Letter: N

Nitrous oxide is a gas used medically as an anaesthetic. Street names include chargers, balloons, buzz bomb, hippy crack, laughing gas, smart whips, nangs, nitro, N2O, NOS, NOZ, whippet, and whippits.

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

The use of NSAIDs in pregnancy has been associated with an increased risk of miscarriage, malformation (including specific defects, such as cardiovascular defects, septal cardiac defects, and orofacial clefts), preterm delivery and fetal growth impairment. However, the available evidence is often conflicting, is confounded, and may have also been influenced by methodological limitations. Causal relationships between NSAID use in pregnancy and these outcomes are therefore considered unproven.

Data regarding the safety of maternal nabumetone use in human pregnancy is limited to a single population-based cohort study which investigated preterm delivery risks following early pregnancy nabumetone exposure. There are no data regarding other pregnancy outcomes, and it is therefore not possible to provide an evidence-based assessment of the fetal risks following gestational exposure.

Exposure to NSAIDs after 20 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 the risks of persistent pulmonary hypertension of the newborn (PPHN) following antenatal use of NSAIDs. Further evidence is required to assess whether this is a risk. Where published data regarding 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 after 20 weeks of pregnancy. In circumstances where the maternal clinical condition requires short-term treatment with nabumetone (such as acute, short-lived pain), treatment should be limited to the shortest duration possible. There is currently no evidence-based guidance about how long use should be restricted for but pragmatic advice is to limit use to no longer than three days. Longer term use, for example for treatment of chronic arthritis, or any use in the third trimester (28 weeks of gestation or beyond), should be avoided. As fetal urine production begins at approximately 10 weeks’ gestational age, UKTIS recommends referral to a Fetal Medicine Unit for monitoring of DA patency and oligohydramnios following prolonged NSAID exposure after the first trimester.

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.

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

There are no large, controlled studies assessing risks of specific pregnancy outcomes following gestational exposure to nadolol. While case reports and a small study do not raise concerns of adverse fetal effects, ongoing data collection is required for confirmation.

 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 intrauterine growth restriction (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

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

The use of NSAIDs in pregnancy has been associated with an increased risk of miscarriage, malformation (including specific defects, such as cardiovascular defects, septal cardiac defects, and orofacial clefts), preterm delivery and fetal growth impairment. However, the available evidence is often conflicting, is confounded, and may have also been influenced by methodological limitations. Causal relationships between NSAID use in pregnancy and these outcomes are therefore considered unproven.

Twelve studies which collectively report more than 11,000 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 20 weeks of gestation is associated with an increased risk of premature closure of the ductus arteriosus (DA) and oligohydramnios. These effects are mediated by the inhibitory effect of NSAIDs on prostaglandin production. There are conflicting findings regarding the risks of persistent pulmonary hypertension of the newborn (PPHN) following antenatal use of NSAIDs. Further evidence is therefore required before this possible association can be confirmed. Where published data regarding 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 after 20 weeks of pregnancy. In circumstances where the maternal clinical condition requires short-term treatment with naproxen (such as acute short-lived pain), treatment should be limited to the shortest duration possible. There is currently no evidence-based guidance about how long use should be restricted for but pragmatic advice is to limit use to no longer than three days. Longer term use, for example for treatment of chronic arthritis, or any use in the third trimester (28 weeks of gestation or beyond), should be avoided. As fetal urine production begins at approximately 10 weeks’ gestational age, UKTIS recommends referral to a Fetal Medicine Unit for monitoring of DA patency and oligohydramnios following prolonged NSAID exposure after the first trimester.

Where use of naproxen 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.

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.

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 2,200 natalizumab-exposed pregnancies, including approximately 1,250 first trimester exposures, do not indicate that natalizumab is a major structural teratogen. Current data do not raise concern that natalizumab exposure is associated with higher risks of miscarriage, impaired fetal growth, preterm birth or adverse neurodevelopmental outcomes but are insufficient to evaluate risk of stillbirth. Small case series and a cohort study have reported haematological abnormalities (anaemia and thrombocytopenia) among infants exposed to natalizumab in the late second trimester and/or the third trimester.  

Natalizumab does not cross the placenta during the first trimester but is actively transported during the second and third trimesters. 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 specialists consider giving the last dose during pregnancy at approximately 34 weeks and restarting soon after delivery (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 latent 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 (now the UK Health Security Agency) [issued 2017] specifies that live vaccines should not be used until the infant is 6 months old following in utero biologic immunosuppressant exposure.

Where natalizumab is continued 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.

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

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 exposure is associated with reduced fetal growth. There are no further studies assessing the risks of adverse pregnancy outcomes following gestational exposure to nebivolol.

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

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 during the third trimester of pregnancy is not recommended due to a theoretical risk of haemolytic anaemia in the neonate owing to immature erythrocyte enzyme systems. However, this risk should be carefully weighed against the potential benefit of treatment, particularly if culture and sensitivity results support the use of nitrofurantoin and alternative antibiotics are unsuitable.

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.

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

Although use of NSAIDs in pregnancy has been associated with an increased risk of miscarriage, malformation (including specific defects, such as cardiovascular defects, septal cardiac defects and orofacial clefts), preterm delivery and fetal growth impairment, the available evidence is often conflicting, is considered likely confounded, and may have also been influenced by methodological limitations. Causal relationships between NSAID use in pregnancy and these outcomes are therefore considered unproven.

The available data on NSAID use in pregnancy do not suggest an association with stillbirth or attention problems in the child.

Exposure to NSAIDs after 20 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 and fetal renal toxicity. There are conflicting findings regarding an increased risk of persistent pulmonary hypertension of the newborn (PPHN) following antenatal use of NSAIDs. Further evidence is therefore 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 after 20 weeks of pregnancy. In circumstances where the maternal clinical condition requires short-term treatment (such as acute short-lived pain: post-operative, dental, skeletal injury), this should be limited to the shortest duration possible whilst using the lowest effective dose. There is currently no evidence-based guidance about how long use should be restricted for, but pragmatic advice is to limit use to no longer than three days. Longer-term use, for example for treatment of chronic arthritis, or any use in the third trimester (28 weeks of gestation or beyond), should be avoided. As fetal urine production begins at approximately 10 weeks’ gestational age, referral to a Fetal Medicine Unit for monitoring of DA patency and oligohydramnios is recommended following prolonged NSAID use after the first trimester.

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.