Letter: D

Diclofenac is a non-steroidal anti-inflammatory drug (NSAID) used to treat acute and chronic pain (including dysmenorrhoea), and in the management of rheumatoid arthritis.

Use of NSAIDs in pregnancy has been associated with an increased risk of miscarriage, persistent pulmonary hypertension of the newborn (PPHN), oligohydramnios, premature closure of the ductus arteriosus (DA), structural cardiovascular defects, and a number of other congenital anomalies, including orofacial clefts. However, the available data are limited, confounded and often conflicting; further research is therefore required to define the risk of these outcomes more accurately.

Twelve studies collectively including approximately 15,000 unique diclofenac-exposed pregnancies have investigated the risk of adverse fetal effects following in utero exposure. These studies have provided conflicting evidence, with a small number describing statistically significant increased risks of miscarriage, cardiovascular malformation, and abnormal birth weight outcomes. However, it is possible that these results may have been produced as a result of data confounding. Further studies using additional datasets are required before robust conclusions can be drawn concerning the fetal effects of maternal diclofenac use in pregnancy.

No evidence of associations with intrauterine death/stillbirth or preterm delivery has been provided from a small number of studies. No controlled studies investigating neurodevelopmental impairment or malignancy risks were located.

Exposure to NSAIDs after 20 weeks of gestation has been associated with an increased risk of premature closure of the DA and oligohydramnios. These effects are thought to be mediated by the inhibitory effect of NSAIDs on prostaglandin production. There have been case reports of premature closure of the DA occurring after a single dose of diclofenac and following use of a topical preparation. There are also conflicting findings regarding the risks of PPHN following antenatal use of NSAIDs. Further evidence is required before this possible association can be confirmed. Where published data concerning the fetal effects of gestational exposure are unavailable or limited, a possible class effect for these associations should be considered for all NSAIDs.

All NSAIDs should, where possible, be avoided after twenty weeks of pregnancy. In circumstances where the maternal clinical condition requires short-term treatment with diclofenac (such as acute short-lived pain: post-operative, dental, skeletal injury), treatment should be limited to the shortest duration possible. There is currently no evidence-based guidance about how long use should be restricted for, but pragmatic advice is to limit use to no longer than 3 days. Longer term use, for example for treatment of chronic arthritis, should be avoided. As fetal urine production begins at approximately 10 weeks’ gestational age, referral to a Fetal Medicine Unit for monitoring of DA patency and oligohydramnios is recommended following prolonged NSAID use after the first trimester.

Where use of diclofenac is being considered at any stage of pregnancy, the available pregnancy data should be discussed with the patient to support informed decision-making regarding the risks and benefits of treatment.

Please refer to the NSAID overview monograph for more information. 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. Discussion with UKTIS is recommended for all cases of diclofenac exposure in pregnancy.

Dicobalt edetate is an antidote used in the treatment of severe cyanide poisoning.  Dicobalt edetate is toxic in the absence of cyanide ions, therefore use is reserved for cases of confirmed severe poisoning.

There are no published data available to provide a risk assessment on the potential effects following exposure to dicobalt edetate in pregnancy.  Where maternal toxicity occurs following cyanide poisoning, there is a potential for fetal toxicity.  In cases of severe maternal systemic poisoning, it is important to treat the mother appropriately to reduce the risks of maternal and fetal toxicity. 

If dicobalt edetate is required in the management of severe cyanide poisoning then treatment should not be withheld at any stage in pregnancy.  Enhanced antenatal surveillance may be warranted and should be decided on a case-by case basis. Discussion with UKTIS is recommended in all cases of exposure to dicobalt edetate at any stage of pregnancy. 

Disulfiram is an aldehyde dehydrogenase inhibitor licensed for specialist use as an adjunct in the treatment of alcohol dependence.

The available human pregnancy disulfiram exposure data are both highly limited, consisting mainly of uncontrolled case reports/series and a single small prospective cohort study, and potentially confounded by publication bias and the possibility of underreported concomitant alcohol and recreational substance misuse.

