USE OF SOTALOL IN PREGNANCY

Sotalol is a non-selective beta blocker with antiarrhythmic effects and is licensed in the UK for the treatment and prophylaxis of cardiac arrhythmias, including ventricular and supraventricular tachyarrhythmias. It is not used in the treatment of hypertension. Sotalol is sometimes used off-licence in the transplacental treatment of fetal tachyarrhythmias.

There are no studies of rates of specific pregnancy outcomes following gestational exposure to sotalol. While a handful of case reports do not raise concern of adverse effects following exposure mainly in the third trimester, there are no data on the absolute risks of congenital malformation, miscarriage, stillbirth, intrauterine growth restriction (IUGR), preterm delivery and adverse neurodevelopmental effects following in utero exposure.

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, 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 sotalol 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.

USE OF STATINS IN PREGNANCY

Statins (atorvastatin, fluvastatin, pravastatin, rosuvastatin and simvastatin) are a class of HMG-CoA reductase inhibitors used to lower cholesterol. They act by inhibiting the conversion of HMG-CoA to mevalonate which is a rate-limiting step in the production of cholesterol in the liver. Statins may be indicated, as an adjunct to diet, for the treatment of primary hypercholesterolaemia or mixed dyslipidaemia when non-pharmacological treatments (e.g. diet, exercise, weight reduction) are inadequate, or for reduction of cardiovascular morbidity and mortality in manifest atherosclerotic cardiovascular disease or diabetes mellitus.

Cholesterol is required for normal development of the placenta and fetus, therefore theoretical concerns of teratogenic effects exist for any drug that inhibits endogenous cholesterol production. Retrospectively collected data from post-marketing surveillance and case reports have described malformations following statin use, however a meta-analysis and prospective cohort studies have not shown any increase in overall congenital malformation rates following first trimester exposure. Data on risk of specific malformations are, however, very limited, and as the physical features associated with inherited defects in cholesterol synthesis may be subtle, it is not possible to exclude adverse effects of statins on fetal development. Cholesterol synthesis disorders of genetic origin are also often associated with developmental, behavioural and cognitive impairment; neurodevelopmental outcomes in statin-exposed cohorts remain uninvestigated.

As yet there is no conclusive evidence of an increased risk of congenital malformation or low birth weight following statin exposure, however the available data are limited and confounded, and not all outcomes have been systematically studied. Higher rates of preterm delivery have been demonstrated in women being treated with statins but no causal association has been established. Data relating to risk of spontaneous abortion are conflicting. Current guidelines on diseases for which statins are frequently prescribed recommend that women wishing to become pregnant stop use of statins three months prior to attempting to conceive, or as soon as pregnancy is confirmed, due to the theoretical risk of fetal abnormality. Where statins are prescribed for conditions associated with high cholesterol, temporary suspension of therapy for the duration of pregnancy is not thought to compromise maternal health. Early research into the use of statins after the first trimester in the prevention of pre-eclampsia is, however, ongoing, with pilot data suggesting benefit with treatment.

Exposure to statins at any stage of pregnancy would not usually be regarded as medical grounds for termination of pregnancy. However, women exposed to statins are more likely to have other risk factors such as obesity and pre-pregnancy diabetes which confer additional independent risks to the fetus and pregnancy. Clinicians are reminded of the importance of consideration of such factors when performing case-specific risk assessments.

USE OF SULFASALAZINE IN PREGNANCY

Sulfasalazine (sulphasalazine) is a sulphonamide aminosalicylic acid compound which is licensed for the induction and maintenance of remission of ulcerative colitis, and for treating active Crohn’s disease and rheumatoid arthritis.

Most of the data relating to sulfasalazine exposure during pregnancy derive from studies of women undergoing treatment for inflammatory bowel disease. Active (uncontrolled) inflammatory bowel disease has been associated with increased risks of certain adverse pregnancy outcomes, including congenital malformations, preterm delivery, and small for gestational age infants. Control of the maternal condition throughout pregnancy may therefore prove beneficial to both mother and fetus.

