USE OF NABUMETONE IN PREGNANCY

Nabumetone is a non-steroidal anti-inflammatory drug (NSAID) used to treat pain and inflammation in rheumatic disease.

Use of NSAIDs in pregnancy has been associated with an increased risk of miscarriage, persistent pulmonary hypertension of the newborn (PPHN), oligohydramnios, premature closure of the ductus arteriosus (DA), structural cardiovascular defects and a number of other congenital anomalies, including orofacial clefts. However, the available data are limited, confounded and often conflicting; further research is therefore required to define the risk of these outcomes more accurately.

There are no published data concerning the safety of maternal nabumetone use in human pregnancy and it is therefore not possible to provide an adequate evidence-based assessment of the fetal risks following gestational exposure.

Exposure to NSAIDs after 30 weeks of gestation has been associated with an increased risk of premature closure of the DA and oligohydramnios. These effects are thought to be mediated by the inhibitory effect of NSAIDs on prostaglandin production. There are conflicting findings regarding the risks of PPHN following antenatal use of NSAIDs. Further evidence is required to assess whether this is a risk. Where published data concerning the fetal effects of gestational exposure are unavailable or limited, a possible class effect for these associations should be considered for all NSAIDs.

All NSAIDs should, where possible, be avoided during the third trimester. In circumstances where the maternal clinical condition requires treatment with nabumetone during the third trimester, discussion with a Fetal Medicine Unit regarding antenatal monitoring for oligohydramnios and ductus arteriosus patency is recommended. Where use of nabumetone is being considered at any stage of pregnancy the available NSAID class exposure pregnancy safety data should be discussed with the patient to support informed decision-making regarding the risks and benefits of treatment.

Please refer to the NSAID overview monograph for more information. 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 for all cases of mefenamic acid exposure in pregnancy.

USE OF NADOLOL IN PREGNANCY

Nadolol is a non-selective beta blocker licensed for the treatment of hypertension, angina pectoris, cardiac arrhythmias, migraine and thyrotoxicosis.

There are no studies of rates of specific pregnancy outcomes following gestational exposure to nadolol. An evidence-based assessment of the potential risks of congenital malformation, miscarriage, stillbirth, intrauterine growth restriction (IUGR), preterm delivery and adverse neurodevelopmental effects following in utero exposure is therefore not possible.

Studies of beta blockers as a class do not show that use during pregnancy is associated with fetal structural malformation. Use of beta blockers in pregnancy has been associated with adverse effects on fetal growth, although because maternal hypertension is linked to IUGR, the relative contribution of beta blocker exposure to this outcome remains unquantified. Overall, data do not suggest that gestational beta blocker exposure 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 advised.

Exposure to nadolol 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 cardiac disease, regardless of pharmacotherapy. Additional growth scans should be offered following gestational exposure to beta blockers. 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.

Related document: Use of beta blockers in pregnancy

USE OF NAPROXEN IN PREGNANCY

Naproxen is a non-steroidal anti-inflammatory drug used primarily for the treatment of pain and inflammation in rheumatic disease and other musculoskeletal disorders.

Use of NSAIDs in pregnancy has been associated with an increased risk of miscarriage, persistent pulmonary hypertension of the newborn (PPHN), oligohydramnios, premature closure of the ductus arteriosus DA, structural cardiovascular defects and a number of other congenital anomalies, including orofacial clefts. However, the available data are limited, confounded and often conflicting; further research is therefore required to define the risk of these outcomes more accurately.

Ten studies which collectively report more than 5,000 pregnancies have investigated the fetal effects of maternal naproxen use in pregnancy. Conflicting findings have been reported relating to the risks of miscarriage and some specific congenital malformations. However, it is possible that this is a result of data confounding and further studies are required.

Exposure to NSAIDs after 30 weeks of gestation is associated with an increased risk of premature closure of the DA and oligohydramnios. These effects are mediated by the inhibitory effect of NSAIDs on prostaglandin production. There are conflicting findings regarding the risks of PPHN following antenatal use of NSAIDs. Further evidence is therefore required before this possible association can be confirmed. Where published data concerning the fetal effects of gestational exposure are unavailable or limited, a possible class effect for these associations should be considered for all NSAIDs.