A small cohort study of first trimester disulfiram use in human pregnancy (n=25) failed to identify a significant increase in overall fetal malformation rates. Miscarriage, low birth weight and neurodevelopmental delay have been reported sporadically.

Due to the limited data, it is not currently possible to draw any conclusions regarding the fetal effects of maternal disulfiram use in pregnancy. As such, routine disulfiram use in human pregnancy cannot currently be recommended. Where use is being considered, it is important that pregnant women are fully counselled on the unknown risks associated with disulfiram use in pregnancy and that these are balanced against the known risks of continued maternal alcohol use.

The autonomic instability resulting from the disulfiram-alcohol reaction, particularly when the reaction is severe, may pose a risk to both mother and fetus. Pregnant women should be managed as for the non-pregnant patient but may require additional fetal monitoring or intervention. For current guidelines on the management of disulfiram co-ingested with ethanol it is advisable to consult TOXBASE and contact UKTIS.

Exposure to disulfiram 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.

Diuretics are given to reduce oedema and used in the management of heart failure and other conditions associated with fluid overload. They are also used to treat hypertension, although are generally contraindicated in pregnancy for this sole purpose. This document focuses on the diuretics amiloride, chlorothiazide, furosemide and spironolactone, which are among some of the more commonly prescribed diuretics for which there is pregnancy outcome data 

Diuretics are not routinely recommended in pregnancy due to the potential risk of altered uteroplacental blood flow, and in the case of spironolactone and eplerenone, antiandrogenic effects which could theoretically affect the development of a male fetus. However, their use may be justified under specialist supervision in cases of severe maternal illness for which other treatments are likely to be ineffective or have to be discontinued due to pregnancy (such as an ACE-inhibitor or ARB).

There are few controlled studies of diuretic use during pregnancy, and for each individual diuretic; data are therefore limited. The decision to use a diuretic during pregnancy is clinical, based on the benefits of effectively treating the maternal condition versus the possible risks to the fetus. Where a diuretic is being used to treat a life-threatening condition or is prescribed to replace a drug with established adverse fetal effects (such as an ACE-inhibitor or ARB), the benefits of treatment are likely to outweigh the possible risks.

Women being treated with a diuretic who are either planning a pregnancy or become pregnant should be offered a medication review by their specialist.

Exposure to a diuretic at any stage in pregnancy would not usually be regarded as medical grounds for termination of pregnancy. Additional monitoring of fetal and maternal wellbeing is advised. Other risk factors may also be present in individual cases which may independently increase the risk of adverse pregnancy outcome and therefore the need for additional monitoring.

Data relating to diuretic use in pregnancy are limited. Clinicians treating pregnant women with diuretics are therefore encouraged to report any exposures to UKTIS to facilitate surveillance of pregnancy outcomes.

Dimercaptosuccinic acid (DMSA) is an organosulfur antidote used orally in the treatment of heavy metal poisoning; particularly lead and arsenic.  There are insufficient published data available to provide a risk assessment on the potential effects following exposure to DMSA in pregnancy.  Where maternal toxicity occurs following heavy metal poisoning, there is a potential for fetal toxicity.  In cases of severe maternal systemic poisoning, it is important to treat the mother appropriately to reduce the risks of maternal and fetal toxicity.

The antidotes used in the treatment of heavy metal poisoning are not without risk and may offer only limited benefit in reducing fetal exposure when used during pregnancy.  There is also a risk that maternal chelation therapy will result in mobilisation of the heavy metal from the mother into fetal tissue.  It is therefore recommended that guidelines for non-pregnant adults should be followed in the pregnant patient, with chelation therapy reserved for patients with severe toxicity.

Alternative chelating agents to DMSA may be recommended as first-line treatment of heavy metal poisoning.  Where DMSA is required in the management of severe poisoning then treatment should not be withheld at any stage of pregnancy.  Discussion with UKTIS is recommended in all cases where chelation therapy is being considered.

Exposure to DMSA 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. Enhanced antenatal surveillance may be warranted and should be decided on a case-by case basis.

Dolutegravir is an inhibitor of HIV integrase that is used (usually in combination with other antiretroviral drugs) to treat HIV infection.

