Letter: B

Benzylpenicillin is a penicillin antibiotic indicated for the treatment of throat infections, otitis media, pneumonia, cellulitis, endocarditis, anthrax, meningitis, meningococcal disease, and severe diphtheria.

The limited data regarding overall congenital malformation risk following prenatal benzylpenicillin exposure are conflicting and likely heavily confounded by indication. No studies investigating the risk of miscarriage, intrauterine death, low birth weight (LBW), preterm delivery, or neonatal complications following maternal exposure to benzylpenicillin were identified. Where possible associations with adverse outcomes have been suggested, findings are considered likely influenced by the effects of maternal infection during pregnancy.

The extensive body of data relating to maternal use of penicillin antibiotics as a class does not indicate an increased risk of adverse fetal outcomes, although not all pregnancy outcomes have been studied in sufficient detail to fully exclude an increased risk. However, due to the potential adverse consequences of untreated maternal infection during pregnancy, the use of penicillin antibiotics, including those with limited or no pregnancy safety data, may be considered where clinically necessary.

Where possible, the results of culture and sensitivity tests should be available before making a treatment choice in accordance with local prescribing guidelines. It is important to ensure adequate treatment of infection in order to avoid adverse maternal and fetal effects from uncontrolled infection or pyrexia.

The Royal College of Obstetricians and Gynaecologists (RCOG) advises routine intrapartum antibiotic prophylaxis (IAP) for all women in preterm labour, with or without pre-labour rupture of membranes (PROM). Benzylpenicillin should be used preferentially, but a cephalosporin should be used in women 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.

Exposure to benzylpenicillin 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.

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.

Household bleach usually contains ≤6% sodium hypochlorite. Industrial strength bleach (>6% sodium hypochlorite) is used as a disinfectant and bleaching agent in the chemical, paper, textile, water treatment, and dairy industries.

This document includes data relating to chlorine-based bleach containing sodium hypochlorite. Oxygen-based bleaches containing hydrogen peroxide are not discussed.

There are limited data on the effects of household or industrial strength bleach exposure in human pregnancy; however, the use of household bleach as directed by the manufacturer at any stage in pregnancy is considered unlikely to pose a risk.

Accidental ingestion of small amounts of diluted household bleach (for example, residual bleach remaining in a mug after cleaning) is a common exposure. Where maternal toxicity is absent and only a small quantity has been ingested, no additional pregnancy surveillance is generally required.

As with all chemicals, unnecessary exposure to industrial strength bleach should be avoided, but where exposure is unavoidable, appropriate personal protective equipment should be worn and precautions should be taken to ensure that the area is well-ventilated and that no symptoms suggestive of toxicity occur.

Exposure to chlorine-based bleach 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.

Baloxavir marboxil is a Cap-dependent endonuclease inhibitor. It is used as a single-dose antiviral, licensed in the UK for post-exposure prophylaxis of influenza and in the treatment of uncomplicated influenza in patients aged 12 years or older.

Natural physiological and immunological adaptations result in pregnant women being at increased risk of severe influenza infection compared to the general population. Influenza infection in pregnancy carries increased risks of intensive care admission, preterm delivery, low birth weight, congenital anomalies, fetal demise and maternal death.

Although the manufacturer states that it is preferable to avoid the use of baloxavir during pregnancy, randomised controlled trials have shown single dose baloxavir treatment to have a similar efficacy as five days of oseltamivir treatment and to be associated with greater reductions in viral load and fewer adverse events in the non-pregnant population. Baloxavir treatment may be of particular benefit to pregnant women with influenza, as they are at increased risk of developing severe disease. Preclinical animal models of exposure in pregnancy do not provide evidence of adverse embryo-fetal effects at doses up to five and seven times the human therapeutic dose respectively. The risk of harm from baloxavir in pregnancy is likely to be low given the animal model data, together with the therapeutic target for baloxavir being a virus specific enzyme. However, given that no human data are available, it is recommended that a cautious approach is taken and baloxavir use in pregnancy be reserved to clinical trial settings with careful collation of pregnancy outcome data.

Exposure to baloxavir 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.  Given the lack of pregnancy data available, it is recommended that all exposures to baloxavir in pregnancy are reported to UKTIS.

