Letter: V

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 an increased risk of small for gestational age infants, preterm delivery, infantile rickets and maternal pre-eclampsia. 

Routine supplementation: Vitamin D supplements of 400IU (10µg)/day vitamin D (or equivalent) are currently recommended for all 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 maternal vitamin D supplementation during pregnancy and the risk of miscarriage. Vitamin D supplementation is not associated with an increased risk of preterm delivery, small for gestational age, low birth weight, intrauterine or neonatal death.

Treatment of deficiency: There are insufficient data to provide recommendations regarding high dose vitamin D for established vitamin D deficiency in pregnancy. RCOG Scientific Impact Paper recommends the treatment of vitamin D-deficient pregnant women with either colecalciferol 20,000IU/week or ergocalciferol 10,000IU twice a week for 4–6 weeks. No adverse outcomes were identified in a small case series of pregnant women with hypoparathyroidism treated with vitamin D2 doses up to 6.25mg (250,000IU) per day. Whilst reassuring, due to the small study population size, these data are considered too limited to exclude the possibility of risk.

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. Regular monitoring of plasma calcium concentration is advised for all pregnant patients receiving high doses of vitamin D.

Use of vitamin D or vitamin D analogues (present in dietary supplementation products) taken at the recommended dose do 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.

There are no data regarding neonatal complications following gestational exposure to vortioxetine. Due to the mechanism of action, neonatal complications may theoretically be similar to those observed following exposure to selective serotonin reuptake inhibitors (SSRIs), which include respiratory problems, low Apgar score 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).

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). Vortioxetine has a similar mechanism of action to the SSRIs and there are theoretical concerns that gestational vortioxetine exposure could also increase the risk of PPHN. Although there are no published data which identify an association between gestational exposure to vortioxetine and PPHN, the available data are insufficient to disprove this theory and an increased risk of PPHN cannot be excluded, although the absolute risk is likely to be low. As PPHN is potentially serious, this should be discussed with women considering vortioxetine use in pregnancy.

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, as vortioxetine has a similar mechanism of action to the SSRIs, there are theoretical concerns that gestational vortioxetine exposure could increase the risk of PPH. Careful assessment of the risk of PPH versus the risk of maternal relapse should the medication be discontinued is advised when considering continued use in late pregnancy. Prescribers are also encouraged to ensure maternal compliance with heparin self-administration in all 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 clinically appropriate, non-pharmaceutical management of depression and/or anxiety could be considered during pregnancy. However, 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 maternal relapse. In cases where treatment with vortioxetine is continued in pregnancy, the lowest effective dose should be used.

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.

Data from cohort studies on the use of venlafaxine in human pregnancy do not indicate an increased risk of congenital malformation overall. However, evidence regarding the risk of specific malformations is currently conflicting. A small number of retrospective case-control studies, which may be influenced by various methodological biases, have shown associations with specific anomalies such as hypospadias, gastroschisis, cleft palate, and limb and heart defects (both for any heart defect and specific heart defects). Single prospective cohort studies have described associations with non-severe cardiac malformation (approximate absolute risk of 1.5 to 1.8%, relative to a background risk of 0.9%), hypoplastic left heart syndrome (approximate absolute risk of 0.4%, relative to a background risk of 0.025%) and respiratory malformation (approximate absolute risk of 0.1%, relative to a background risk of 0.05%). Given the data for some of these associations are conflicting, and with other prospective cohort studies not replicating the findings, it is currently unclear if these anomalies are truly associated with venlafaxine use or whether the associations have been described due to methodological bias and/or data confounding. The benefits of venlafaxine use in pregnancy in preventing depression and its associated effects are likely to outweigh the small absolute risks of these specific defects.

An increased risk of miscarriage has been reported in a small number of studies. However, the data are inconsistent and likely confounded by indication and other factors, with better quality studies not identifying increased risks. A single study has suggested a possible association between venlafaxine use and preterm delivery. Current data do not suggest an increased risk of intrauterine death or small for gestational age (SGA) infants following gestational venlafaxine exposure; however, the data are insufficient for an increased risk to be excluded.

Neonatal complications observed in infants exposed to venlafaxine in utero are similar to those reported with selective serotonin reuptake inhibitors (SSRIs) and include respiratory problems, low Apgar score 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.

As in utero SSRI exposure is associated with an increase in the occurrence of persistent pulmonary hypertension of the newborn (PPHN), there are theoretical concerns that in utero venlafaxine exposure could also result in PPHN. Although there are no published data which identify an association, data are insufficient to disprove this theory. An increased risk of PPHN cannot be excluded, although the absolute risk is likely to be low.

Reports of lower than average IQ in children exposed to antidepressants in utero have been published; however, the effects of venlafaxine exposure on neurodevelopment have not been widely studied. Preliminary findings suggest that children exposed to antidepressants in utero, including venlafaxine, and children of untreated depressed women have lower IQs and exhibit more behavioural problems than children of non-exposed, non-depressed women.

Where maternal treatment with venlafaxine is clinically indicated, the benefits of treatment are likely to outweigh both the risks that have been described in the available evidence and the risks of leaving the patient untreated.

At present there is insufficient evidence to warrant additional fetal monitoring for congenital malformations. 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 considering the need for additional pregnancy monitoring. Discussion with UKTIS is recommended in all cases.

Vigabatrin is an anticonvulsant used predominantly in combination with other antiepileptic drugs (AEDs) in the treatment of resistant partial 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 has been reported in animal studies. An initial report by the manufacturer of high rates of congenital malformation among children exposed in utero is likely to be heavily biased by concomitant maternal medication use and retrospective reporting.

The very limited available data, derived from isolated case reports, small uncontrolled case series, cohort studies and a network meta-analysis do not currently provide reputable evidence which demonstrates that vigabatrin use in pregnancy increases the risk of congenital malformation, miscarriage, intrauterine fetal death, preterm delivery or intrauterine growth restriction. However, given the available data is highly limited, it is not possible to exclude the risk of such effects and further studies are therefore required.

Vigabatrin therapy in the non-pregnant patient 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 ruled out. 

Vigabatrin may impact upon maternal folate status. UK guidelines state that women who take any anti-epileptic medication should be prescribed high dose folic acid (5mg).

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 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.

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 RCOG states that there is no strong evidence to support routine supplementation of the B vitamins (with the exception of folic acid) during pregnancy.

Vitamin B12 is naturally occurring in many foods derived from animal sources. 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. In a woman with a healthy and 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 usually 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.