Letter: F

Flucloxacillin, piperacillin, temocillin, and ticarcillin are broad-spectrum penicillin antibiotics indicated in the treatment of numerous mild to moderately severe infections caused by susceptible micro-organisms. Penicillin antibiotics can be used in pregnancy if clinically indicated.

No studies specifically investigating the risk of adverse pregnancy outcome following exposure to flucloxacillin, piperacillin, temocillin, or ticarcillin were located. A large body of evidence on penicillin antibiotics as a class shows no increased risk of congenital malformations, miscarriage, intrauterine death, low birth weight, preterm delivery, or neonatal complications following maternal exposure. Where possible associations with adverse outcomes have been suggested, findings are considered likely influenced by the effects of maternal infection during pregnancy.

The extensive body of data relating to prenatal use of penicillin antibiotics as a class does not indicate an increased risk of adverse fetal outcomes, although not all pregnancy outcomes have been studied in sufficient detail to fully exclude an increased risk. However, due to the potential adverse consequences of untreated maternal infection during pregnancy, the use of penicillin antibiotics, including those with limited or no pregnancy safety data, may be considered where clinically indicated.

Where possible, the results of culture and sensitivity tests should be available before making a treatment choice in accordance with local prescribing guidelines. It is important to ensure adequate treatment of infection in order to avoid adverse maternal and fetal effects from uncontrolled infection or pyrexia.

The Royal College of Obstetricians and Gynaecologists (RCOG) advises routine intrapartum antibiotic prophylaxis (IAP) for all women in preterm labour, with or without pre-labour rupture of membranes (PROM). Benzylpenicillin should be used preferentially, but a cephalosporin should be used in women with a non-severe penicillin allergy, or vancomycin where the allergy is severe. The National Institute for Health and Care Excellence (NICE) guidelines also state that women with pre-labour PROM should be offered oral erythromycin (250mg, 4 times a day) for a maximum of 10 days or until the woman is in established labour (whichever is sooner), with oral penicillin offered to women who cannot tolerate erythromycin.

Exposure to flucloxacillin, piperacillin, temocillin, or ticarcillin 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.

Urinary incontinence, defined as the involuntary leakage of urine, has multiple causes which may require different management strategies. Stress incontinence is common during pregnancy, caused by the hormonal changes of pregnancy and pressure on the bladder from the expanding uterus. Pharmacological treatment is not routinely indicated for urinary stress incontinence that has occurred due to pregnancy.

Women with pre-existing conditions that cause urinary frequency, enuresis and incontinence may require ongoing treatment during pregnancy under specialist supervision. Human pregnancy safety data is limited or lacking for most of the drug options, and the risks and benefits should therefore be considered on a case-by-case basis, taking into account the severity of the woman’s condition and likely effects on her health and quality of life if an established medication regimen is altered.

Oxybutynin is the best studied treatment for urinary frequency during pregnancy, although data are still very limited. Neither of two studies nor a handful of case reports raise concern that oxybutynin exposure is associated with infant congenital malformation. Increased risks of preterm delivery and low infant birth weight were noted in one of the studies but may be related to the underlying maternal condition. These findings require confirmation.

There are no further published human pregnancy exposure data for drugs to treat urinary frequency, enuresis and/or incontinence. A small number of pregnancy outcomes have been reported to UKTIS following prenatal exposure to oxybutynin, solifenacin, tolterodine, fesoterodine, mirabegron, propantheline, and trospium, with no major congenital malformations described. Data are absent for darifenacin, flavoxate, and propiverine.

Adverse fetal effects have been observed in preclinical (animal) studies of darifenacin, propiverine, fesoterodine, mirabegron, oxybutynin, and tolterodine; however, some exposures were at maternally toxic doses.

Exposure to drugs used to reduce symptoms of urinary frequency, enuresis and incontinence at any stage in pregnancy would not usually be regarded as medical grounds for termination of pregnancy; however, due to the lack of data, additional fetal monitoring may be warranted. 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.

Urinary incontinence, defined as the involuntary leakage of urine, has multiple causes which may require different management strategies. Stress incontinence is common during pregnancy, caused by the hormonal changes of pregnancy and pressure on the bladder from the expanding uterus. Pharmacological treatment is not routinely indicated for urinary stress incontinence that has occurred due to pregnancy.

Women with pre-existing conditions that cause urinary frequency, enuresis and incontinence may require ongoing treatment during pregnancy under specialist supervision. Human pregnancy safety data is limited or lacking for most of the drug options, and the risks and benefits should therefore be considered on a case-by-case basis, taking into account the severity of the woman’s condition and likely effects on her health and quality of life if an established medication regimen is altered.

