Introduction

Lupus is an autoimmune disorder that causes widespread inflammation in multiple body organs. It commonly occurs in people assigned female at birth compared to those assigned male at birth. The peak age of presentation is during the reproductive years. It is a lifelong disease that affects the functions and processes of organs including the reproductive system. The disease comes in periods of flares and remissions. The disease has multiple effects on reproductive health, including fertility, menstruation, sexual health, and pregnancy. Individuals should discuss concerns with their healthcare provider.

Types of lupus

There are four basic types of lupus:¹

• Systemic lupus erythematosus(SLE) - Causes widespread inflammation in many body parts. This is the most common type
• Cutaneous lupus - Manifests in the form of skin rash or lesions
• Drug-induced lupus - Caused by the ingestion of certain drugs
• Neonatal lupus - Occurs in the newborn as a result of the transfer of antibodies during gestation

Systemic lupus erythematosus (SLE) is the most severe and is usually associated with reproductive problems. 

Who is affected?

Most countries lack data on the incidence of lupus.² It is estimated that 1.5 million Americans have SLE, with an average of 5 million people worldwide. 9 out of 10 people with lupus are people assigned female at birth (AFAB). The maximum age of occurrence in people with AFAB is between 15-44 years.² In America, those from minority ethnic groups are more affected. The disease is also more common in people with a family history of autoimmune disease. 

Diagnosis and symptoms of lupus

Lupus is an autoimmune disease, meaning that the immune system attacks the body's cells. It can manifest in almost all organs. Because of the varying forms of presentation in different individuals, lupus can be difficult to unrecognize for years. That is why it is sometimes called the ‘invisible disease’.

Diagnosis is usually through history, examination, and investigation.

The symptoms include:

• Fever
• Joint pains/swelling
• Headache
• Rash around the cheeks and nose (Butterfly rash)
• Extreme weakness
• Numbness and swelling in the hands or feet
• Hair loss
• Chest pain

The combination of fever, joint pain, and rash in a person assigned female at birth of childbearing age should raise the suspicion of lupus.²

Diagnosis may include:

• Magnetic Resonance Imaging (MRI) and Computed Tomography (CT) scans 
• Lumbar puncture (analysis of cerebrospinal fluid surrounding the spinal cord and brain) and arthrocentesis (analysis of fluid from the joints).
• Blood tests: the level of the autoantibodies Antinuclear antibodies (ANA)

Effects of lupus on reproductive health

Reproductive health refers to a state of complete physical, mental, and emotional well-being in all matters relating to the reproductive system. Lupus may affect the reproductive health of women and men. Lupus is more common in people AFAB of reproductive age and can have an effect on reproductive processes. This may include being at greater risk of early menopause and increased risk of pregnancy complications.⁴

Lupus may also cause infertility in some patients; One study found that 1.5% of people AFAB who were receiving IVF for infertility also had undiagnosed lupus.⁵ However, whether lupus significantly affects fertility or not is yet to be conclusively determined as more research is needed.⁶

Causes of infertility in lupus

The effect of lupus on fertility can have indirect or direct causes.

Indirect

• Cyclophosphamide, one of the drugs used to treat lupus, could affect the ovary by interrupting the rapidly dividing cells of the ovary. This leads to premature ovarian failure- resulting in early menopause ⁷
• Other medications like non-steroidal anti-inflammatory drugs and high-dose corticosteroids can also affect fertility, by disrupting ovulation and causing changes in the menstrual cycle.
• Attempts to conceive may be deferred to allow the disease to be remitted. This may lead to age-related infertility⁸
• Low self-esteem, depression, and physical difficulties associated with the disease may lead to loss of libido, which may affect conception
• The production of free radicals and low body mass index in lupus patients may also contribute to problems with ovulation and infertility⁹

Direct

• Reduced ovarian reserve - Lupus may affect the ovaries by reducing the ovarian reserve. Reduced Antimullerian hormone levels (AMH) levels have been demonstrated in patients with lupus who are not receiving cyclophosphamide treatment¹¹
• Abnormal uterine bleeding- Patients with lupus report abnormalities in their menstrual cycle, including changes in frequency, quantity, or duration. Menstrual irregularities could lead to difficulty conceiving¹¹
• Fertilization and implantation failure -The antibodies from a patient with lupus can lead to another disease known as secondary Antiphospholipid Syndrome (APL). Early research suggests that it can impact fertility by influencing fertilization and implantation
• In men, the disease has been demonstrated to impair sexual function. The presence of the disease has been shown to result in reduced volume of the testis, low sperm count, and reduced sperm motility. This effect was observed in those receiving cyclophosphamide^{10, 12}

Menstrual problems

Lupus can affect menstruation by either prolonging the cycles or stopping the menstrual flow completely. This is usually due to many factors, including:¹³ 

• The direct effect of the disease on the ovary
• The effect of medications
• The psychological stress of the disease 

Pregnancy and Lupus

Lupus can adversely affect pregnancy outcomes. Lupus can affect both the gestational carrier and the foetus.

