Connective tissue diseases in pregnancy

What is connective tissue disease?

Connective tissue is the structure that holds the body together and is composed largely of collagen and elastin. Connective tissue disorders are classified into a number of groups.

For women with autoimmune diseases, the course of pregnancy is highly variable. Some autoimmune diseases tend to improve during pregnancy and do not to result in any serious obstetric complications. Others may worsen during pregnancy, with deterioration of the maternal condition as well as obstetric and perinatal complications. In systemic lupus erythematosus, placental transfer of specific autoantibodies may cause fetal or neonatal disease.¹

• Hereditary connective tissue disorders (HCTDs) includes such diseases as Ehlers-Danlos syndrome, Marfan's syndrome and pseudoxanthoma elasticum (PXE).

• Mixed connective tissue disease (MCTD):
  

  • This was initially considered as an overlap or combination of systemic lupus erythematosus (SLE), scleroderma, and polymyositis.

  • Patients have features of each of these three diseases. Typically, they also have very high titres of antinuclear antibodies (ANAs) and antibodies to ribonucleoprotein (anti-RNP).

  • Often the disease evolves to become dominated by features of one of the three component illnesses, most commonly the scleroderma features.

• Unclassified connective tissue disorders (UCTDs) means that there may be some features of connective tissue disorders such as ANA or perhaps features of three different diseases and it is not possible to classify to a specific disease. Follow-up of UCTD shows conversion to a specific disease in about 20%.

The hereditary forms tend to manifest fairly early in life. They are not often apparent at birth but are usually diagnosed before the advent of reproduction. The autoimmune forms tend to present after the reproductive years but it is not at all uncommon for them to present before middle age. Reproductive problems may be the presenting feature.

Pre-conception counselling should be conducted routinely, with the goal of planning for pregnancies during periods of disease quiescence in order to optimise maternal and fetal outcomes.

During pregnancy and the postpartum period, frequent monitoring by a multidisciplinary team is imperative.

Active disease may be more detrimental to the fetus than potential side effects of medications. Therefore, medications necessary for disease control and that are deemed compatible with pregnancy should not be withheld.²

How common are connective tissue diseases? (Epidemiology)

• The HCTDs are usually inherited in a typical Mendelian form as autosomal dominant. Males and females are equally affected.

• The autoimmune diseases are acquired rather than inherited but they do tend to run in families. The exact aetiology is uncertain but if there is an external trigger, it would appear that a genetic predisposition is involved.

Pregnancy in hereditary connective tissue disorders

• For the hereditary forms, genetic counselling is important, ideally before the woman becomes pregnant.

Ehlers-Danlos syndrome

The risk varies considerably according to the type of the condition:

• Obstetric complications include risk of uterine rupture during labour, damage to the vagina and perineum, bleeding and rupture of blood vessels and the colon during the puerperium.³

• In type IV there is a risk for severe bleeding and vessel rupture associated with pregnancy.⁴

• A Shirodkar's suture may be required to treat cervical incompetence.

• Generally Ehlers-Danlos syndrome is well tolerated in pregnancy except for type IV.

Marfan's syndrome

• The major risk for women with Marfan's syndrome is aortic dissection in pregnancy. Family history may indicate the level of this risk but echocardiography to assess the aortic root in pregnancy should be used.

• Aortic dissection is not the only problem and a multidisciplinary approach is recommended.⁵

• Surgery may be required before embarking on pregnancy. Aortic repair can be performed during pregnancy.

• Beta-blockers may be protective although they are associated with the risk of low birth-weight babies.⁶

Pseudoxanthoma elasticum (PXE)

• PXE is characterised by degeneration of elastic tissue. Clinically, its effects are most readily noted in the skin, retina, blood vessels, and myocardium.

• It is not associated with particularly increased fetal loss or adverse outcomes. A few pregnancies are associated with worsening of skin manifestations.⁷

• The incidence of gastric bleeding is probably higher than in the unaffected population.

• Retinal complications are uncommon.

Pregnancy in autoimmune connective tissue disorders

As well as any effects caused directly by the connective tissue disorder, the woman may be taking drugs for the condition and these may be teratogenic - eg, methotrexate which induces abortion. The relative risks and benefits of the various drugs in pregnancy need to be carefully weighed.

Fetal loss

• The risk of fetal loss is much higher than in the general population and this is particularly marked in those with SLE or a component of the disease in their connective tissue disease disorder.

• The highest risk of all comes with those with antiphospholipid antibodies, and the problem of pregnancy is discussed in the separate article on Antiphospholipid Syndrome. Not only is there a high incidence of miscarriage in the first trimester, but there is a significant risk of intrauterine death in the second and third trimesters.

In women with SLE the acronym 'PATH' represents:

• Proteinuria.

• Antiphospholipid syndrome.

• Thrombocytopenia.

• Hypertension early in pregnancy.

All of these are serious risk factors for adverse pregnancy outcomes.⁸

Pregnancy in patients with rheumatoid arthritis

Rheumatoid arthritis (RA) is relatively common in women of reproductive age. Women with RA have impaired fertility resulting from the use of certain medications and active disease. RA usually improves during pregnancy, however almost half of the patients still have active disease in the 3rd trimester. Pregnancy outcomes are slightly less favourable, especially in women with high disease activity. Managing RA during pregnancy is challenging, because treatment options are limited.⁹

Pregnancy in patients with systemic lupus erythematosus

In pregnant women with SLE who have inactive or stable mild/moderate disease, severe flares are infrequent and, in the absence of specific risk factors, outcomes are favourable. In severe SLE, pregnancy should be delayed until the disease is better controlled.¹⁰

See also the separate article on Systemic Lupus Erythematosus.

Effects on fertility and obstetric complications

• Women with rheumatoid arthritis (RA) have fewer children than average but this appears to be a combination of impaired fertility and a conscious decision related to the difficulty of rearing children, with the limitations of the disease.¹¹

• A survey of American women with SLE and RA found that:¹²

  • Hypertensive disorders of pregnancy occurred in 23.2% of those with SLE and 11.1% of those with RA compared with 7.8% of the general population.

  • They tended to have more caesarean sections and longer stays in hospital.

  • They also tended to be older than the general population having babies but this did not account for the difference.