Letter: S

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.

Statins (atorvastatin, fluvastatin, pravastatin, rosuvastatin and simvastatin) are a class of HMG-CoA reductase inhibitors used to lower cholesterol. They are 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.

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. A high proportion of pregnant women taking statins will have pre-existing diabetes, and/or obesity, both of which carry independent risks for fetal malformation and other adverse pregnancy outcomes.

Although the available data are limited for some pregnancy outcomes, they do not suggest that in utero statin exposure increases the risks of overall malformation, stillbirth, preterm delivery, fetal growth impairment or neonatal complications.

Evidence relating to the risk of cardiac malformation is conflicting and possibly confounded; however, a small increased risk cannot be excluded. An absolute risk of approximately 1.5 to 2%, relative to a background risk of approximately 1%, may be suggested by the available data.

Several studies have described small increased risks of miscarriage following maternal statin use in pregnancy; however, these data may be influenced by data confounding and methodological limitations.

Offspring neurodevelopment following gestational statin exposure has not been studied. As neurodevelopmental impairment is a key feature of several genetic cholesterol synthesis disorders, an effect cannot be ruled out and ongoing data collection is required.

Current guidelines on diseases for which statins are frequently prescribed recommend that statins are discontinued three months prior to attempting to conceive, or as soon as pregnancy is confirmed. Where statins are prescribed for conditions associated with high cholesterol, temporary suspension of therapy for the duration of pregnancy is thought unlikely to compromise maternal health. However, there may be some conditions, such as familial hypercholesterolaemia, where continued statin use in pregnancy may be considered. Discussion with UKTIS is recommended in all such cases.

Exposure to statins at any stage of pregnancy would not usually be regarded as medical grounds for termination of pregnancy. However, other risk factors for adverse pregnancy outcome are likely to be present in women exposed to statins, such as obesity and diabetes. Clinicians are reminded of the importance of consideration of such factors when performing case-specific risk assessments.

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.

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.

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.

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.

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.

Sodium cromoglicate is a mast cell stabiliser which inhibits the release of histamine after exposure to specific antigens. Sodium cromoglicate is typically used as 2% w/v eye drops for the treatment of allergic conjunctivitis, but is also available in oral form for the treatment of food allergy and aerosol for the treatment of asthma. It is poorly absorbed, thus any exposure of the fetus following use during pregnancy is expected to be low.

The available data do not suggest an increased risk of congenital malformation following in utero exposure to sodium cromoglicate. Other pregnancy outcomes have not been studied.

Exposure to sodium cromoglicate at any stage of 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.

Household bleach usually contains ≤6% sodium hypochlorite. Industrial strength bleach (>6% sodium hypochlorite) is used as a disinfectant and bleaching agent in the chemical, paper, textile, water treatment and dairy industries.

No published data on the possible adverse effects of household or industrial strength bleach on human reproductive function or in human pregnancy have been found. Environmental exposure to water chlorination by-products has been associated with preterm delivery and reduced fetal growth; however, data are inconclusive and their relevance to exposure to household bleach is uncertain.

As with all chemicals, unnecessary exposure should be avoided. Where exposure is unavoidable, precautions should be taken to ensure that the area is well-ventilated and that no symptoms suggestive of toxicity occur.

Use of household bleach as directed by the manufacturer at any stage in pregnancy is unlikely to pose a risk and 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.

Sodium thiosulfate is an inorganic reducing agent used in commercial/industrial processes and as an antidote for cyanide poisoning.

There are no human pregnancy exposure data regarding the fetal effects of sodium thiosulfate exposure. The available animal data, although limited, have not demonstrated teratogenic effects for sodium thiosulfate. Improved maternal and fetal outcomes have been demonstrated when sodium thiosulfate was administered in the treatment of cyanogenic compound exposure in pregnant ewes.

If sodium thiosulfate is required in the management of cyanide poisoning during pregnancy, treatment should not be withheld on account of pregnancy.

As with all chemicals, unnecessary exposure to sodium thiosulfate should be avoided. Where occupational exposure is unavoidable, precautions should be taken to ensure that exposure is well within the recommended exposure limits and not associated with toxic symptoms.

Exposure to sodium thiosulfate 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.

Where exposure to cyanide has occurred in pregnancy, enhanced antenatal monitoring may be warranted and discussion with UKTIS is recommended in all cases.