USE OF PERAMPANEL IN PREGNANCY

Perampanel is licensed as an adjunctive treatment for partial-onset seizures with or without secondarily generalised seizures, and primary generalised tonic-clonic seizures in people with idiopathic generalised epilepsy.

It is important that maternal epilepsy remains well-controlled during pregnancy.

There is limited evidence regarding the safety of perampanel use in pregnancy, with data provided by a small number of uncontrolled studies which collectively describe the outcomes of 96 exposed pregnancies, mainly exposed in early pregnancy only. As such, the available evidence regarding perampanel exposure in later pregnancy is highly limited.

Although the available data do not clearly indicate increased risks of adverse pregnancy or fetal outcomes following maternal perampanel use in early pregnancy, these data are highly limited and higher quality studies are required before a more accurate safety assessment can be provided. Additionally, no studies have investigated the risk of longer-term childhood outcomes such as neurodevelopmental impairment.

A case of presumed perampanel withdrawal and two cases of low Apgar scores have been described. Use of any centrally acting drug throughout pregnancy or near delivery may be associated with withdrawal symptoms in the neonate and/or poor neonatal adaptation syndrome (PNAS). These symptoms are likely to be more severe in infants exposed in utero to more than one CNS acting drug. Delivery should be planned in a unit with neonatal intensive care facilities.

Although not predicted from the recognised pharmacology of perampanel, it is unknown whether use prior to conception or during pregnancy may impact upon maternal folate status. UK guidelines state that women who take any anti-seizure medication should be prescribed high-dose folic acid (5mg).

More research is required to define the pregnancy safety profile of perampanel. Pregnant women and women of childbearing potential should be made aware of the limited data for most pregnancy outcomes, and highly limited data regarding exposure in late pregnancy. Perampanel should only be used during pregnancy where the benefits of treatment are considered to outweigh any potential risks. In view of the limited human pregnancy data, close monitoring of mother and fetus should be considered following perampanel use in pregnancy. 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.

‘THERAPEUTIC’ USE OF PARACETAMOL IN PREGNANCY

Paracetamol is an antipyretic analgesic indicated for the treatment of mild-to-moderate pain and pyrexia. For the purpose of this monograph, ‘therapeutic’ use of oral paracetamol is regarded as 500-1000mg up to four times a day, with a maximum dose of 4g within a 24-hour period. Where this dose is exceeded or other factors such as prolonged use or low maternal weight are present, an assessment for paracetamol overdose may need to be considered. Please refer to our monograph ‘Paracetamol overdose in pregnancy’ for further information.

Animal studies have indicated that a rise in maternal core body temperature of 1.5°C may be associated with teratogenicity and there are limited human data that suggest that maternal fever, specifically a rise in temperature of 2°C, in the first trimester of pregnancy may increase the risk of neural tube defects (NTDs) in the offspring, however data are conflicting. Severe or chronic pain, if inadequately treated, may also impact on maternofetal outcome through alteration of both maternal cardiovascular function and uteroplacental perfusion. Adverse effects on maternal and fetal outcome due to the underlying maternal condition for which paracetamol is used should therefore be considered when interpreting pregnancy safety data.

Several studies which have investigated overall congenital malformation rates following in utero exposure found no increase in risk. No increase in risk has been reported for miscarriage, small for gestational age/low birth weight infants or preterm delivery.

A large number of studies have investigated neurodevelopmental outcomes following in utero exposure to paracetamol, with conflicting results. Three meta-analyses have analysed the prevalence of ADHD. Although these meta-analyses identified an increased likelihood of ADHD in children exposed to paracetamol in utero, when one of the meta-analyses accounted for unmeasured confounding, no statistically significant difference in the rates of ADHD in paracetamol-exposed and unexposed cohorts was found. Additionally, evidence of familial confounding has been described. Therefore, residual confounding cannot be excluded. Due to significant methodological limitations of these studies, the conclusions that can be drawn are limited and a causal association remains unproven.

Frequent paracetamol use during late pregnancy (20-32 weeks) has been associated with an increased incidence of wheezing or childhood asthma in some studies but not others.