The available human data relating to sulfasalazine use in pregnancy do not suggest that maternal use during pregnancy is associated with an increased overall risk of congenital malformation or of a number of specific malformations. Risk of miscarriage is currently undetermined, although a single study of 5-acetylsalicylic acid medications as a class did not identify a significant increased risk. No robust evidence of increased risks of stillbirth, low birth weight, or preterm delivery has been provided from a small number of studies, though additional data are required before suitably evidence-based conclusions can be drawn. No studies have investigated the risk of neurodevelopmental impairment or cancer among infants exposed to sulfasalazine in utero.

There are theoretical concerns regarding an increased risk of neonatal hyperbilirubinaemia following in utero sulfasalazine exposure, although there is no good evidence confirming this association. Sulfasalazine has been shown to actively inhibit the absorption and metabolism of folic acid, which may result in folic acid deficiency. Pregnant women undergoing treatment with sulfasalazine may therefore require supplementary folic acid. At present there are no published guidelines regarding the dose or duration of folate supplementation for pregnant women using sulfasalazine. In general, high dose folic acid (5mg) is recommended periconceptually for all women considered to be at increased risk of folate deficiency (e.g. those with a family history of neural tube defects, concurrent treatment with drugs which interfere with folate metabolism, or maternal obesity). However, no studies have investigated whether there is increased benefit of this higher dose.

Exposure to sulfasalazine 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 SULPIRIDE IN PREGNANCY

Sulpiride is an atypical antipsychotic (AAP) used in the treatment of schizophrenic disorders.

There are no studies which specifically investigate the use of sulpiride during pregnancy. Although sulpiride exposures are included in a small number of studies which report on the fetal outcomes of women exposed to antipsychotics (APs) as a group, sulpiride exposures represented only a very small proportion of the total study cohort and the outcomes have not been analysed separately. There has been one small controlled prospective study which specifically examined the outcomes of 162 pregnancies following gestational exposure to the s-enantiomer of sulpiride, levosulpiride. This study found no significantly increased risk of miscarriage, major malformation, stillbirth or specific neonatal complications in exposed pregnancies compared to age-matched non-exposed controls. However, this study is statistically underpowered and mainly reports outcomes following short inadvertent exposures early in the first trimester. While data do not currently raise concern of increased risks of adverse pregnancy outcomes, they are currently too limited to exclude such associations.

Studies of APs/AAPs as therapeutic classes that include a collective total of >13,600 exposures do not raise concerns of adverse pregnancy outcomes directly related to use. Although findings relating to stillbirth and preterm delivery rates are conflicting, the studies reporting possible associations for these outcomes may be confounded by concomitant risk factors related to the underlying condition. Further research is therefore required. Neurodevelopmental outcomes following in utero exposure to APs have not been sufficiently studied to permit any further assessment of risk.

In the non-pregnant population, use of AAPs (particularly olanzapine and clozapine) is a risk factor for impaired glucose homeostasis and type 2 diabetes. Theoretical concerns regarding an increased risk of maternal gestational diabetes mellitus (GDM) and its sequelae therefore exist following gestational antipsychotic use. There are no data that investigate risk of GDM with use of sulpiride specifically.

Use of APs throughout pregnancy or near delivery has been associated with withdrawal symptoms in the neonate 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. For all pregnancies with exposure to CNS-acting medication, delivery should be planned in a unit with adequate neonatal facilities.

It is important to ensure that maternal mental health is treated appropriately. Where a woman’s illness is stabilised on sulpiride, either prior to conception or during pregnancy, the risk of discontinuing or changing medication, or reducing the dose, should be carefully weighed against the risk of relapse of the maternal condition. Where clinically appropriate, clinicians are encouraged to discuss the advantages and disadvantages of continued sulpiride use during pregnancy with the patient. Where the benefit of continued treatment is considered to outweigh any potential or known risks, sulpiride use in pregnancy may be the best option for both mother and baby.

Exposure to sulpiride 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. Owing to the lack of data regarding malformation risks, women who have been exposed to sulpiride in the first trimester are particularly encouraged to attend their routine detailed fetal anomaly scan, which is generally conducted at around 18 to 20 weeks of pregnancy.

USE OF SUNBEDS AND TANNING BOOTHS IN PREGNANCY

Tanning beds and booths emit ultraviolet (UV) radiation within the UVA and UVB spectrum. Use of tanning equipment is primarily for cosmetic reasons. Although EU regulations limit the maximum effective irradiance of commercial tanning equipment to 0.3 W/m2, a wide variation in strength is likely.