Beta-blockers are used in the management of hypertension, angina, myocardial infarction, arrhythmia, heart failure, thyrotoxicosis, anxiety, and migraine. Topical preparations are also used to treat glaucoma.

Guidance from the National Institute for Health and Care Excellence (NICE) states that labetalol is the preferred antihypertensive for use in pregnancy. 

Studies of beta-blockers as a class do not, collectively, provide conclusive evidence that use during pregnancy is associated with an overall increased risk of fetal structural malformation, or of a number of specific malformations.

Use of beta-blockers in pregnancy has been associated with adverse effects on fetal growth; however, because maternal hypertension itself increases the risk of intrauterine growth restriction, causal analysis is complex and the contribution of beta-blocker exposure to this outcome remains unquantified.

Overall, the available data do not suggest that gestational beta blocker exposure independently increases the risk of stillbirth or preterm delivery. There are no robust data on the risk of miscarriage or adverse neurodevelopmental outcomes following use of beta-blockers in pregnancy.

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

Exposure to beta-blockers 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 beta-blockers have 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.

Related document: Use of labetalol in pregnancy

Bisoprolol is a cardioselective beta-blocker licensed for the treatment of arrhythmia, hypertension, angina pectoris, and as adjunctive therapy in the treatment of stable chronic heart failure with reduced left ventricular function.

A single small prospective cohort study found no increased rate of miscarriage or major congenital malformation following gestational bisoprolol exposure. An increased rate of preterm delivery was identified. A further overlapping cohort study found that bisoprolol/metoprolol-exposed infants were at increased risk of being small for gestational age. However, as these outcomes are associated with maternal hypertension and cardiac disease, confounding may be an issue. There are no controlled studies assessing rates of other adverse pregnancy outcome following gestational exposure to bisoprolol. Case reports describe both adverse and uneventful outcomes but the uncontrolled nature of these data limits any meaningful conclusion. Due to limited data, it is not possible to quantify the risk (if any) of adverse fetal outcome specifically following bisoprolol use in pregnancy.

Use of beta-blockers in pregnancy has been associated with adverse effects on fetal growth, although because maternal hypertension is linked to IUGR, analysis is complex and any contribution of beta-blocker exposure to this outcome remains unquantified. Overall, data do not suggest that gestational beta-blocker exposure increases the risk of congenital malformation or 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 bisoprolol 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 hypertension and cardiac disease, regardless of pharmacotherapy. 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.

Bisphosphonates inhibit bone resorption by osteoclasts, as well as hydroxyapatite crystal formulation and dissolution, thereby reducing bone remodelling and turnover. They are licensed for the treatment of osteoporosis (both idiopathic and glucocorticoid-induced), Paget’s disease of the bone, and skeletal pain associated with metastatic breast cancer, and are also used off-license in children in the management of osteogenesis imperfecta. Six bisphosphonates are currently available for clinical use in the UK: alendronic acid, ibandronic acid, pamidronate disodium, risedronate sodium, sodium clodronate and zoledronic acid.

 As bisphosphonates are incorporated into bone, the terminal half-life is long (up to 10 years). Fetal exposure could therefore potentially occur in pregnant women with a history of bisphosphonate use prior to conception as a consequence of mobilisation of bisphosphonates stored in maternal bone.

 Some animal studies have demonstrated increased embryofetal resorption/decreased implantation, impaired fetal bone ossification, urinary tract anomalies and orofacial clefting following antenatal exposure to bisphosphonates at doses lower than equivalent human therapeutic doses. Impaired uterine contractility which correlated with decreased maternal calcium concentrations and resulted in obstructed labour has also been described.

 The available human exposure data are limited to a small number of uncontrolled case reports and three small cohort studies which collectively describe the outcomes of approximately 100 pregnancies with bisphosphonate exposure either prior to conception or during pregnancy. Although these data do not clearly indicate that in utero bisphosphonate exposure is directly associated with adverse fetal, pregnancy or neonatal outcomes, they are insufficient to permit an accurate assessment of the risk. Controlled studies have demonstrated possible associations between preconceptual/gestational bisphosphonate exposure and increased risk of miscarriage and neonatal complications. However, these findings may reflect methodological data limitations and/or uncontrolled data confounding. Transient disturbances in neonatal calcium levels have been reported in a small number of cases following maternal bisphosphonate use either prior to or during pregnancy. Monitoring of neonatal calcium levels could therefore be considered if an infant has been exposed in utero.