Exposure to paracetamol at any stage of pregnancy is not 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 THALIDOMIDE, LENALIDOMIDE, AND POMALIDOMIDE IN PREGNANCY

Thalidomide was first marketed in 1957 as a sedative and to combat symptoms associated with morning sickness in pregnant women. Multiple reports of limb reduction defects in offspring exposed in utero led to the withdrawal of the drug from the market by 1962. During this time, over 10,000 children were born worldwide with severe malformations including absent, reduced, and/or hypoplastic limbs, dysplasia or absence of internal organs, deformities of the ears, eye defects, facial palsy and congenital heart defects.

Gestational exposure to thalidomide between 20 and 36 days post-fertilisation (36-50 days after LMP) carries the greatest risk of embryopathy, which has been reported after a single dose of 100mg. The overall risk of fetal malformations in live-born infants exposed to thalidomide during this period is reported at 20-50%, with an estimated 40% of affected children dying soon after birth. Thalidomide use in pregnancy has also been associated with increased risk of fetal loss and neurodevelopmental impairment and seizures.

There are no human pregnancy data regarding the safety of thalidomide analogues lenalidomide and pomalidomide, but these are predicted to be teratogenic based upon their similarity to thalidomide and the results of pre-clinical animal studies.

Thalidomide and its analogues are currently licensed for the treatment of multiple myeloma and certain other specific conditions in patients meeting strict criteria. In order to avoid fetal exposure to these drugs, all patients, prescribers and pharmacies are required to register with the manufacturer before the drugs are dispensed, and both female and male patients must comply with the terms of the manufacturer’s Pregnancy Prevention Programme (PPP).

There are no data regarding pregnancy outcome following exposure to thalidomide (or its analogues) later in pregnancy, and potential adverse neurodevelopmental effects from later exposure remain undetermined.

Use of thalidomide and its analogues is strictly contraindicated at all stages of pregnancy. If exposure to thalidomide, lenalidomide or pomalidomide occurs in early pregnancy, due to the extremely high malformation rate associated with such exposures, the option of elective termination of pregnancy should be discussed with the patient. For ongoing pregnancies a detailed anomaly scan of the fetus, including echocardiography, should be offered to the patient to screen for major structural abnormalities. However, it should be stressed that scans will not detect all structural abnormalities and will not identify neurobehavioural effects. 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 PROPRANOLOL IN PREGNANCY

Propranolol is a non-selective beta-blocker licensed for the treatment of hypertension, angina, migraine prophylaxis, hypertrophic cardiomyopathy, arrhythmias, management of essential tremor and anxiety, adjunctive management of thyrotoxicosis, and prophylaxis of upper gastro-intestinal bleeding in patients with portal hypertension and oesophageal varices.

The published data on use of propranolol in pregnancy are limited. A single case-control study found no association between propranolol exposure and cleft lip and/or palate, and two further case-control studies provide no evidence of an association with hypospadias. These data are limited both in scope and methodology, preventing conclusions being drawn about malformation risk. Data relating to risks of low infant birth weight and preterm delivery are limited and conflicting, and potentially confounded by the physiological effects of maternal hypertension and higher rates of early induction of delivery. There are no controlled studies that report rates of miscarriage, stillbirth, or adverse neurodevelopmental effects following gestational propranolol exposure.

Studies of beta-blockers as a class have not, to date, provided conclusive evidence that use during pregnancy is associated with an increased risk of malformation. Use in pregnancy has been associated with adverse effects on fetal growth, although as described above, maternal hypertension is linked to intrauterine growth restriction and analysis is therefore complex. Overall, data do not suggest that gestational beta-blocker exposure directly increases the risk of 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 thus advised.

Exposure to propranolol 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 maternal hypertension and maternal 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 PROTON PUMP INHIBITORS (PPIs) IN PREGNANCY

Proton Pump Inhibitors (PPIs), omeprazole, lansoprazole, esomeprazole, pantoprazole and rabeprazole are used in the management of dyspepsia, gastro-oesophageal reflux and peptic ulceration. The manufacturer of omeprazole state that it may be used in pregnancy if required.

Although a large meta-analysis indicated an increased risk of any malformation for PPIs as a class, there are methodological flaws associated with this analysis, and combination of the highest quality evidence did not indicate an increased risk of malformation following first trimester PPI exposure. Data from other studies for individual PPIs do not demonstrate that PPI exposure during early pregnancy increases the overall risk of congenital malformation. However, the available data for esomeprazole, pantoprazole, lansoprazole and rabeprazole is currently limited.