There are no controlled studies that assess the risk of adverse pregnancy outcomes following sun bed/tanning booth exposure in pregnancy and women wishing to partake in such exposures should be aware of the lack of evidence. There are theoretical concerns that a rise in core body temperature during use of sunbeds/tanning booths could increase the risk of neural tube defects in the offspring and that UV exposure could cause folate deficiency, leading to an increased risk of neural tube defects. Additionally, there is a clear increased risk of skin cancer in users of sun beds/tanning booths, and on this basis, exposure should be avoided.

Narrowband UVB phototherapy is occasionally used in a clinical setting to treat certain skin conditions such as psoriasis and atopic dermatitis. Therapeutic use in this context is not thought to pose a risk to the fetus, and the European Task Force on Atopic Dermatitis recommend, where feasible, that narrowband UVB and UVA1 can be used liberally in pregnant women. However, the use of psoralens is not recommended due to the theoretical risk of mutagenesis.

Exposure to sun beds, tanning booths, or UV phototherapy 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 independently increase the risk of adverse pregnancy outcome, may be present in individual cases. Clinicians are reminded of the importance of consideration of such factors when performing case specific-risk assessments.

USE OF SEASONAL INFLUENZA VACCINES IN PREGNANCY

Seasonal influenza vaccines are inactivated trivalent or quadrivalent vaccines produced in anticipation of the expected circulating strains of seasonal influenza virus for the coming influenza season.

Data on seasonal and pandemic influenza infection suggest that pregnant women, especially those with pre-existing medical conditions and in the later stages of pregnancy, are at increased risk of influenza complications and are more likely to experience adverse fetal outcomes such as miscarriage or stillbirth. Data regarding the risk of congenital malformation following maternal influenza infection during pregnancy are conflicting. Some studies have reported an association, but a causal link to maternal fever rather than a direct effect of the influenza virus on the fetus has been proposed.

Because the seasonal influenza vaccine antigen formulation changes each year, the currently available data on exposure in pregnancy relate to various formulations of influenza vaccines. Overall, there is no indication that exposure to inactivated influenza vaccines in pregnancy is associated with an increased risk of adverse fetal effects. Additionally, there is evidence that seasonal influenza vaccination during pregnancy confers immunity to influenza in the neonate.

Public Health England recommends that all pregnant women, regardless of stage of pregnancy, should receive the seasonal influenza vaccine given the increased risk of morbidity and mortality associated with influenza infection during pregnancy. 

Although there are no known adverse fetal effects of maternal influenza vaccination in pregnancy, 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 SELECTIVE SEROTONIN REUPTAKE INHIBITORS IN PREGNANCY

Six selective serotonin reuptake inhibitors (SSRIs) are licensed for the treatment of various forms of anxiety and depression in the UK. 

This document summarises findings from studies which have investigated the fetal effects of prenatal exposure to SSRIs as a class and should therefore be used in conjunction with the relevant individual SSRI monograph (where available), as human pregnancy data varies both in quantity and quality for each specific SSRI, with certain pregnancy outcomes unstudied for some. There is no robust evidence to suggest that fetal or neonatal effects differ substantially for individual SSRIs, and changing from one SSRI to another in pregnancy on the basis of teratogenic concern is therefore not currently recommended.

Data regarding malformation risk for SSRIs as a class are conflicting and confounded. Some studies have suggested a small ~1.2-fold increase in absolute risk of cardiovascular malformation following exposure in utero; however, other studies have found no increased risk. Recent evidence has suggested that the increased cardiac malformation rates observed in some studies may be explained by factors common to women with health conditions for which SSRIs are prescribed, rather than SSRI exposure. Associations with various other specific congenital malformations have also been reported by some studies which analysed SSRIs as a class, but these findings have not been widely replicated. A causal association between use of SSRIs in pregnancy and any type of malformation in the offspring therefore remains unconfirmed.