Risks to the foetus

• Miscarriage
• Risk of congenital anomaly (such as heart blockage)
• Preterm birth
• Intrauterine growth retardation (poor growth in the womb)
• Stillbirth 
• Neonatal Lupus

There is a greater risk of miscarriage in people with Lupus, with a 20% chance of the pregnancy ending in miscarriage or stillbirth. This is irrespective of whether the disease is active or dormant. Patients with secondary APL due to lupus also have a high risk of recurrent miscarriages. Reduced blood flow to the placenta due to the disease and its complications may cause poor growth of the baby, which may cause risk to the foetus’ life. Patients with lupus have a high risk of premature delivery because of the rupture of the membranes (breakage of water) and preeclampsia (pregnancy-related hypertension). Neonatal lupus is rare and typically manifests as heart block in the newborn or lupus rash.

Risks during pregnancy

• Lupus flares: Pregnancy may trigger lupus flares (worsening of symptoms), especially in the postnatal period
• Difficulty treating Lupus due to the risks to the developing foetus
• Urinary tract infections
• Diabetes in pregnancy
• Premature rupture of membranes
• Preeclampsia: may lead to premature delivery
• Increased risk of blood clots due to increased blood clotting in lupus

Worsening of lupus during pregnancy happens in about 20-30% of women in the United States.

The frequency of a flare-up during pregnancy and postnatally increases due to the increase in hormones estrogen and prolactin. It may also be due to adjustment of the dosage of the medications. 

The likelihood of a flare is higher if pregnancy occurs if the disease is not inactive at conception. This is why pregnancy is only recommended when there is complete remission of the disease.⁶ Flares are associated with target organ damage, such as kidney damage (lupus nephritis)¹⁴

Management of the reproductive problems associated with lupus

Fertility problems

Counseling the patient on the reproductive implications of lupus is crucial. Addressing the psychosocial concerns may also improve sexual health and increase the chances of conception in heterosexual couples. Infertility can be a painful source of grief, so seeking support is essential. 

Assisted reproductive techniques can also be employed, which include:

• Intrauterine insemination (IUI)
• In vitro fertilisation (IVF)
• Fertility preservation in patients receiving cyclophosphamide by freezing egg and sperm
• The use of a donor egg or sperm in patients with ovarian failure and/or sperm problems
• Surrogacy may also be considered for patients with unremitting disease⁸

Pregnancy

People assigned females at birth should avoid pregnancy when lupus is active, especially in the presence of active lupus nephritis (lupus with kidney involvement).

To ensure a safe pregnancy, there is a need for preconception counselling.

Preconception counselling

This involves counselling on the need to:

• To get pregnant only when the disease is in remission
• The risk of harm to the baby from the disease and the medications 
• Discontinue some of the drugs, a few months before conception
• Eliminate drugs that cause harm to the pregnancy
• Frequent monitoring of pregnancy
• Be on effective contraception until the disease goes into remission. 

Managing the pregnancy

Pregnancy in the presence of lupus is high risk. A rheumatologist, an obstetrician experienced with high-risk care, and a doctor should be involved in your care.

Low-dose aspirin and low molecular weight heparin may be prescribed to reduce the risk of preeclampsia, blood clots, and miscarriages.

Drugs used to treat SLE, such as prednisolone, azathioprine, hydroxychloroquine, and low-dose aspirin are safe for use in pregnancy. However, drugs like mycophenolate mofetil, cyclophosphamide, and methotrexate are not recommended during pregnancy because of the risk of harm to the baby.

Breastfeeding and post-delivery period

Patients can breast/chest feed if they are not on methotrexate, azathioprine, cyclophosphamide, or mycophenolate. Hydroxychloroquine is also secreted in breast milk, so should be used with caution. There is a risk of flare-ups during the post-delivery period so the patients should be closely monitored.

Summary

The survival rate for lupus has improved because of improved detection and management. However, lupus can have significant effects on reproductive health. A multidisciplinary approach to management is crucial to mitigate the risks, but individuals with lupus may need assisted reproductive technology (ART) if they wish to conceive, and may require additional care during pregnancy.