‘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 increases the risk of NTDs in the offspring, however other 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 investigated overall congenital malformation rates following in utero exposure found no increase in risk. Findings regarding a possible increased risk of cryptorchidism in male offspring following paracetamol use during pregnancy are conflicting.

A number of studies have examined the effects of in utero paracetamol exposure on various aspects of neurodevelopment. While single studies have shown no association with IQ, attention disorders, or psychosis respectively, one study found that children exposed in utero to paracetamol were more likely to have poorer gross motor development, communication skills, externalising and internalising behaviours, and to have higher activity levels than siblings who had not been exposed to paracetamol. Four studies have analysed the prevalence of behaviour subtypes that may be indicative of ADHD. Although three of these studies identified an increased likelihood of these behaviours in children exposed to paracetamol in utero, associations were generally only of marginal statistical significance. One study found that boys exposed to paracetamol in utero were more likely to exhibit symptoms of autism spectrum disorder (ASD) but did not observe the association in girls, while a further study found an increased risk of ASD with hyperkinetic symptoms in children gestationally exposed to paracetamol, but no increased risk of ASD without hyperkinetic symptoms. In most studies, risk of abnormal neurodevelopment correlated with duration of paracetamol exposure. However, significant methodological limitations of these studies limit the conclusions that can be drawn 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, some of which were included in a recent meta-analysis which showed a weak association.

Data regarding other fetal effects of maternal paracetamol use in pregnancy are limited and conflicting. An association with an increased risk of any adverse fetal outcome following therapeutic paracetamol use in pregnancy remains to be proven.

Exposure to paracetamol at any stage of 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 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.

USE OF PRIMODOS AND HORMONAL PREGNANCY TESTS IN PREGNANCY

An Expert Working Group (EWG) of the UK’s Commission on Human Medicines (CHM) has published their report on the use of hormone pregnancy tests (HPTs) and adverse effects relating to pregnancy including possible birth defects. Please click here for further information.

Primodos (10mg norethisterone acetate + 0.02mg ethinyloestradiol) was used as an oral hormonal pregnancy test from 1953 to 1975. Concern was raised in the mid-1960’s regarding a possible increase in congenital malformations in infants exposed in utero to Primodos and other oral hormonal pregnancy tests. As a consequence of the introduction of urine-based pregnancy tests and the withdrawal of Primodos from the market, pregnancy safety data are limited.

Although some studies have suggested a possible association between Primodos exposure and increased rates of specific congenital malformations, the more methodologically robust prospective controlled studies have not provided evidence of such. Similarly, the methodologically limited data relating to oral hormonal pregnancy tests as a group do not conclusively provide evidence of an increased risk of malformation or specific pattern of malformation in exposed fetuses.

Referral to a clinical geneticist is recommended in all cases where a causal association between a congenital malformation and in utero exposure to an oral hormonal pregnancy test is being questioned, as identification of an underlying genetic cause may have implications in terms of recurrence risk for the individual and other members of the family.