There is currently no evidence that gestational use of PPIs as a class is associated with an increased risk of miscarriage, preterm delivery, low birth weight or stillbirth. Data regarding these outcomes for lansoprazole, esomeprazole, pantoprazole and rabeprazole are currently too limited to allow an evidence-based assessment of their pregnancy safety profile. The data for omeprazole are currently reassuring, but also limited. There are no data on neurodevelopmental outcomes in children exposed to PPIs in utero.

Studies have shown that gastric acid suppression during pregnancy may increase the likelihood of atopy in the infant. There is some evidence that this effect may not be drug-specific. The currently available data on PPIs are, however, limited and conflicting; more research is therefore required before a link can be confirmed or refuted.

Exposure to a PPI 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 PYRIDOSTIGMINE IN PREGNANCY

Pyridostigmine is a reversible cholinesterase inhibitor used in the treatment of myasthenia gravis (MG), paralytic ileus, and post-operative urinary retention. Pyridostigmine is also included in Nerve Agent Pre-treatment Sets (NAPS) issued to military personnel.

Available data on pyridostigmine exposure in human pregnancy are limited to case reports/series describing the treatment of MG. Transient neonatal myasthenia gravis (TNMG) and arthrogryposis multiplex congenita (AMC) are recognised neonatal complications of maternal MG and are attributed to the transplacental transfer of maternal antibodies to acetylcholine (ACh) receptors. The published data therefore focus primarily on the link between maternal MG and these two fetal conditions, and not on the teratogenic potential of pyridostigmine.

The very limited published data do not suggest that pyridostigmine is a major teratogen, although one case report has suggested a potential effect of high dose (supratherapeutic) pyridostigmine (>40mg/kg/day, standard dose <10mg/kg/day) on fetal brain development. Data relating to other adverse pregnancy outcomes are too limited to facilitate a robust evidence-based assessment of risk, and although increased risks are not suggested by the available data, pregnant women being prescribed pyridostigmine should be made aware of the data limitations.

Inadvertent exposure to pyridostigmine at any stage of pregnancy would not usually be regarded as medical grounds for termination of pregnancy. Enhanced antenatal surveillance may be warranted and should be decided 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. Discussion with UKTIS is recommended in all cases of exposure to pyridostigmine at any stage of pregnancy. 

Where treatment with pyridostigmine is clinically indicated it should not be withheld because of pregnancy. International consensus guidelines state that oral pyridostigmine is recommended as the first line treatment for MG. MG in pregnancy may be associated with a greater risk of maternal respiratory failure and transient neonatal MG, therefore management by a multidisciplinary team is recommended.

USE OF PYRIDOXINE (VITAMIN B6) IN PREGNANCY

Pyridoxine (vitamin B6) is an essential vitamin. It is converted to pyridoxal-5’-phosphate which is the co-enzyme for a variety of metabolic transformations. Pyridoxine is used at varying doses in the treatment of nausea and vomiting of pregnancy (NVP), isoniazid-induced peripheral neuritis, idiopathic sideroblastic anaemia and vitamin B6 deficiency states.

The majority of human pregnancy data relate to use of pyridoxine in combination with doxylamine in the treatment of NVP. Rates of infant congenital malformation following in utero exposure to products containing this combination of drugs have been widely studied, with the majority of analyses providing no evidence of an increased risk. No increased risk of miscarriage has been observed following gestational pyridoxine exposure. No association with low birth weight, preterm delivery, intrauterine death or neonatal complications has been identified, although data are too limited to exclude an increase in risk.

Exposure to pyridoxine 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 POTASSIUM IODIDE IN PREGNANCY

Potassium iodide (KI) is an inorganic salt used in the management of iodine deficiency and thyroid disorders. Specific indications include the treatment of thyrotoxic crises, as a thyroid protection agent following the release of radioactive-iodine and during MIBG (iodine-131-metaiodobenzylguanidine) scans. Potassium iodide is present in some dietary supplements, including some commercially available prenatal multivitamins. It is also used topically as an antiseptic.

Iodine deficiency or excess can perturb normal fetal thyroid function and development. A joint statement by the World Health Organization (WHO) and the United Nations Children’s Fund (UNICEF) recommends that in situations where iodised salt is unavailable, all pregnant and lactating women should receive iodine supplementation at a dose of 250mcg/day.

Case reports document fetal goitre and abnormal fetal thyroid function, in some instances with persisting postnatal effects, following maternal potassium iodide treatment in pregnancy (at higher doses than used for supplementation). However, the degree to which the underlying maternal disease contributed to fetal outcome in some cases is uncertain.

