Letter: V

E-cigarettes, commonly referred to as vapes, deliver nicotine without involving the burning of tobacco. While there is growing evidence that nicotine-containing e-cigarettes can aid smoking cessation, concerns remain as to the potential health risks.

Use of e-cigarettes (vapes) during pregnancy is not recommended. Data on the safety and efficacy of e-cigarettes for smoking cessation in pregnancy are limited and conflicting, and fetal effects are largely unknown. Vaping during pregnancy has been associated with preterm delivery and low infant birth weight, although there is some evidence that vaping in pregnancy may pose a lower risk of impaired fetal growth when compared with cigarette smoking.  

Pregnant women are encouraged to avoid cigarette smoking due to the increased risk of adverse pregnancy outcomes, fetal harm and long-term health effects in their children. The NHS recommends the use of nicotine replacement therapy (NRT) products when required to achieve smoking cessation during pregnancy. Overall, the evidence does not compellingly indicate NRT increases the risks of adverse pregnancy outcomes, whereas smoking is consistently associated with fetal harm. Evidence for vaping is more limited than for use of traditional NRT; therefore, it is not recommended as a smoking cessation method during pregnancy.

E-cigarettes are not routinely recommended during pregnancy, as there are more fetal safety data for traditional forms of NRT (gums, sublingual tablets, inhalators, lozenges, oromucosal/nasal sprays and transdermal patches). However, some smoking cessation charities and the NHS pragmatically advise that, where traditional forms of NRT are declined or have been ineffective, use of e-cigarettes during pregnancy, although not without health risks, may be preferable to cigarette smoking.

Women who are pregnant or planning a pregnancy and who vape could potentially be offered traditional pharmacological NRT to aid cessation. For further details, please see the UKTIS monograph on NRT and the NHS advice on How to quit vaping.

Exposure to e-cigarettes at any stage in pregnancy would not usually be regarded as medical grounds for termination of pregnancy or any additional fetal monitoring. Women who have used e-cigarettes heavily during later pregnancy may be offered additional fetal growth monitoring. Other risk factors which independently increase the risk of adverse pregnancy outcome, or for which enhanced follow-up is required, may be present in individual women. Clinicians are reminded of the importance of considering such factors when performing case-specific risk assessments.

Vanzacaftor is a Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) modulator licensed for the treatment of cystic fibrosis.

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. Current NICE guidelines recommend NRT in combination with behavioural support for smoking cessation in pregnancy, and also state that varenicline should not be routinely offered to pregnant women.

Published human pregnancy exposure data for varenicline are provided from two uncontrolled and three prospective cohort studies, which together describe approximately 1,500 exposed pregnancies, around 1,100 of which were exposed in the first trimester. The available evidence does not indicate an increased risk of miscarriage, major congenital malformation, intrauterine death, impaired fetal growth, preterm delivery or neonatal complication. Some studies have suggested lower risks of adverse pregnancy outcomes, such as impaired fetal growth and preterm delivery, among varenicline-exposed pregnancies in comparison with continued smoking in pregnancy.

There are no randomised controlled trials of varenicline use as a smoking cessation treatment in pregnant women. However, a single observational study has provided limited evidence of efficacy, describing an improved smoking cessation rate in comparison with NRT patch users.

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. Current NICE guidelines recommend NRT in combination with behavioural support for smoking cessation in pregnancy, and also state that varenicline should not be routinely offered to pregnant women.

Published human pregnancy exposure data for varenicline are provided from two uncontrolled and three prospective cohort studies, which together describe approximately 1,500 exposed pregnancies, around 1,100 of which were exposed in the first trimester. The available evidence does not indicate an increased risk of miscarriage, major congenital malformation, intrauterine death, impaired fetal growth, preterm delivery or neonatal complication. Some studies have suggested lower risks of adverse pregnancy outcomes, such as impaired fetal growth and preterm delivery, among varenicline-exposed pregnancies in comparison with continued smoking in pregnancy.

