Letter: F

Fingolimod is a sphingosine 1-phosphate (S1P) receptor modulator approved as a single disease-modifying therapy (DMT) for highly active relapsing remitting multiple sclerosis (MS) in patients who meet specific clinical criteria.

Preclinical animal studies using fingolimod dosages of less than or equivalent to the human therapeutic dose have demonstrated increased rates of cardiac defects in the offspring and embryo/fetal death following administration to pregnant rats.

Human pregnancy exposure data are available for more than 1,350 fingolimod-exposed pregnancies. However, the evidence base remains limited as it predominantly consists of uncontrolled studies where fingolimod was discontinued in early pregnancy in the majority of cases.

Higher than expected rates of malformation have been described in some uncontrolled studies, and the manufacturer states that first trimester fingolimod exposure may be associated with a two-fold increased risk of malformation. However, supportive evidence of this effect is considered weak. Furthermore, available data from methodologically robust controlled studies are highly limited; therefore it is not currently possible to exclude an increased risk of malformation following first trimester fingolimod exposure.

The available evidence, although limited, does not currently identify increased risks of miscarriage, intrauterine fetal death, or preterm delivery following fingolimod exposure in early pregnancy. However, there is no evidence regarding the risk of preterm delivery or intrauterine fetal death following exposure in the later stages of pregnancy. A small number of case reports describe small for gestational age and infant neurodevelopmental impairment following maternal fingolimod use in early pregnancy. However, the lack of a control group prevents a meaningful assessment of the risk of these outcomes.

Owing to the possible increased risk of malformation, the manufacturers of fingolimod recommend that women should avoid pregnancy for two months after discontinuing therapy and that fingolimod should be discontinued in all patients who become pregnant. However, several studies have described MS relapse during pregnancy among women who discontinued fingolimod, either prior to conception or in early pregnancy. Close monitoring of the maternal condition is recommended where fingolimod is discontinued.

Detailed anomaly scans are recommended following first trimester fingolimod exposure. The anomalies which have been most commonly described in the literature include cardiac, renal and musculoskeletal anomalies. Exposure to fingolimod 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.

Flecainide is a class Ic antiarrhythmic licensed for the treatment of AV nodal reciprocating tachycardia, arrhythmias associated with accessory conducting pathways, paroxysmal ventricular arrhythmia where the symptoms are severe and life-threatening, and paroxysmal atrial arrhythmias. It is also used occasionally as an off-license treatment for intrauterine fetal arrhythmia.

The available human pregnancy data primarily consist of a small retrospective cohort study, case reports and small case series documenting maternal flecainide administration to treat fetal tachyarrhythmias. One meta-analysis has been published; however the aim was to evaluate the efficacy of transplacental treatment of fetal tachyarrhythmia, therefore limited pregnancy outcome information was reported. Furthermore, pregnancy outcomes in these reports are influenced by the underlying fetal arrhythmia for which flecainide was administered.

The number of confirmed first trimester-exposed infants identified in the literature is limited to three cases. Therefore, it is not possible to provide an accurate assessment of the risk of congenital malformation following flecainide exposure. Case series/case reports describing preterm delivery, low birth weight, intrauterine/neonatal death and neurodevelopmental delay have been published. However, these are likely to be confounded by fetal arrhythmia, for which flecainide was prescribed to treat. Given the lack of controlled prospective studies, limited conclusions regarding the fetal effects of flecainide exposure can be provided.

Maternal arrhythmia in pregnancy may impact on haemodynamic stability and placental perfusion, with potential risks to the developing fetus. Similarly, fetal arrhythmia poses a serious risk of adverse pregnancy outcome. Where flecainide is needed to treat either a maternal or fetal arrhythmia, it should not be withheld for drug safety concerns. Given the arrhythmogenic side effects of flecainide, additional fetal and maternal monitoring is required. Treatment should be overseen by a clinician with experience in treating fetal or maternal arrhythmia.

Fluconazole is a triazole antifungal commonly used in the treatment of candidiasis. Standard fluconazole therapy generally comprises a single 150mg oral dose. Fluconazole is not recommended for use during pregnancy. However, vaginal candidiasis is common in pregnancy, and as fluconazole is sometimes prescribed to treat candidiasis that has not responded to topical/intravaginal clotrimazole treatment, exposure during pregnancy is not uncommon.

Data on the outcomes of over 43,000 fluconazole-exposed pregnancies, the majority of which were exposed to a single 150mg oral dose, do not reliably indicate increased risks of malformation overall, cardiac malformation overall, or orofacial clefts. Some studies have identified increased risks of specific cardiac defects, including tetralogy of Fallot, hypoplastic left heart, and transposition of the great arteries. However, these findings still require confirmation in additional datasets. Should these anomalies be related to low dose fluconazole exposure in the first trimester, the absolute risk to the fetus is still likely to be very small (<0.5%).