Data regarding exposure to potassium iodide are limited, and although no association between gestational exposure to potassium iodide and increased risks of miscarriage, congenital malformation, impaired fetal growth, preterm delivery, intrauterine death, or neurodevelopmental delay has been identified, an increased risk cannot be excluded. Limited evidence from a single study on pregnant women with Graves’ disease suggests that risk of miscarriage and congenital malformation may be reduced by switching from methimazole (a teratogen associated with a rare embryopathy) to potassium iodide early in the first trimester. A risk-benefit analysis that takes into account stage of pregnancy and likelihood of maternal disease relapse would, however, need to be undertaken on a case-by-case basis and routine switching is not currently advised.

Where potassium iodide is maternally administered at therapeutic doses, additional fetal and/or neonatal monitoring (e.g., fetal ultrasound, neonatal thyroid function tests) is advised as the presence of a fetal goitre or fetal thyroid dysfunction may impact on delivery and/or the postnatal wellbeing of the neonate. Early discussion with an obstetrician or materno/fetal medicine specialist is recommended for all women on potassium iodide therapy who are pregnant or planning a pregnancy.

Exposure to potassium iodide at any stage of 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. Discussion with UKTIS is recommended in all cases of therapeutic exposure.

USE OF PRALIDOXIME IN PREGNANCY

Pralidoxime (1-methylpyridinium-2-aldoxime, 2-PAM) is an oxime drug used in conjunction with atropine in the treatment of poisoning due to organophosphorus (OP) insecticides or nerve agents.

Published data regarding the use of pralidoxime during pregnancy are limited to case reports describing a total of seven pregnancies. No adverse fetal effects have been reported, however available data are insufficient for accurate assessment of risk.

Where exposure to acetylcholinesterase inhibitors has occurred, maternal toxicity is likely to be a major determinant of risk to the fetus. Owing to the severity of complications associated with OP poisoning, treatment of the pregnant patient should be the same as for the non-pregnant patient. If pralidoxime use is clinically indicated, it should not be withheld due to pregnancy.

Enhanced antenatal surveillance may be warranted in all cases of poisoning and should be decided on a case-by-case basis. Discussion with UKTIS is recommended in all cases of exposure to pralidoxime at any stage of pregnancy.

USE OF PREGABALIN IN PREGNANCY

Please note, this document considers the study which was communicated by the MHRA in their April 2022 Drug Safety Update in addition to all other published evidence regarding the fetal risks associated with pregabalin use in pregnancy.

Pregabalin is an anticonvulsant used as adjunctive therapy in adults with partial seizures, with or without secondary generalisation, and in the treatment of neuropathic pain and generalised anxiety disorder.

The available data do not currently provide conclusive evidence that maternal pregabalin use in the first trimester, or at any stage of pregnancy, is associated with increased risks of either overall malformation or any specific malformations. Although some studies have described increased risks of malformation overall and for specific anomalies (including central nervous system (CNS), eye, genital and urinary anomalies, and orofacial clefts), these results may have been influenced by data confounding and methodological limitations. Furthermore, the absolute risks indicated by those studies describing increased risks were generally small and therefore do not preclude the use of pregabalin in pregnancy where the indication for treatment is compelling.

Collectively, the available data do not conclusively indicate that maternal pregabalin use in pregnancy is associated with increased risks of miscarriage, stillbirth, preterm delivery, fetal growth restriction or neurodevelopmental impairment.

Although controlled studies have not identified increased risks of poor neonatal adaptation following prenatal pregabalin exposure, one uncontrolled study has described a small number of affected infants, including one case of neonatal withdrawal. Use of any centrally acting drug throughout pregnancy or near delivery may potentially be associated with withdrawal symptoms in the neonate and/or poor neonatal adaptation syndrome (PNAS). These symptoms are likely to be more severe in infants exposed to more than one CNS-acting drug. For all pregnancies with exposure to CNS-acting medication, delivery should be planned in a unit with adequate neonatal facilities.

Pregabalin is not known to impact maternal folate status. However, guidelines in the UK state that women who take any anti-epileptic medication should be prescribed high dose folic acid (5mg). Women should be made aware that it is not known whether high dose folic acid supplementation offers any benefit or protective effects over standard dose regimes when taking pregabalin pre-conceptually or during pregnancy.

Exposure to pregabalin 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.