Connective Tissue Diseases in Pregnancy

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. The significance of pregnancy varies considerably according to the type of the disease:

• Hereditary connective tissue disorders (HCTD) includes such diseases as Ehlers-Danlos syndrome, Marfan's syndrome and pseudoxanthoma elasticum.
• Mixed connective tissue disease (MCTD):
  • Was first described in 1972,¹ and was considered as an overlap or combination of systemic lupus erythematosus, scleroderma, and polymyositis.
  • Patients have features of each of these 3 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 (UCTD) means that there may be some features of connective tissue disorders such as antinuclear antibody or perhaps features of 3 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.

• The hereditary connective tissue diseases are usually inherited in a typical Mendelian form as an 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.
• The conditions are commoner in women.

• 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.²
• In type IV there is a risk for severe bleeding associated with pregnancy.³
• In type II a Shirodkar suture may be required to treat cervical incompetence.⁴
• Type III does not seem to be a particular risk.⁵
• Generally Ehlers-Danlos syndrome is well tolerated in pregnancy except in type IV.⁶

Marfan's syndrome

• The major risk 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.⁷
• Aortic dissection is not the only problem and a multidisciplinary approach is recommended.⁸
• 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.⁹

Pseudoxanthoma elasticum (PXE)

• This disease is characterised by degeneration of elastic tissue. Clinically, its effects are most readily noted in the skin, retina, blood vessels, and myocardium.
• A review states that several hundred patients with this condition which usually appears during the early part of the reproductive years, have been reported.¹⁰ Fertility is unaffected.
• Another review from 21 years later found that fetal outcome was not adversely affected and that the risk of gastric bleeding was overstated.¹¹

• 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, e.g. methotrexate which induces abortion.
• The relative risks and benefits of the various drugs in pregnancy needs 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 systemic lupus erythematosus (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 article on antiphospholipid syndrome (APS). 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.

Obstetric conditions

Obstetric complications associated with connective tissue disorders include:

• Pre-eclampsia
• Intrauterine growth retardation
• Abnormal fetal heart rate tracings
• Preterm delivery
• Miscarriage

Medical conditions

Medical problems associated with antiphospholipid antibodies may be an additional problem in pregnancy:

• Arterial thrombosis and venous thrombosis
• Autoimmune thrombocytopenia
• Autoimmune haemolytic anaemia
• Livedo reticularis
• Chorea
• Pulmonary hypertension
• Chronic leg ulcers

The International Consensus Workshop in 1998 proposed a preliminary classification criteria for APS that included the following obstetric component:

• 3 or more unexplained consecutive miscarriages with anatomical, genetic, or hormonal causes excluded .
• 1 or more unexplained deaths of a morphologically normal fetus at or after the 10th week of gestation.
• 1 or more premature births of a morphologically normal neonate at or before the 34th week of gestation associated with severe preeclampsia or severe placental insufficiency.

In women with SLE, the acronym PATH represents Proteinuria, Antiphospholipid syndrome, Thrombocytopenia, and Hypertension early in pregnancy, all of which are serious risk factors.¹²

• Fertility is normal and pregnancy is safe in mild or stable lupus. In severe lupus, pregnancy should be delayed until the disease is better controlled.
• Morbidity in pregnancy is common, especially if the woman has antiphospholipid antibodies.
• Complications include recurrent early loss of pregnancy, pre-eclampsia, intrauterine growth retardation and preterm delivery. Women are at increased risk of thrombosis, especially in the puerperium.
• The risks of pregnancy are greatly increased in the presence of lupus nephritis, hypertension and active disease, especially at the time of conception.¹³
• Pre-existing renal disease may worsen in pregnancy and hypertension may be difficult to control.

• A review of 82 consecutive pregnancies in 54 women with antiphospholipid syndrome compared those who were treated during pregnancy with:¹⁴
  • Prednisone and low-dose aspirin
  • Heparin and low-dose aspirin
  • Prednisone, heparin, and low-dose aspirin
  • Other combinations of these medications or immunoglobulin.
• The overall neonatal survival rate was 73%, excluding spontaneous abortions, but treatment failures, meaning fetal and neonatal deaths occurred in all treatment groups.
• Patients with successfully treated pregnancies had fewer previous fetal deaths than those with unsuccessful treated pregnancies.
• There were no significant differences in outcome among the four treatment groups.
• Pre-eclampsia and fetal distress occurred in half of all pregnancies, and intrauterine growth retardation occurred in nearly one-third.
• Preterm delivery due to maternal or fetal indications was required in 37% of the pregnancies.
• Four pregnancies were also complicated by postpartum thrombosis during treatment.
• The study concluded that pregnancy in women with antiphospholipid syndrome appears to be improved by treatment, but fetal loss may occur despite treatment. Pre-eclampsia, fetal distress, fetal growth impairment, and premature delivery are common. Because of the clinically significant risk of thrombotic episodes, thrombosis prophylaxis should be considered in these patients.
• Another study compared outcomes of treatment with low dose aspirin alone and heparin with low dose aspirin.¹⁵ Viable infants were delivered in 44% of the women treated with aspirin and 80% of the women treated with heparin and aspirin.
• Another study compared women who were given low dose aspirin plus heparin and those who received low does aspirin plus heparin plus 40 mg daily of prednisolone. Those receiving prednisolone fared significantly worse.¹⁶

• Women with rheumatoid arthritis have fewer children than average but this appears to be a conscious decision related to the difficulty of rearing children with the limitations of the disease rather than problems of fecundity.¹⁷
• However, a survey of American women with SLE and RA found that 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.¹⁸
• In women with stable SLE, the use of oral contraceptives does not increase the risk of flare-up.¹⁹