An increased risk of miscarriage among women exposed to standard dose oral fluconazole in early pregnancy has also been observed. Considering the best quality evidence currently available, the absolute risk of miscarriage following standard dose fluconazole exposure in early pregnancy could be estimated at 15 to 30% in comparison with an expected background rate of 10 to 20%.

Other adverse pregnancy outcomes, including intrauterine death/stillbirth, premature delivery, low birth weight and neonatal death, have not been linked to standard dose fluconazole therapy. 

No studies have evaluated whether neurodevelopmental outcomes are altered in infants exposed to fluconazole in utero.

Prolonged high dose fluconazole therapy (400-800 mg/day) during the first trimester has been linked to a distinctive pattern of birth defects. Because this type of exposure is rare and controlled or denominator-based data are lacking, the magnitude of risk following high dose exposure remains to be determined. There is no information regarding risks of other adverse pregnancy outcomes after prolonged exposure to high dose fluconazole. 

Exposure to standard dose fluconazole 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 high dose fluconazole therapy is necessary, or has inadvertently occurred during the first trimester, patients should be counselled about the possibility of birth defects, and where pregnancy is ongoing, offered a detailed anomaly scan. Features which have been observed among malformed fetuses/infants exposed to high dose fluconazole have also been described in Antley-Bixler syndrome. As such, genetic investigation is recommended for all suspected cases of high dose fluconazole embryopathy to exclude the possibility of a genetic condition, as there may be a risk of recurrence in any future pregnancy.

Fluoxetine is a selective serotonin reuptake inhibitor (SSRI) used in the treatment of depression, obsessive-compulsive disorder and bulimia nervosa.

The available data regarding gestational use of fluoxetine are conflicting, with the majority of studies not demonstrating statistically significant increased risks of major malformation or of cardiac malformation specifically. It is therefore unclear whether the available findings concerning maternal fluoxetine 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 (up to 1.18 times the background risk for malformations overall and up to 1.6-fold for cardiac malformations).

Studies which have investigated the risk of miscarriage, intrauterine death, preterm delivery, low birth weight and neurodevelopmental delay following fluoxetine 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 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 maternal mental health conditions are treated appropriately. As such, fluoxetine 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 fluoxetine, 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 fluoxetine is continued in pregnancy, the lowest effective dose should be used.

Exposure to fluoxetine 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.

Folic acid (pteroylglutamic acid/PGA) is a synthetic derivative of the water-soluble form of vitamin B9 (also known as folate).  It requires metabolism to dihydrofolic acid and then to its biologically active form tetrahydrofolate.  Folate is necessary for the production of blood cells and DNA.  Folic acid is used in the treatment of nutritional megaloblastic anaemias and prophylactically in individuals at risk of deficiency e.g. due to chronic haemolysis or renal dialysis. 

During pregnancy folate requirements are increased 5- to 10-fold and pregnant women are therefore at risk of folate deficiency.  Maternal folate deficiency is an established risk factor for neural tube defects.

There is good evidence that supplementation with folic acid (when used prior to conception and before closure of the neural tube at doses ≥360mcg) reduces the risk of primary and recurrent NTDs.  Some studies have also suggested a reduced risk of spontaneous abortion and congenital heart defects with folic acid supplementation peri-conceptually, however there is no conclusive evidence of a protective effect, or whether any possible benefit may be restricted to women at increased risks of these outcomes.  There is conflicting evidence regarding whether gestational folic acid supplementation reduces the risk of preterm delivery and low infant birth weight.  Studies have suggested that neurodevelopmental outcomes may be improved in children exposed in utero to folic acid, however data confounding cannot be ruled out.

Peri-conceptual folic acid supplementation is universally advised.  In certain countries basic food products such as flour and/or bread are routinely fortified with folic acid.  This is not the case in the UK, and current UK guidelines recommend 400mcg/day of folic acid pre-conceptually and until at least 12 weeks of gestation.  In women considered to be at increased risk of folate deficiency, e.g. those with a family history of neural tube defect, concurrent treatment with drugs which interfere with folate metabolism or maternal obesity, higher dose folic acid (5mg) is recommended peri-conceptually.  However, it is unclear whether there is increased benefit of a higher dose.  As maternal requirements for folate peak at around five months gestation, folic acid supplementation throughout pregnancy is often advised, however there is no definitive evidence of benefit of supplementation beyond the point of fetal neural tube closure.

Fentanyl is a synthetic opioid analgesic approximately 100 times more potent than morphine. Fentanyl can be administered orally, intravenously, intranasally, topically (in the form of transdermal patches), epidurally or intrathecally.