An ongoing birth surveillance study is currently the only controlled study to assess rates of adverse pregnancy outcomes following in utero exposure to dolutegravir. In 2018 this study reported four cases of neural tube defects among 426 infants exposed to dolutegravir around the time of conception (rate of 0.94% compared to that of 0.12% in infants whose mothers took other HIV medication). While this signal is being evaluated the manufacturer of dolutegravir and the European Medicines Agency have recommended that use of dolutegravir should be avoided during pregnancy and in women seeking to become pregnant. A negative pregnancy test should be obtained before initiation of treatment, effective contraception should be used throughout, and if first trimester pregnancy is confirmed during treatment, the patient’s therapy should be switched unless there is no suitable alternative. In practice there may be some cases where the potential risks of first trimester dolutegravir treatment are considered to be outweighed by the benefit of continued HIV viral suppression. Discussion with the patient should occur in all such cases.

The birth surveillance study discussed above includes data from >1,700 women exposed to dolutegravir at any stage of pregnancy and provides no evidence of associations with other adverse outcomes including preterm delivery, small for gestational age, stillbirth, or neonatal death, although data are too limited to rule this out. Neurodevelopmental outcomes and rates of childhood cancer following gestational exposure to dolutegravir have not yet been assessed.

Women who have been exposed to dolutegravir around the time of fetal neural tube closure (usually up to 5 weeks’ gestation) should be offered additional fetal anomaly scans to screen for neural tube defects prior to their routine anomaly scan at 20 weeks gestation. Other risk factors which independently increase the risk of adverse pregnancy outcome may also be present in individual cases. Clinicians are reminded of the importance of consideration of such factors when performing case-specific risk assessments.

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

The data on duloxetine exposure in pregnancy do not suggest increased risks of congenital malformation overall or cardiac defects specifically, miscarriage, stillbirth, fetal growth impairment, or preterm delivery. Increased risks of poor neonatal adaptation have been observed following third trimester exposure.

Although there are no published data which identify an increased risk of persistent pulmonary hypertension of the newborn (PPHN) with maternal duloxetine use, SNRIs share similar mechanistic properties with 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 score, 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.

It is important to ensure that mental health conditions are treated appropriately. As such, duloxetine 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 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.

Diazepam is a long-acting benzodiazepine used as a hypnotic, anxiolytic, anticonvulsant and muscle relaxant.  Its actions are mediated by enhancement of the activity of gamma-aminobutyric acid (GABA), a major inhibitory neurotransmitter in the brain.

Data on the risk of congenital malformation following use of diazepam in pregnancy are highly confounded by the research techniques employed in the majority of the available studies.  Evidence is therefore conflicting; with some older studies suggesting possible increased risks of congenital malformation, including orofacial clefts and cardiac malformations.  More recent, better designed studies, have failed to identify such associations.  Where clinically justifiable use of diazepam in the first trimester may be considered, ideally following discussion regarding these data with the patient.  The lowest effective dose should be used and only for as long as considered clinically necessary.  The potential effects of diazepam use at any stage of pregnancy on fetal neurodevelopmental outcome is unknown.

There are no data available relating specifically to the risk of spontaneous abortion (SA) following diazepam exposure in pregnancy, and although an increased risk of spontaneous abortion following exposure to benzodiazepines as a group has been reported, these data are considered too limited and confounded to be certain that a clinically relevant increased risk of spontaneous abortion exists.

Abrupt withdrawal of diazepam is not recommended as this may destabilise the maternal condition, or potentially lead to self-administration of other medications or drugs of abuse, like alcohol, which may confer a significant risk to the developing fetus.

Prolonged use of benzodiazepines near term, especially in high doses, is associated with a risk of neonatal withdrawal syndrome and/or “floppy infant syndrome” and monitoring for neonatal respiratory depression is advised.  Use of diazepam around term should therefore be avoided unless use can be clinically justified.

Exposure to diazepam during pregnancy would not usually be regarded as medical grounds for termination of pregnancy.  In light of conflicting data concerning the risk of congenital malformation, detailed fetal ultrasound scans may be considered following first trimester exposure.