detailed anomaly scans are recommended following first trimester modafinil exposure. However, the anomalies described in the literature include limb defects, unspecified cardiac defects, spina bifida, Pierre-Robin sequence, congenital torticollis, and hypospadias, some of which may not 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.