Where clinically indicated, treatment with naproxen in the first or second trimester may be considered. Naproxen should, where possible, be avoided during the third trimester. However, in circumstances where the maternal clinical condition requires treatment with naproxen during the third trimester, discussion with a Fetal Medicine Unit regarding fetal monitoring for oligohydramnios and neonatal monitoring for ductus arteriosus patency is recommended.

Please refer to the overview monograph ‘Use of non-steroidal anti-inflammatory drugs (NSAIDs) in pregnancy’ for more information. 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 NATALIZUMAB IN PREGNANCY

Natalizumab is a recombinant humanised anti-α4-integrin antibody licensed for the treatment of highly active relapsing remitting multiple sclerosis (MS). 

Data consisting of approximately 760 natalizumab-exposed pregnancies, including approximately 500 first trimester exposures, do not indicate that natalizumab is a major structural teratogen but are too limited to exclude an increased risk. Current data do not raise concern that natalizumab exposure is associated with higher risks of miscarriage and preterm birth but are insufficient to evaluate risks of stillbirth and small for gestational age (SGA).

Natalizumab does not cross the placenta during the first trimester but is actively transported during the second and third trimesters, and exposure late in pregnancy has been associated with the development of reversible mild-to-moderate anaemia and thrombocytopenia in the neonate. To minimise fetal exposure, UK consensus guidelines from the Association of British Neurologists recommend considering giving the last dose during pregnancy at approximately 34 weeks and restarting soon after birth (within 8-12 weeks of the last dose). The decision to stop or delay a dose of natalizumab should be carefully weighed against the risk of relapse.

Use of natalizumab in non-pregnant patients has been associated with an increased risk of progressive multifocal leukoencephalopathy (PML) as a result of reactivation of the commonly carried dormant Polyomavirus JC. Transmission of the Polyomavirus JC to the fetus may be of concern, although there have been no congenital cases of PML described to date. Due to the limited experience of natalizumab use in pregnancy, data investigating both the risk of PML development amongst pregnant patients and the risk of viral transmission to the fetus is currently unavailable.

There is theoretical concern that immunosuppressant antibodies which actively cross the placenta during pregnancy could result in neonatal/infant immunosuppression and an increased risk of infection. There are currently no data regarding the effect of in utero natalizumab exposure on the neonatal/infant immune system. Guidance from Public Health England (PHE) [issued 2017] specified that live vaccines should not be used until the infant is 6 months old following in utero biologic immunosuppressant exposure.

Where treatment with natalizumab is clinically indicated during pregnancy, close monitoring of maternal neurological function is advised. UK consensus guidelines recommend that routine MR brain imaging and monitoring for PML should continue during pregnancy as required. Should maternal symptoms of PML present during pregnancy, enhanced fetal and neonatal monitoring may also be warranted. 

Other risk factors may also be present in individual cases which may independently increase the risk of adverse pregnancy outcome. Clinicians are reminded of the importance of consideration of such factors when performing case-specific risk assessments. Discussion of individual cases with UKTIS is recommended.

USE OF NEBIVOLOL IN PREGNANCY

Nebivolol is a cardioselective beta blocker licensed for the treatment of hypertension and chronic heart failure.

The available data relating to nebivolol use in pregnancy are highly limited. There is a single case report of an infant, liveborn at term with a normal birth weight following exposure during the final four months of pregnancy to nebivolol. Additionally, two uneventful pregnancy outcomes associated with nebivolol exposure have been reported to UKTIS. A single, small study found no adverse effects on fetal growth following in utero exposure to nebivolol. Further research is required to confirm this finding, particularly given that beta blocker class data have suggested such effects. There are no further studies of rates of specific pregnancy outcomes following gestational exposure to nebivolol. An evidence-based assessment of the potential risks of congenital malformation, miscarriage, stillbirth, preterm delivery and adverse neurodevelopmental effects is therefore not possible.

Studies of beta blockers as a class do not show that use during pregnancy is associated with fetal structural malformation. Use of beta blockers in pregnancy has been associated with adverse effects on fetal growth; however maternal hypertension is linked to intrauterine growth restriction, therefore the relative contribution of beta blocker exposure to this outcome remains unquantified. Overall, data do not suggest that gestational beta blocker exposure 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 advised. There is a single case report of a term infant exposed to nebivolol during the final four months of pregnancy with neonatal hypoglycaemia, jaundice, polycythaemia, mild thrombocytopenia and hyponatremia. Due to the nature of this report, causality cannot be ascribed to nebivolol exposure.