Data regarding the use of fentanyl during pregnancy consist of a small number of published case reports, and pregnancy exposures (n=30) reported to UKTIS by healthcare professionals. Within these data, no congenital malformations were observed among the first trimester exposed cases (n=20). Three retrospective reports to UKTIS describe congenital malformations, however first trimester use was only confirmed in one case, concomitant medications were used, and no pattern of malformations was identified. The available data do not currently raise concerns about other adverse pregnancy outcomes or altered neurodevelopment in the child. However, data are too limited to permit an evidence-based assessment of these risks.

Use of any opioid during pregnancy, particularly around the time of delivery, confers a risk of neonatal respiratory depression. Prolonged use of opioids throughout pregnancy may also result in neonatal withdrawal. Where there is a compelling clinical indication for administration of fentanyl in the management of maternal pain or another condition, then use in pregnancy may be considered but at the lowest effective dose for the shortest period possible and should involve discussion with the patient regarding the lack of human pregnancy data.

Exposure to fentanyl at any stage of pregnancy would not usually be regarded as medical grounds for termination of pregnancy. The need for additional fetal monitoring or prenatal investigations should be decided on a case-by-case basis. 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. Infants exposed to fentanyl in utero for extended periods and/or around the time of delivery should ideally be delivered in a unit with facilities for the treatment and support of neonatal opioid withdrawal.

Fexofenadine is a non-sedating antihistamine used for the symptomatic relief of allergic disorders. Although there are very limited data on the use of fexofenadine in pregnancy, this drug is the active metabolite of terfenadine, which was previously considered the non-sedating antihistamine of choice in pregnancy prior to its withdrawal in the UK in the late 1990s (due to non-pregnancy-related adverse effects).

There are insufficient data to determine the risks of adverse pregnancy outcome following use of fexofenadine or terfenadine in pregnancy. The limited published data that are available do not suggest an increased risk of spontaneous abortion, intrauterine death or preterm delivery after maternal exposure. Neither has an increased risk of having an infant with a congenital malformation, low birth weight, neonatal problems or neurodevelopment delay up to one year of age been found following in utero exposure to either fexofenadine and/or terfenadine in pregnancy. The available evidence is, however, very limited.

Due to the limited data, use of fexofenadine should be reserved for cases where no other suitable treatment is available and both prescriber and patient should take into account the relative lack of experience of use in pregnancy.

Exposure to fexofenadine at any stage in pregnancy would not usually be regarded as medical grounds for 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.

Fluoroacetic acid derivatives (organofluorines) such as sodium fluoroacetic acid, methyl fluoroacetic acid and fluoroacetamide have been used as rodenticides.  Occupational exposure can occur in formulators and pest control workers.  Due to their extreme toxicity the use of these compounds is not widespread.  Fluoroacetic acid derivatives dissociate to yield the fluoroacetate anion which is converted to fluorocitrate, inhibiting the Krebs cycle.

Animal studies have shown adverse effects following exposure to sodium fluoroacetic acid during gestation, with reports of congenital malformations in exposed fetuses.

There are no human data following acute exposure to fluoroacetate compounds during pregnancy, and therefore an accurate evidence-based risk assessment is not possible. Maternal toxicity is likely to be a major determinant of risk to the fetus and if exposure occurs, treatment should be as for a non-pregnant person.  The need for additional fetal monitoring should be considered on a case-by-case basis, even in the absence of maternal toxicity.  Discussion with UKTIS is recommended in all cases.  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.

Formaldehyde is an organic compound that is often used in an aqueous solution called formalin. Formaldehyde is used widely in the manufacture of plastics and resins, and as a disinfectant and tissue preservative. There has also been concern surrounding the production of formaldehyde, as a by-product of some professional keratin-based hair straightening products, at levels in excess of occupational exposure limits.  

Epidemiological studies assessing occupational exposure to formaldehyde during human pregnancy do not demonstrate an increased risk in those adverse fetal outcomes that have been studied, however data are limited and adverse effects on the fetus cannot be ruled out, and these analyses may not reflect risk where exposure in excess of recommended limits has occurred.

As with all chemicals, unnecessary exposure to formaldehyde/formalin should be avoided. Where occupational exposure is unavoidable, precautions should be taken to ensure that any recommended PPE is used, and that exposure is well within the recommended exposure limits and not associated with toxic symptoms.

Maternal toxicity as a result of exposure in pregnancy is likely to be a major determinant of the risk posed to the developing fetus. However, due to limitations in the available data, it is not currently possible to state that an absence of maternal toxicity excludes the possibility of adverse fetal effects. Where maternal treatment is required, treatment should be the same as for the non-pregnant patient. Additionally, 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. Enhanced antenatal surveillance may be warranted after exposure to formaldehyde and should be decided on a case-by case basis. Discussion with UKTIS is recommended in all cases of formaldehyde exposure at any stage of pregnancy.