USE OF BALOXAVIR IN PREGNANCY

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. 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.

USE OF BETA-ADRENOCEPTOR BLOCKING DRUGS (BETA-BLOCKERS) IN PREGNANCY

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

USE OF BISOPROLOL 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.

USE OF BISPHOSPHONATES IN PREGNANCY

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.    

USE OF BUPRENORPHINE IN PREGNANCY

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.

USE OF BUPROPION IN PREGNANCY

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.

USE OF BACLOFEN IN PREGNANCY

Baclofen is a gamma-aminobutyric acid (GABA) agonist licensed for oral or intrathecal administration to alleviate spasticity of voluntary muscle in patients with multiple sclerosis, spinal cord lesions, cerebral palsy, cerebrovascular accidents, traumatic head injury, and meningitis.

Data on the use of baclofen in human pregnancy are derived from one small cohort study (presented in abstract only), case reports and two small case series (one presented only in abstract) and, as such, are too limited to accurately assess risks to the infant or pregnancy. An increased risk of congenital malformation following in utero exposure has been reported by a small cohort study; however, no pattern of defects was observed, and due to the small numbers of cases, consequent wide confidence intervals and lack of consideration of the impact of concomitant risk factors, the conclusions that can be drawn from this single study are limited. No evidence of an increased risk of miscarriage was provided from a small cohort study. There are insufficient data to assess the risk of intrauterine death, low birth weight, preterm delivery and adverse neurodevelopmental effects.

Neonatal withdrawal has been reported following maternal use of oral baclofen. Delivery in a unit with adequate neonatal facilities is therefore advised if maternal use has occurred in the weeks prior to delivery.

Due to the lack of safety data, the need for additional fetal monitoring needs to be considered 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.

EXPOSURE TO BOTULINUM TOXIN IN PREGNANCY

Botulinum toxin type A (BTX-A) is licensed for the treatment of blepharospasm, hemifacial spasm, idiopathic cervical dystonia, focal spasticity, bladder dysfunction, the prophylaxis of headaches in adults with severe migraine, and in the management of severe axial hyperhidrosis. BTX-A is also used in aesthetic dermatology to temporarily improve the appearance of facial lines.

Botulinum toxin is produced by the bacterium Clostridium botulinum and is the cause of botulism, a potentially severe illness that can lead to paralysis and acute respiratory failure.

There are limited data on which to base an assessment of the safety of BTX-A in human pregnancy. Animal studies of exposure to high doses of BTX-A have demonstrated teratogenic risk. Data from human pregnancies exposed to Clostridium botulinum infection or to BTX-A do not raise concern of adverse pregnancy outcomes but are too limited to formally exclude any increase in risk. It is noteworthy that significant systemic exposure to BTX-A is not expected when it is administered as per the manufacturer’s instructions; fetal risk is therefore expected to be low in the absence of systemic side-effects.

If botulism infection is suspected, due to the potential severity of the illness, treatment during pregnancy should be the same as for the non-pregnant patient. Data on maternal treatment with botulinum antitoxin are very limited but have not shown evidence of fetal harm, and where clinically indicated, treatment with the antidote should not be withheld on account of pregnancy. Additional fetal monitoring may be warranted in cases of maternal botulism, particularly if exposure is associated with maternal hypoxia. Discussion with UKTIS is recommended in all cases.

 Use of BTX-A during pregnancy should usually be reserved for therapeutic indications where there is no suitable alternative treatment. However, prescribers should consider that use of BTX-A can, in some circumstances (e.g. for headache prophylaxis), avoid systemic drug exposure and may therefore be the option associated with lowest potential risk. It is pragmatically recommended that use of BTX-A for cosmetic indications during pregnancy should be avoided. Pregnant women with inadvertent exposure to BTX-A can be reassured that, in the absence of systemic side-effects, the risk to the fetus is low. 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.

EXPOSURE TO BREVETOXIN IN PREGNANCY

Brevetoxins are cyclic polyether neurotoxic compounds produced by marine organisms such as the dinoflagellate Karenia brevis that bioaccumulate in filter feeding molluscs. Brevetoxins bind to the sodium channels in nerve cells leading to disruption of neurological processes resulting in neurotoxic shellfish poisoning. Aerosolisaton of brevetoxin is also possible during algal blooms.

There are no data regarding brevetoxin exposure in human pregnancy. Animal studies have demonstrated placental transfer of the toxin in pregnant rats, and direct fish embryo culture with the toxin produced CNS, spinal and skull malformations. However, these data may not be relevant to human exposure scenarios.

Owing to the potential severity of brevetoxin exposure, treatment during pregnancy should be the same as for the non-pregnant patient. Due to a lack of human exposure data, it is not possible to state that maternal exposure which does not result in toxicity would not pose a risk to the developing fetus. However, maternal toxicity is likely to be a major determinant of risk to the fetus after maternal brevetoxin exposure.

Due to a lack of data following exposure in human pregnancy, it is not currently possible to offer an evidence-based assessment of the risk that maternal brevetoxin exposure poses to a developing fetus. Where exposure to brevetoxin has occurred, even in cases which did not result in maternal toxicity, enhanced fetal monitoring may be warranted. Discussion with UKTIS is recommended in all cases.

EXPOSURE TO BZ (AGENT 15) IN PREGNANCY

BZ (Agent 15) is a glycolic anticholinergic compound with structural and pharmacological similarities to atropine and hyoscine. It acts as a competitive inhibitor of the acetylcholinergic (muscarinic) receptor in the cholinergic nervous system. Exposure results in inhibition of the parasympathetic nervous system with development of anticholinergic symptoms. BZ was originally developed as a non-lethal incapacitating chemical weapon by the US army, but is now primarily used in cholinergic nervous system research and pharmaceutical manufacturing.

There are no published data regarding maternal exposure to BZ, or guidelines for the treatment of BZ poisoning during pregnancy. It is therefore not currently possible to offer an evidence-based assessment of the risk that maternal BZ exposure poses to a developing fetus, although maternal toxicity is likely to be a major determinant of fetal risk. Where treatment is required, management of the pregnant patient should be the same as for the non-pregnant patient.

Exposure to BZ 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 human pregnancy data and the broad anticholinergic effects of BZ, additional fetal monitoring may be warranted on a case-by-case. Discussion with UKTIS is recommended for all cases of gestational exposure.