Exposure to nebivolol 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/or maternal cardiac disease, regardless of pharmacotherapy. Additional growth scans should be offered following gestational exposure to beta blockers. 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.

Related document: Use of beta blockers in pregnancy

USE OF NITROFURANTOIN IN PREGNANCY

Nitrofurantoin is an antibiotic used for the treatment and prophylaxis of acute or recurrent uncomplicated lower urinary tract infections (UTIs) and pyelitis. It is specifically indicated for the treatment of infections due to susceptible strains of Escherichia coli, Enterococcus, Staphylococcus, Citrobacter, Klebsiella, and Enterobacter.

There is no strong evidence of an association between in utero nitrofurantoin exposure and an overall increased risk of congenital malformation. While individual studies have suggested possible increased risks of hypoplastic left heart, talipes, hypospadias, an/microphthalmia, atrial septal defect, and cleft lip/palate, no pattern of defects is evident, the studies are limited by methodology, and ongoing research is required to confirm or refute these findings. The increase in risk, if any, of congenital malformation following exposure to nitrofurantoin is likely to be small, given that systemic absorption and transfer to the fetus is low.

No statistically significant increased risks of miscarriage, stillbirth, low birth weight, or preterm delivery have been identified, although data are limited for some of these outcomes. An increased incidence of neonatal jaundice has been observed in infants exposed to nitrofurantoin in the month preceding delivery.

Nitrofurantoin in the non-pregnant patient can, in rare cases, cause serious adverse reactions, including peripheral neuropathy, pulmonary toxicity, and fatal hepatic injury. It has also been associated with haemolysis in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Nitrofurantoin use is generally avoided during labour and delivery because of the theoretical possibility of haemolytic anaemia in the neonate due to immature erythrocyte enzyme systems.

Guidance on UTI in pregnancy suggests immediate antibiotic treatment, with nitrofurantoin as the recommended first-line option unless contraindicated or not tolerated. Treatment should be reviewed if culture and sensitivity testing of urine sampled before antibiotics were started suggests a more suitable alternative. Any possible risks to the fetus from the drugs used to treat maternal UTI should be weighed against the potential adverse effects for the mother and fetus from an untreated infection. Use of nitrofurantoin near term should be avoided due to a theoretical risk of haemolytic anaemia in the neonate owing to immature erythrocyte enzyme systems.

Exposure to nitrofurantoin 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 NON-LIVE VACCINES IN PREGNANCY

This document summarises the available evidence regarding the safety of vaccines that are either inactivated, replication deficient or only contain structural components of the viral/bacterial pathogen (i.e. ‘non-live’ vaccines). In the United Kingdom (UK), these vaccines are used to provide immunity against hepatitis A, hepatitis B, seasonal influenza, poliomyelitis, rabies, haemophilus influenza type B, human papillomavirus, pertussis, pneumococcal and meningococcal disease, and COVID-19.

Large amounts of pregnancy exposure safety data are available for some of these vaccines, with >100,000 exposed pregnancies being reported in the literature for COVID-19, seasonal influenza and tetanus, diphtheria, pertussis and poliomyelitis (Tdap-IPV) vaccines.

There are currently no proven fetal risks following gestational exposure to ‘non-live’ vaccines. It is therefore considered highly unlikely that such vaccines would be harmful if administered in pregnancy. However, for some of these vaccines, information regarding the safety of administration in pregnancy is either limited or lacking.

Where required, the benefits of ‘non-live’ vaccines, in preventing maternal infection and associated adverse maternal and/or fetal outcomes, are likely to outweigh the risks.

Exposure to ’non-live’ vaccines 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 NON-STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDs) IN PREGNANCY

Non-steroidal anti-inflammatory drugs (NSAIDs) are used to treat pain and inflammation in various disease states.

Individual studies have associated NSAID use in early pregnancy with increased risks of congenital malformation overall and other more specific anomalies including cardiovascular defects, septal cardiac defects and orofacial clefts. As these studies are isolated, and there are currently no published studies which corroborate these findings, it is difficult to draw firm conclusions regarding these associations.