There are no randomised controlled trials of varenicline use as a smoking cessation treatment in pregnant women. However, a single observational study has provided limited evidence of efficacy, describing an improved smoking cessation rate in comparison with NRT patch users.

Venlafaxine is a serotonin and noradrenaline reuptake inhibitor (SNRI) indicated for the treatment of depression, anxiety and panic disorders, as well as menopausal symptoms in women with breast cancer.

Data on the use of venlafaxine in human pregnancy do not indicate an increased risk of overall congenital malformation. Single studies have described increased risks of non-severe cardiac malformation (absolute risk 1.5 to 1.8%; background risk 0.9%), hypoplastic left heart syndrome (HLHS) (absolute risk 0.4%; background risk 0.025%), and respiratory malformation (absolute risk 0.1%; background risk 0.05%). There is also weak evidence of associations with a number of other unrelated malformation subtypes. The data for these associations arise from single studies or are conflicting, and it is possible that they were produced due to methodological bias and/or data confounding.

The best available evidence does not show an increased risk of miscarriage following venlafaxine use. A single study has suggested a possible association with preterm delivery. There is no indication of increased risks of intrauterine death or small for gestational age (SGA) infants following gestational venlafaxine exposure; however, data are limited and these findings require confirmation.

Neonatal complications following prenatal exposure to venlafaxine are similar to those reported with selective serotonin reuptake inhibitors (SSRIs) and include respiratory problems, low Apgar scores, and convulsions. Use of centrally acting drugs throughout pregnancy or around the time of delivery is associated with an increased risk of poor neonatal adaptation syndrome (PNAS). Monitoring of the neonate post-delivery is therefore advised.

Exposure to SSRIs beyond 20 weeks’ gestation has been linked to a small increased risk of persistent pulmonary hypertension of the newborn (PPHN). The estimated absolute risk is <0.4% (background 0.1–0.2%). Although there are no published data to support an association between PPHN and venlafaxine use, due to the similar mechanism of action between SSRIs and SNRIs, an increased risk of PPHN cannot be excluded. As PPHN can be severe, this theoretical increased risk should be discussed with women considering the use of venlafaxine in pregnancy.

The potential effects of venlafaxine exposure on neurodevelopment are not well studied. Preliminary findings have associated both prenatal exposure to antidepressants (including venlafaxine) and untreated maternal depression with reduced offspring IQ and increased risk of behavioural problems. The relative contribution of the medication exposure is therefore unclear.

The Medicines and Healthcare products Regulatory Agency (MHRA) advises a small increased risk of postpartum haemorrhage (PPH) with SSRI/SNRI use in the month before delivery. Some studies suggest up to a 1.6 fold increase, suggesting an absolute risk of ~3-8% (vs. accepted background risk 2-5%). Decisions about continuing treatment should balance this against the risk of maternal relapse. Pregnant women with risk factors for venous thromboembolism should continue appropriate heparin prophylaxis.

Mental health conditions should be managed appropriately in pregnancy. Venlafaxine may be suitable following individualised risk–benefit assessment. Non pharmacological options may be considered where clinically appropriate. For patients already stable on venlafaxine, the risks of stopping, switching, or reducing the dose should be weighed carefully against relapse risk. If continued, the lowest effective dose should be used.

Exposure to venlafaxine at any stage of pregnancy is not usually considered grounds for pregnancy termination or for additional fetal monitoring. However, other individual risk factors may independently increase the likelihood of adverse outcomes, and clinicians should ensure these are carefully considered during case specific risk assessments.

Vigabatrin is an anti-seizure medication (ASM) used predominantly in combination with other ASMs in the treatment of resistant partial epilepsy (focal onset seizures), with or without secondary generalisation, where all other potential drug combinations have proved ineffective, are contraindicated, or not tolerated.

There is very limited information on the use of vigabatrin in pregnancy. Fetal toxicity and congenital malformation have been reported in animal studies. An initial report by the manufacturer describing a high incidence of congenital malformation among children exposed in utero is likely to be heavily biased by concomitant maternal medication use and retrospective reporting.