Oxybutynin is the best studied treatment for urinary frequency during pregnancy, although data are still very limited. Neither of two studies nor a handful of case reports raise concern that oxybutynin exposure is associated with infant congenital malformation. Increased risks of preterm delivery and low infant birth weight were noted in one of the studies but may be related to the underlying maternal condition. These findings require confirmation.

There are no further published human pregnancy exposure data for drugs to treat urinary frequency, enuresis and/or incontinence. A small number of pregnancy outcomes have been reported to UKTIS following prenatal exposure to oxybutynin, solifenacin, tolterodine, fesoterodine, mirabegron, propantheline, and trospium, with no major congenital malformations described. Data are absent for darifenacin, flavoxate, and propiverine.

Adverse fetal effects have been observed in preclinical (animal) studies of darifenacin, propiverine, fesoterodine, mirabegron, oxybutynin, and tolterodine; however, some exposures were at maternally toxic doses.

Exposure to drugs used to reduce symptoms of urinary frequency, enuresis and incontinence at any stage in pregnancy would not usually be regarded as medical grounds for termination of pregnancy; however, due to the lack of data, additional fetal monitoring may be warranted. 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.

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 1,500 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 2-fold increased risk of malformation. However, the evidence base is weak as the majority of data do not derive from methodologically robust studies. It is therefore not possible to confirm or exclude an association between malformation and 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 data relating to 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 fingolimod use in early pregnancy. As these data are provided from uncontrolled studies, it is not possible to conclude that fingolimod is a causal factor for these outcomes.

Owing to the possible increased risk of malformation, the Medicines and Healthcare products Regulatory Agency and manufacturers of fingolimod recommend that women should avoid pregnancy for two months after discontinuing therapy and that fingolimod should be discontinued in all women who become pregnant. 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. 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 two small retrospective cohort studies, a clinical trial with only a small number of flecainide exposures, case reports and small case series documenting maternal flecainide administration to treat fetal tachyarrhythmias. Two meta-analyses have 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 five cases. While no malformations were reported, the number of exposures is too limited to allow 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 most commonly used in the treatment of vaginal candidiasis. Standard fluconazole therapy generally comprises a single 150mg oral dose. Fluconazole is not generally recommended for use during pregnancy as clotrimazole is an effective topical alternative. However, fluconazole is occasionally prescribed to treat vaginal candidiasis during pregnancy that has not responded to topical treatment. High dose fluconazole (typically >400mg/day) is also used in the treatment of serious mycotic infections, including cryptococcal meningitis, coccidioidomycosis, and disseminated candidiasis.

Prolonged high dose fluconazole therapy (400-800mg/day) during the first trimester has been linked to a distinctive pattern of birth defects resembling those seen with the genetic condition Antley-Bixler syndrome. Because this type of exposure is rare, controlled or denominator-based data are lacking, and the absolute risk is unclear. There is no information regarding risks of other adverse pregnancy outcomes after exposure to high dose fluconazole.

Data on the outcomes of over 53,000 fluconazole-exposed pregnancies, the majority of which were exposed to a single 150mg oral dose, do not reliably indicate increased risks of malformation overall. There is some evidence of an increased risk of specific cardiac defects following fluconazole exposure in the first trimester, including tetralogy of Fallot, hypoplastic left heart, and transposition of the great arteries. However, data may be confounded by increased frequency of diabetes in women using fluconazole, and if an increased risk exists, the absolute risk of each defect 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, 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%. These data may also be confounded by the underlying illnesses in women more likely to experience vaginal candidiasis (such as diabetes and those leading to immunosuppression).

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.

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. Investigations are also recommended to rule out an underlying genetic cause for all suspected cases of high dose fluconazole embryopathy.

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 (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.

Folic acid supplementation during pregnancy is universally recommended. Folate requirements during pregnancy are increased 5- to 10-fold, leading to risk of deficiency. Folate deficiency in early pregnancy is an established risk factor for infant neural tube defects (NTDs).

There is good evidence that folic acid supplementation before closure of the neural tube, at doses ≥360mcg, reduces the risk of primary and recurrent NTDs. Some studies have also suggested reduced risks of miscarriage, congenital heart defects (including atrial septal defects), and cleft lip and palate. There is conflicting evidence regarding whether folic acid supplementation reduces the risks 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 are likely confounded.

Current UK guidelines recommend routine supplementation with 400mcg/day folic acid prior to conception and until at least 12 weeks of pregnancy. Higher dose folic acid (5mg/day) is recommended for women at increased risk of folate deficiency or of having a child with an NTD. However, data do not unequivocally show increased benefit of a higher dose. As maternal requirements for folate peak at around five months’ gestation, continued folic acid supplementation after the first trimester can be considered; however, there is no definitive evidence of benefit 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.