 Exposure to bisphosphonates at any stage in pregnancy would not usually be regarded as medical grounds for termination of pregnancy. Where exposure to bisphosphonates has occurred, either prior to or during pregnancy, skeletal development and neonatal calcium levels may be warranted. However, other risk factors may be present in individual cases. Clinicians are reminded of the importance of consideration of such factors when performing case-specific risk assessments.    

Buprenorphine is a semi-synthetic opioid derived from the morphine alkaloid thebaine which has mixed agonist-antagonist properties. It is typically administered intramuscularly, intravenously, by sublingual tablet, or via transdermal patch. Buprenorphine is used for the treatment of moderate-to-severe pain and, when combined with psychological treatment, as a substitution treatment in the management of opioid dependence.

Acute opioid withdrawal during pregnancy carries a risk of fetal death. Opioid substitution therapy is recommended in pregnancy as it carries a lower risk to the fetus than continued use of illicit drugs. Where a woman is stabilised on buprenorphine for treatment of opioid dependence, therapy should be continued in pregnancy.

The limited available data relating to use of buprenorphine during human pregnancy have not identified increased risks of congenital malformation, preterm delivery, or low infant birth weight. However, studies have generally assessed the risk of these outcomes in comparison with cohorts exposed to other opioid substitution therapies, which means that data are lacking about the risk of adverse pregnancy outcomes in comparison with the general population. This also limits the conclusions that can be provided about use of buprenorphine as an analgesic. Data on rates of intrauterine death, miscarriage and adverse neurodevelopment following buprenorphine exposure do not currently raise concern but are too limited to state definitively that no increased risk exists.

Use of any opioid during pregnancy, particularly around the time of delivery, confers a risk of neonatal respiratory depression. Prolonged use of opioids throughout pregnancy may result in neonatal withdrawal and this has been documented specifically in buprenorphine-exposed infants. Therefore, infants exposed to buprenorphine in utero should ideally be delivered in a unit with facilities to provide monitoring and treatment for these conditions.

Where buprenorphine 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 buprenorphine at any stage in pregnancy would not usually be regarded as medical grounds for termination of pregnancy. Additional fetal monitoring may be required in pregnancies complicated by severe pain or opioid addiction on a case-by-case basis. 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.

Bupropion is a noradrenaline and dopamine selective reuptake inhibitor (NDRI) licensed for use as a smoking cessation aid in the UK. In other countries bupropion is also licensed for use at a higher dose as an antidepressant. More recently, the long-acting form of bupropion has been used off-label in the treatment of attention deficit hyperactivity disorder (ADHD). Much of the available pregnancy exposure data are collected from studies investigating its use as an antidepressant, which limits the conclusions we are able to provide concerning its use as a smoking cessation aid.

Published human pregnancy exposure data do not currently provide evidence of an increased risk of miscarriage, major congenital malformation overall, cardiac malformation overall, intrauterine death, low birth weight or preterm delivery following maternal bupropion use in pregnancy. Although single case-control studies have suggested possible associations with specific cardiac malformations, including coarctation of the aorta and ventricular septal defects, as well as diaphragmatic hernia, these observations have not been replicated in other studies.

One study has provided evidence that there may be an increased risk of ADHD in the offspring of women who were treated with bupropion for depression. However, this finding was based on a small number of exposed infants with ADHD, resulting in an imprecise risk estimate which may have been confounded by the underlying maternal condition. This observation therefore requires confirmation in further studies.

Tobacco smoking during pregnancy is associated with a higher risk of adverse pregnancy and offspring outcomes, and smoking cessation is therefore strongly advised for both women considering pregnancy and those already pregnant. Where bupropion use during pregnancy is being considered, patients should be made aware of the limited efficacy and pregnancy safety data, and other therapeutic options should be discussed. Current NICE guidelines recommend NRT in combination with behavioural support for smoking cessation in pregnancy, and also state that bupropion should not be routinely offered to pregnant women.

Exposure to bupropion 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.