The human data on vigabatrin use in pregnancy are derived from isolated case reports, small uncontrolled case series, small cohort studies, and a network meta-analysis. While there is no compelling evidence that vigabatrin use in pregnancy increases the risk of congenital malformation, miscarriage, intrauterine fetal death, preterm delivery, or intrauterine growth restriction, the limited nature of these data mean it is not possible to accurately determine the risk of such effects.

Vigabatrin therapy in the non-pregnant population has been associated with retinal and optic atrophy, peripheral field loss and electroretinogram abnormalities. It is unknown whether in utero exposure is also associated with visual disturbance in the offspring and until further data are available the possibility of an effect on fetal visual development cannot be accurately determined.

Vigabatrin may impact upon maternal folate status. UK guidelines state that women who take any ASM should be prescribed high-dose folic acid (5mg), although it is currently not known whether high-dose folic acid supplementation offers any additional benefit or protective effects over standard dose regimes when taking vigabatrin periconceptually or during pregnancy.

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.

More research is required to define the pregnancy safety profile of vigabatrin. Pregnant women and women of childbearing potential should be made aware of the lack of data for all pregnancy outcomes. Vigabatrin 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 with use of vigabatrin 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.

Exposure to vigabatrin 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 which could independently increase the risk of adverse pregnancy outcome may be present in individual cases. Such factors are important to consider when performing case-specific risk assessments.

Vitamin B12 refers to a group of cobalt-containing vitamers including, hydroxocobalamin and cyanocobalamin. Both of these forms of vitamin B12 have been used in the prophylaxis and treatment of anaemia due to vitamin B12 deficiency. Hydroxocobalamin is also used in much higher doses as an antidote for cyanide poisoning. No specific UK guidelines regarding vitamin B12 supplementation during pregnancy currently exist. The Royal College of Obstetricians and Gynaecologists (RCOG) does not recommend routine supplementation of B vitamins (with the exception of folic acid) during pregnancy.

Vitamin B12 is naturally occurring in many foods derived from animal sources. Women who follow a vegan diet may be at an increased risk of being vitamin B12 deficient and should ensure adequate intake of vitamins and minerals.

There are limited published data regarding the use of supplemental vitamin B12 (in any form) during pregnancy; however, there is no evidence or reason to expect that use would be associated with an increased risk of congenital malformation or other adverse fetal effects. High maternal vitamin B12 concentrations have been associated with autism spectrum disorder in the offspring; however, further studies are required. Maternal vitamin B12 deficiency has been associated with increased risks of adverse pregnancy outcome, such as miscarriage, neural tube defects, low birth weight, and adverse neurodevelopment. In a woman with a varied diet, the use of additional vitamin supplements in pregnancy would not usually be required; however, where a deficiency state exists, or where vitamin B12 is required in the management of maternal illness or poisoning, treatment should not be withheld.

The use of supplemental vitamin B12 at any stage in pregnancy would not be regarded as medical grounds for termination of pregnancy or any additional fetal monitoring. Where use of high-dose vitamin B12 has been administered as an antidote during pregnancy in maternal poisoning, enhanced antenatal surveillance may be warranted and should be decided on a case-by-case basis. Discussion with UKTIS is recommended in all such cases.

Vitamin D encompasses a large family of fat-soluble steroid preprohormones. Humans require vitamin D2 (ergocalciferol), present in some foods such as fungi, and vitamin D3 (colecalciferol), which is synthesised in the skin and present in oily fish/cod liver oil. In the UK, vitamin D deficiency is defined as calcifediol (25(OH)D) <25nmol/l. 

Vitamin D deficiency in pregnancy may be associated with increased risks of small for gestational age infants, preterm delivery, infantile rickets and pre-eclampsia. 

Routine supplementation: Vitamin D supplements of 400IU (10µg)/day vitamin D (or equivalent) are recommended for pregnant and breastfeeding women. There is no evidence from epidemiological studies that use of the above dose of vitamin D, or any of its analogues, is associated with an increased risk of congenital malformation, however data are limited. There are insufficient data to determine whether there are any associations between vitamin D supplementation during pregnancy and the risk of miscarriage. Vitamin D supplementation is not associated with increased risks of preterm delivery, small for gestational age, low birth weight, intrauterine or neonatal death.