A number of studies have demonstrated an association between NSAID exposure and an increased risk of miscarriage. However, these study findings are also likely to be influenced by data confounding and no definitive conclusion has yet been reached. The available data on NSAID use in pregnancy do not suggest an association with stillbirth, low infant birth weight or preterm delivery.

Exposure to NSAIDs after 30 weeks of gestation has been associated with an increased risk of premature closure of the ductus arteriosus (DA) and oligohydramnios. These effects are thought to be mediated by the inhibitory effect of NSAIDs on prostaglandin production. There are conflicting findings regarding an increased risk of persistent pulmonary hypertension of the newborn (PPHN) following antenatal use of NSAIDs. Further evidence is required. A potential class effect for these associations should be considered for all NSAIDS where published data concerning the fetal effects of gestational exposure to a specific NSAID are unavailable.

All NSAIDs should, where possible, be avoided during the third trimester. If their use cannot be avoided it is recommended that the lowest effective dose is used for the shortest period only. In circumstances where the maternal clinical condition requires treatment with NSAIDs during the third trimester, discussion with a Fetal Medicine Unit regarding antenatal monitoring for oligohydramnios and ductus arteriosus patency is recommended. Where use of an NSAID is being considered at any stage of pregnancy the available pregnancy data should be discussed with the patient to support informed decision-making regarding the risks and benefits of treatment.

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 for all cases of NSAID exposure in pregnancy.

For information on specific NSAIDs please refer to the appropriate monograph, where available.

TREATMENT OF NAUSEA AND VOMITING IN PREGNANCY

Nausea and vomiting of pregnancy (NVP) is extremely common and is generally reported between weeks 6-16, though may persist for longer in a minority of women. Symptoms can range from mild, to those that severely impair quality of life.

Women with mild NVP should be advised of self-management strategies including eating smaller regular meals, avoiding fatty foods and food with strong odours, and drinking adequate fluids. Eating foods containing ginger and use of acupressure can also be tried for mild cases. Where treatment with anti-emetics is required, the Royal College of Obstetricians and Gynaecologists (RCOG) recommends the antihistamines cyclizine and promethazine, or the phenothiazines prochlorperazine or chlorpromazine as first-line options. A doxylamine/pyridoxine combination product (Xonvea®) was licensed for the treatment of NVP in the UK in 2018 and can also be offered as a first-line option. Metoclopramide, domperidone, and ondansetron can be considered as second-line treatments.

Hyperemesis gravidarum (HG) is thought to affect less than 1% of pregnant women and is defined as intractable vomiting resulting in 5% of pre-pregnancy weight loss, dehydration, and electrolyte disturbance. Ambulatory day care (where locally available) or hospital admission may be warranted for treatment with intravenous fluids, electrolytes, vitamins, and anti-coagulants, as well as anti-emetics. In severe cases of HG, where first- and second-line anti-emetic treatments have proved ineffective, treatment with corticosteroids may be considered and enteral or parenteral nutrition may be indicated.

NICOTINE POISONING IN PREGNANCY

Nicotine is an alkaloid obtained from the dried leaves of the tobacco plant, present in cigarettes, nicotine replacement therapy (gum, patches, inhalers, nasal sprays), traditional herbal remedies and insecticides.

Nicotine is highly toxic by ingestion, inhalation and skin contact.  The fatal dose of nicotine has been estimated to be as little as 40mg in an adult, however ingestion of just a few milligrams can cause severe symptoms. There are no reported cases that specifically describe nicotine poisoning during human pregnancy.

There is a wealth of data concerning fetal effects of tobacco exposure during pregnancy, however nicotine is one of many harmful components of cigarette smoke and the dose of nicotine delivered via smoking is lower than in a poisoning scenario.  Please consult the specific UKTIS documents on tobacco and nicotine replacement therapy in pregnancy for further details.

Following nicotine poisoning in a pregnant patient, maternal toxicity is likely to be a major determinant of fetal risk.  Given that chronic low-level nicotine exposure is associated with adverse fetal effects, it is possible that nicotine poisoning in the absence of severe maternal symptoms may also be associated with a teratogenic effect.  Given the paucity of data regarding exposure in this context, it is not possible to predict the likelihood of an adverse effect on fetal development.  In all cases of nicotine poisoning in pregnancy, extended maternal and fetal monitoring may be warranted.  Discussion with UKTIS is recommended in all cases.