Maternal SSRI use in pregnancy has been associated with an increased risk of miscarriage, low birth weight and preterm delivery in some, but not all studies. However, the available data are conflicting and, in some instances, limited by the study methods. The impact that maternal SSRI use in pregnancy has on the incidence of these outcomes therefore remains unclear. Furthermore, increased risks for all these outcomes have been associated with maternal depression; therefore, in many studies, confounding by indication cannot be excluded. The available data do not suggest that SSRI use in pregnancy increases the risk of stillbirth.

Data on neurodevelopmental impairment following maternal SSRI use in pregnancy are conflicting. Some studies have suggested possible adverse effects on early infant motor development and behaviour. However, study sample sizes are often small, and many assessments were undertaken in children under one year of age. A number of studies have suggested an association with autism spectrum disorder (ASD), but as some of these studies have also suggested, associations may exist between ASD and the underlying maternal condition; therefore, findings may be confounded. Offspring neurodevelopment following maternal use of SSRIs in pregnancy requires further investigation before additional conclusions can be provided.

In utero exposure to SSRIs in the weeks prior to delivery confers a risk of transient neonatal withdrawal syndrome and infants should be delivered in hospital and monitored for central nervous system, motor, respiratory and gastrointestinal symptoms.

An increased risk of persistent pulmonary hypertension of the newborn (PPHN) has been reported following exposure to SSRIs as a class beyond 20 weeks of gestation. The current estimate of the absolute risk of PPHN following SSRI exposure is <0.4% (background rate 0.1 to 0.2%), suggesting that it remains uncommon following exposure. However, as PPHN is potentially serious, this should be discussed with women considering SSRI 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/SNRI use in the month prior to delivery, but this risk may be higher in women with other risk factors for abnormal bleeding. Studies have identified up to a 1.3-fold increased risk following gestational use of an SSRI; should this prove accurate, the absolute risk of PPH among SSRI-exposed women would range from 13 to 20% (background 10 to 15%). Careful assessment of the risk of PPH versus the risk of maternal relapse, should the medication be discontinued, is advised when considering continued SSRI/SNRI antidepressant 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, SSRIs 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 an SSRI, 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 an SSRI is continued in pregnancy, the lowest effective dose should be used.

USE OF SERTRALINE IN PREGNANCY

Sertraline is a selective serotonin reuptake inhibitor (SSRI) used in the treatment of depression, obsessive-compulsive disorder, post-traumatic stress disorder, social anxiety disorder and panic disorder with or without agoraphobia.

The available data regarding gestational use of sertraline are conflicting, with the majority of studies demonstrating no statistically significant increase in the overall risk of any malformation or of cardiovascular malformations following first trimester exposure. It is therefore unclear whether the available findings concerning maternal sertraline use in pregnancy represent a risk with the individual drug, a class effect of SSRIs, or are produced due to confounding from other factors related to the maternal illness. Those studies which have indicated increased risks have generally suggested that the absolute risks remain low (~1.4 times the background risk).

Studies which have investigated the risk of miscarriage, intrauterine death, preterm delivery, low birth weight and neurodevelopmental delay following sertraline use in pregnancy are reassuring overall but are generally too limited to fully rule out increased risks.

In utero exposure to SSRIs in the weeks prior to delivery confers a risk of transient neonatal withdrawal syndrome and infants should be delivered in hospital and monitored for associated central nervous system, motor, respiratory and gastrointestinal symptoms.

An increased risk of persistent pulmonary hypertension of the newborn (PPHN) has been reported following exposure to SSRIs as a class beyond 20 weeks of gestation. The current estimate of the absolute risk of PPHN following SSRI exposure is <0.4% (background rate 0.1 to 0.2%), suggesting that it remains uncommon following exposure. However, as PPHN is potentially serious, this should be discussed with women considering SSRI use in pregnancy.

The Medicines and Healthcare products Regulatory Agency (MHRA) has advised that there is, overall, a small overall increased risk of postpartum haemorrhage (PPH) attributable to SSRI/SNRI use in the month prior to delivery, but this risk may be higher in women with other risk factors for abnormal bleeding. Studies have identified up to a 1.3-fold increased risk following gestational use of an SSRI; should this prove accurate, the absolute risk of PPH among SSRI-exposed women would range from 13 to 20% (background 10 to 15%). Careful assessment of the risk of PPH versus the risk of maternal relapse, should the medication be discontinued is advised when considering continued SSRI/SNRI antidepressant 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, sertraline 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 sertraline, 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 sertraline is continued in pregnancy, the lowest effective dose should be used.