Treatment of deficiency: There are limited data on fetal outcomes following use of high-dose vitamin D. There are no official UK guidelines regarding treatment of vitamin D deficiency in pregnancy. Given the well-established increased risks associated with vitamin D deficiency in pregnancy, UKTIS pragmatically suggests that prescribers aim to rapidly correct vitamin D deficiency in pregnancy, including use of loading doses of vitamin D where clinically appropriate. Factors such as severity of deficiency and patient compliance to treatment should be considered when selecting a loading dose regimen. Prescribers should be aware of the lack of data to inform the safety of large doses of vitamin D in pregnancy. 

Treatment with very high doses of vitamin D may induce hypercalcaemic vitamin D toxicity, although this is usually associated with serum calcifediol levels in excess of 350nmol/l and is not expected following treatment to correct vitamin D deficiency. Regular monitoring of plasma calcium concentration is advised for all pregnant women receiving high-dose vitamin D. 

Use of vitamin D or vitamin D analogues (present in dietary supplementation products) at the recommended dose does not require 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. Where exposure to larger doses has occurred, discussion with UKTIS is recommended.

Vortioxetine is a novel multimodal antidepressant of the bisarylsulfonyl amine class. Vortioxetine acts as a serotonin reuptake inhibitor as well as being active at a number of serotonergic receptors. In addition, vortioxetine administration has been reported to increase the efflux of norepinephrine, dopamine and acetylcholine. Vortioxetine is used in the treatment of major depressive episodes.

Data regarding gestational exposure to vortioxetine are limited, and although there is currently no good evidence of an association between gestational exposure to vortioxetine and miscarriage, congenital malformation, intrauterine death, low birth weight or preterm delivery, an increased risk cannot be excluded. There are no data regarding neurodevelopment following gestational vortioxetine exposure.

Use of centrally acting drugs around the time of delivery is associated with an increased risk of poor neonatal adaptation syndrome. Due to similar mechanisms of action, neonatal complications following exposure to vortioxetine are likely to resemble those observed with selective serotonin reuptake inhibitors (SSRIs), which include respiratory problems, low Apgar score and convulsions. Accordingly, a case report describes a neonate with respiratory problems and low Apgar scores following gestational vortioxetine exposure.

Gestational SSRI exposure is associated with a small increased risk (<0.4% vs. 0.1 to 0.2%) of persistent pulmonary hypertension of the newborn (PPHN). Due to similar mechanisms of action, there are theoretical concerns that vortioxetine could also increase the risk of PPHN. Although there are no published reports of PPHN following vortioxetine exposure, the available data are insufficient to rule out an increased risk, although the absolute risk is likely to be low.

The Medicines and Healthcare products Regulatory Agency (MHRA) has advised that there is a small overall increased risk of postpartum haemorrhage (PPH) attributable to SSRI/selective noradrenaline reuptake inhibitor (SNRI) use in the month prior to delivery, but this risk may be higher in women with other risk factors for abnormal bleeding. Although no studies have investigated an association between vortioxetine and PPH, its similar mechanism of action to the SSRIs raises theoretical concerns that gestational vortioxetine exposure could increase the risk of PPH. Prescribers are advised to assess the risk of destabilisation of the maternal condition, including in the postnatal period, if considering alterations to vortioxetine treatment in late pregnancy. Prescribers are also advised to encourage compliance with heparin self-administration in pregnant women with risk factors for venous thromboembolism.

It is important to ensure that mental health conditions are treated appropriately. As such, vortioxetine may be suitable for use in pregnancy following an individualised assessment of the risks and benefits. Where a patient is stabilised on vortioxetine, either prior to conception or during pregnancy, the risk of discontinuing treatment, changing the medication, or reducing the dose should be carefully weighed against the risk of relapse. In cases where treatment with vortioxetine is continued in pregnancy, the lowest effective dose should be used.