Letter: D

Direct oral anticoagulants (DOACs) include Factor Xa inhibitors (apixaban, rivaroxaban, edoxaban) and the direct thrombin inhibitor (dabigatran). These drugs act on specific components of the coagulation cascade, resulting in reduced thrombin generation and inhibition of fibrin clot formation. They are widely used for stroke prevention in atrial fibrillation, and the treatment and prevention of venous thromboembolism.

Direct oral anticoagulants (DOACs) include Factor Xa inhibitors (apixaban, rivaroxaban, edoxaban) and the direct thrombin inhibitor (dabigatran). These drugs act on specific components of the coagulation cascade, resulting in reduced thrombin generation and inhibition of fibrin clot formation. They are widely used for stroke prevention in atrial fibrillation, and the treatment and prevention of venous thromboembolism.

Published data relating to DOAC exposure in pregnancy are highly limited (~400 exposed pregnancies) and derive primarily from a large case series, a disproportionality analysis of adverse event reporting, and two additional case reports. The majority of data relate to short -term exposure to rivaroxaban in early pregnancy (>300 exposures). 

The limited available information does not raise concern that rivaroxaban is a major structural teratogen, but data are too limited to exclude an increased risk. Data relating to miscarriage, preterm birth and small for gestational age are highly limited but do not provide compelling evidence of increased risks. There are no data relating to risks of stillbirth or adverse neurodevelopmental outcomes. Data for apixaban, dabigatran and edoxaban are extremely limited, and it is not currently possible to characterise pregnancy risks for these agents individually. 

The European Society of Cardiology guidelines recommend that women taking DOACs receive pre‑pregnancy counselling. Where possible, DOACs should be discontinued and replaced with low-molecular-weight heparin (LMWH) either prior to conception or as soon as pregnancy is recognised. 

DOACs cross the placenta, presenting a theoretical risk of fetal and neonatal anticoagulation and bleeding complications. Women receiving anticoagulant therapy in late pregnancy are at increased risk of bleeding complications during labour and delivery. 

Exposure to DOACs at any stage of pregnancy would not usually be regarded as medical grounds for termination of pregnancy. No additional fetal monitoring is required solely due to DOAC exposure. However, given the paucity of pregnancy safety data, women should be strongly encouraged to attend their routine anomaly scan (at 18-22 weeks of pregnancy). As maternal cardiovascular pathology independently increases adverse pregnancy outcome risks, individualised risk assessment is essential when counselling and managing pregnant women requiring anticoagulant therapy.

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.

Deutivacaftor is a Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) modulator licensed for the treatment of cystic fibrosis.

Dupilumab is a recombinant human IgG4 monoclonal antibody that decreases mediators of inflammation by inhibiting interleukin-4 and interleukin-13 signalling. Dupilumab is used to treat atopic dermatitis and asthma, and as an add-on therapy in the treatment of severe chronic rhinosinusitis with nasal polyps.

The available human pregnancy exposure and outcome data are highly limited, provided by a small retrospective cohort study, a disproportionality analysis of spontaneous adverse drug reaction reports, and case reports/series, which together describe 95 dupilumab-exposed pregnancies, with 47 exposed in at least the first trimester.

There is no evidence of an association between in utero dupilumab exposure and an increased risk of either miscarriage, congenital malformation, neonatal complications, or neurodevelopmental impairment. However, the available data are highly limited, and therefore further data are required to confirm these findings. Although there are a small number of uncontrolled case reports of dupilumab exposure which describe impaired fetal growth (n=3) and preterm delivery (n=2), an influence of the underlying maternal condition is possible, and causality cannot be attributed to dupilumab exposure. There are no data regarding the risk of intrauterine death.

Uncontrolled maternal asthma is associated with a number of adverse pregnancy outcomes, including fetal loss, preterm birth, and low infant birth weight, as well as adverse maternal events such as preeclampsia. Where clinically indicated, the benefit of continued treatment with dupilumab in pregnancy is likely to outweigh any theoretical risk posed to the fetus. Dupilumab therapy should not be discontinued on account of pregnancy without careful consideration of the risk to both mother and fetus of uncontrolled maternal asthma.

Where moderate-to-severe atopic dermatitis has been assessed as causing significant social or psychological problems (e.g. sleep disturbance), and where clinically indicated, the benefit of continued maternal treatment with dupilumab in pregnancy may outweigh any theoretical risk posed to the fetus.

There is a theoretical concern that immunosuppressant antibodies which actively cross the placenta during pregnancy could result in neonatal/infant immunosuppression and an increased risk of infection. There are currently no data regarding the effect of in utero dupilumab exposure on the neonatal/infant immune system. Guidance from Public Health England (PHE), issued 2017, specified that live vaccines should not be used until the infant is 6 months old following in utero biologic immunosuppressant exposure. This advice means that rotavirus should usually be avoided and the risks/benefits of BCG (if relevant for the infant) should be weighed up at the time.

The European Respiratory Society/Thoracic Society of Australia and New Zealand (ERS/TSANZ) task force and a Dermatology Association of Ontario (DAO) expert panel has classified dupilumab as possibly safe for use during pregnancy (and breastfeeding).

Exposure to dupilumab 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 could independently increase the risk of adverse pregnancy outcome may be present in individual cases. Such factors are important to consider when performing case-specific risk assessments.

Duloxetine is a serotonin noradrenaline reuptake inhibitor (SNRI) indicated for the treatment of major depressive disorder, diabetic peripheral neuropathic pain, generalised anxiety disorder, and moderate-to-severe stress urinary incontinence.

Current data do not suggest increased risks of congenital malformation (including cardiac defects), miscarriage, stillbirth, fetal growth impairment, or preterm delivery with duloxetine use in pregnancy. Increased risks of poor neonatal adaptation have been observed following third trimester exposure.

Although no studies identify an increased risk of persistent pulmonary hypertension of the newborn (PPHN), SNRIs share similar mechanistic properties with selective serotonin reuptake inhibitors (SSRIs), which are associated with an increased risk of PPHN following use in pregnancy. The possibility of an increased risk of PPHN in the neonate should therefore be considered, particularly as other neonatal problems similar to those reported with SSRIs have also been observed in infants exposed to SNRIs in utero. These include respiratory problems, low Apgar scores, hypoglycaemia, and convulsions. Infants exposed to antidepressants in utero should ideally be delivered in a unit with neonatal support and the delivery team made aware of the exposure. The neonate should be monitored for adverse effects post-delivery.

The Medicines and Healthcare products Regulatory Agency (MHRA) advises that there is a small increased risk of postpartum haemorrhage (PPH) with SSRI/SNRI use in the month before delivery. Some studies suggest up to a 1.5-fold increase, implying an absolute risk of ~3–7.5% (vs. accepted background risk of 2–5%). Decisions about continuing treatment should balance this against the risk of maternal relapse. Pregnant women with risk factors for venous thromboembolism should continue appropriate heparin prophylaxis.

It is important to ensure that mental health conditions are treated appropriately. Duloxetine may be suitable in pregnancy following an individualised risk-benefit assessment. Where clinically appropriate, non-pharmaceutical management of depression and/or anxiety could be considered during pregnancy. However, where a patient is stabilised on duloxetine, 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 duloxetine is continued in pregnancy, the lowest effective dose should be used.

Exposure to duloxetine 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.