Exposure to sertraline at any stage in pregnancy would not usually be regarded as medical grounds for termination of pregnancy, or any additional fetal monitoring. 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 SILDENAFIL IN PREGNANCY

Sildenafil is a phosphodiesterase type-5 inhibitor with vasodilatory effects that is most commonly used to treat male erectile dysfunction (commonly sold under the brand name Viagra®). It is also licensed in the UK (brand name Revatio®) to treat pulmonary arterial hypertension. Several clinical trials have explored the use of sildenafil as a maternally-administered in utero treatment to improve fetal outcomes following detection of severe fetal growth restriction.

In 2018 an ongoing multicentre randomised controlled trial (RCT) was halted following the detection of a potential safety signal. One of three study sites reported that persistent pulmonary hypertension of the newborn (PPHN) appeared to be more prevalent in infants exposed in utero to sildenafil (n=93) compared to placebo-exposed infants. Two further study sites for this trial (numbers of participants as yet unreported) detected no increased risk of PPHN and overall this trial has not identified a clear beneficial effect of sildenafil on fetal outcome. A further four small RCTs/cohort studies that include a total of 159 sildenafil-exposed pregnancies raise no cause for concern regarding neonatal death rates compared to those in control groups, although for one of these studies exposure times were short. Case reports/series describe fetal outcomes for a further 18 sildenafil-exposed pregnancies, with no neonatal deaths reported. Further assessment of these data, in particular cases for which adverse outcomes have been reported and the potential role of confounding factors, is required.

Data relating to other pregnancy outcomes following in utero sildenafil exposure are too limited to facilitate an evidence-based assessment of risk or benefit. Case reports document seven confirmed first trimester exposures, with no infant malformations recorded. A small number of studies have found no statistically significant increased risks of stillbirth, preterm delivery or infants being born small for gestational age. There are no data relating to other neonatal or childhood outcomes following gestational sildenafil exposure.

In view of the potential safety signal described above, it has been recommended that ‘sildenafil should not be prescribed for fetal growth restriction outside the setting of high-quality randomized clinical trials’. UKTIS also recommends that general use of sildenafil in pregnancy should be avoided where possible. Where gestational use of sildenafil to treat maternal pulmonary arterial hypertension is being considered, the benefits of treatment should be weighed against the potential risks to fetus/neonate, and to both mother and fetus of discontinuing treatment. Discussion with the patient of the available data relating to use in pregnancy should occur.

Exposure to sildenafil at any stage of pregnancy would not usually be regarded as medical grounds for termination of pregnancy. Additional fetal monitoring may be indicated due to the largely unknown effects of the exposure. The ability of the unit at which a patient is booked for delivery to identify and manage neonates with PPHN should be considered in advance. 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 SIROLIMUS IN PREGNANCY

Sirolimus is a macrolide immunosuppressant licensed for the prophylaxis of organ rejection in adult renal transplant patients at low-to-moderate immunological risk and the treatment of sporadic lymphangioleiomyomatosis with moderate lung disease or declining lung function.

Preclinical animal studies have identified possible associations between maternal gestational exposure and embryo/fetal lethality, delayed skeletal ossification, decreased fetal weight gain and neurodevelopmental impairment. The available data relating to sirolimus exposure in human pregnancy are, however, highly limited, consisting solely of uncontrolled case reports/series which report outcomes of 30 unique first trimester-exposed pregnancies, a small number of which were also exposed into late pregnancy.

Although adverse outcomes have been reported following human pregnancy exposure, including miscarriage, malformation (with no pattern of defects), low birth weight and preterm delivery, there is currently no signal that sirolimus is a major teratogen. However, the lack of adequately controlled studies prevents an accurate assessment of the risk posed to the developing fetus. Any decision to discontinue sirolimus treatment or switch to an alternative medication must take into consideration the possible risk of subsequent maternal ill health for both mother and fetus.

Exposure to sirolimus at any stage in 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. As the available data are highly limited, additional/more detailed ultrasound scans to check the morphological development of the fetus may be indicated following first trimester sirolimus exposure.