Biologics and novel small molecule treatments, reproduction and psoriasis

Introduction

Psoriasis is a common scaly skin condition. If you are pregnant or planning pregnancy and have psoriasis, seek your doctor's advice. This is particularly important if you are on systemic therapy for psoriasis. This article discusses the use of biologics and novel small molecule treatments such as apremilast, in women with psoriasis during their reproductive time of life.

Note

• Psoriasis affects many young people, so the need to plan for pregnancies in psoriasis is common.
• Several biologics and small molecule agents are licensed for the treatment of psoriasis (2015).
• Safety information for biologics in reproduction (from conception to pregnancy and breastfeeding) is limited.
• Clinical trials of biologics exclude pregnant patients and those planning pregnancies, so evidence for safety comes largely from patient registries and case reports.

How does pregnancy affect psoriasis and its treatment?

Active psoriasis is characterised by inflammation throughout the body. The risk to the unborn baby from uncontrolled inflammation must be weighed up against the risk from medication.

• Psoriasis is unpredictable in pregnancy. Most women experience an improvement during pregnancy with a flare after the birth of their baby, but psoriasis in some women worsens during pregnancy.
• Psoriasis does not affect the chances of conceiving.
• Active or untreated psoriasis can be associated with premature birth, low birth-weight babies, and miscarriage.

Other health conditions associated with psoriasis may also complicate pregnancy:

• Metabolic syndrome (obesity, high cholesterol, high blood pressure, and impaired processing of sugars) is associated with premature birth, low birth-weight babies, and the birth of large babies (with subsequent delivery complications).
• Depression is linked to low birth-weight babies.
• High maternal intake of alcohol can lead to fetal alcohol syndrome

Safety of medicines in pregnancy

All medications are categorised by their safety in pregnancy and the risk of harm to the unborn baby. The Australian Drug Evaluation Committee’s categorisation of medicines in pregnancy is summarised in Table 1.

Table 1: Categorisation of medicines in pregnancy

How safe are biologics and small molecule drugs in pregnancy?

Evidence regarding the use of biologics and small molecule medications in pregnancy and when planning a pregnancy is summarised in Table 2.

Table 2. Biologic and small molecules for the treatment of psoriasis

*In general, drugs are eliminated from the body after 5 drug half-lives.
TNF: tumour necrosis factor
IL: Interleukin
PD: phosphodiesterase

Is fertility affected by these agents?

• It is not known if male and female fertility is affected by biologics as studies assessing fertility have not been performed in humans with psoriasis.
• High levels of TNFα in men can reduce sperm function; the anti-TNFα medication can improve sperm function.
• Anti-TNFα medications in arthritis do not appear to adversely affect sperm function or quality.
• Individual reports indicate there is no delay in conception for men and women treated with biologics.
• Less is known about the effects of ustekinumab, secukinumab, and apremilast on fertility in humans, as they are relatively new compared to anti-TNFα medications.

Conclusions

• A conservative approach is to stop biologics and small molecule medications in women at least 5 half-lives prior to conception (see Table 2).
• Anti-TNFα medications can be used safely in potential fathers.

Are these medications harmful during pregnancy?

Biologics and small molecule medications are not routinely recommended in pregnancy because they have not been studied sufficiently; they should only be considered when the potential benefit outweighs the risk. Therefore, contraceptive measures are recommended during treatment with biologics and apremilast and for at least 5 half-lives afterwards.

• Because TNFα inhibitors have been used for more than 10 years to treat inflammatory bowel disease and arthritis, there is more experience in pregnancy with these medications compared to the newer agents.
• Apremilast was not teratogenic in animal studies.
• The frequency of congenital malformations is no higher in women treated with biologics than in the general population.
• Immunoglobulin G type (IgG) antibodies cross the placenta during the third trimester (week 24–36 of pregnancy), when biologics may reach and affect a developing fetus.
• If treatment is continued during pregnancy, it is best to stop biologics and apremilast before week 23 of gestation.

Conclusions

• No biologic agent is recommended during pregnancy.
• Psoriasis can be treated during pregnancy with most topical agents, UVB phototherapy, and oral ciclosporin.
• Biologics may be considered during pregnancy if the risk of treatment is less than the risk of withholding treatment.
• The mother’s psychological and physical wellbeing is of central importance.
• If biologics are continued during pregnancy, the mother should be told that the baby’s immune system may be suppressed during the first months of life.

Should live vaccines be avoided?

Babies whose mothers are treated with a biologic may be at higher risk of infection. It is very important that live vaccinations (live polio, chickenpox/varicella, yellow fever) are avoided in these young infants. See Immunisation in immunosuppressed dermatology patients.

• Infliximab: avoid live vaccines in infants for at least 6 months from birth.
• Adalimumab: avoid live vaccines in infants for 5 months after the mother’s last dose.
• Etanercept: avoid live vaccines in infants for 16 weeks after the mother’s last dose.
• Ustekinumab: there are no recommendations about live vaccination for an exposed infant
• Secukinumab: avoid live vaccines in infants for 16 weeks after the mother’s last dose.
• Apremilast: there are no recommendations about live vaccination for an exposed infant

Can biologics be used during breastfeeding?

It is unknown if biologics are excreted in breast milk or whether they are absorbed by the infant through their gut.

• Etanercept has been detected in the breast milk of treated mothers at low levels but has not been detected in infant blood.
• Apremilast has been detected in the milk of treated animals.
• Infants breastfeeding from mothers taking biologics have not experienced any untoward events.
• The drug half-life (Table 2) must be taken into account when deciding how long after the last dose to introduce breast-feeding.

Conclusions

• Biologics and apremilast are not recommended in breastfeeding mothers.
• The choice of discontinuing breastfeeding or the medication should take into account the importance of continuing the drug to the mother and the benefits of breastfeeding to the mother and child.

Approved datasheets are the official source of information for medicines, including approved uses, doses, and safety information. Check the individual datasheet in your country for information about medicines.

We suggest you refer to your national drug approval agency such as the Australian Therapeutic Goods Administration (TGA), US Food and Drug Administration (FDA), UK Medicines and Healthcare products regulatory agency (MHRA) / emc, and NZ Medsafe, or a national or state-approved formulary eg, the New Zealand Formulary (NZF) and New Zealand Formulary for Children (NZFC) and the British National Formulary (BNF) and British National Formulary for Children (BNFC).