Abstract

A major source of anxiety for women with systemic autoimmune diseases (SADs) who wish to become pregnant is the possible impact of maternal disease and medications on the offspring, in terms of physical and mental development. A recent multicenter survey conducted in 24 Italian Rheumatology Centers showed that more than 50% women affected by SADs restricted their family size mainly because they were afraid that children could get an autoimmune disease or could be harmed by intrauterine exposure to maternal autoantibodies and anti-rheumatic drugs (Dall'Ara, ACR abstract, Arthritis Rheumatol 2016; 68, suppl 10). Therefore, the long-term follow-up children born to mothers with SADs is a topic of major relevance for the counselling on family planning.

First of all, it should be emphasized that preterm birth and other foetal complications, such as low birth weight and babies small for gestational age, are more common in patients with systemic autoimmune diseases as compared to the general population. These conditions carry themselves an increased risk for poorer physical and neuropsychiatric development. Therefore, the prevention of foetal complications should be operated by means of close obstetrical monitoring and tight control of maternal disease activity, which would be detrimental for foetal wellbeing. In this context, the use of “safe” anti-rheumatic drugs is of paramount importance for pregnant women with SADs.

Recently, a dedicated EULAR Task Force has released points to consider for the use of anti-rheumatic drugs during pregnancy and lactation (Gotestam Skorpen, Ann Rheum Dis 2016). The work of this Task Force was focused on updating the information about the use of “conventional synthetic” (cs) DMARDs but also to provide for the first time evidence-base indications on the use of “biologic” (b) DMARDs, mainly anti-TNFalfa agents.

No significant impairment in the maturation and functioning of the child's immune system has been observed for several csDMARDs, supporting their safety of use during pregnancy (Andreoli, J Autoimm 2012).

Turning to bDMARDs, a case-control study on the long-term follow-up of children exposed in utero to anti-TNFalfa drugs showed the safety of use either until the positive pregnancy index or during the second and third trimester of gestation (Dall'Ara, EULAR abstract, Ann Rheum Dis 2016; 75, Suppl 2:493). No differences between exposed and non-exposed children were found in terms of congenital defects, developmental milestones, response to vaccinations and major health problems. No particular problems were also observed in children who were breastfed while maternal anti-TNFalfa intake. The use of anti-TNFalfa agents during breastfeeding had been proposed to women who were strongly motivated based on the following considerations: 1) these drugs are poorly or absolutely not excreted into breast milk as recently demonstrated for certolizumab pegol (Clowse, ACR abstract, Arthritis Rheumatol 2016; 68, suppl 10); 2) even this was the case, the drug will be degraded in the baby's gastrointestinal tract and absorption could not be possible.

Regarding maternal disease, major concerns are linked to fetal exposure to maternal autoantibodies, mainly anti-Ro/SSA (for the development of Neonatal Lupus) and antiphospholipid antibodies (aPL). Therefore, the evaluation of these autoantibodies with potential negative impact on pregnancy and neonatal outcome should be part of the preconception work-up of women with SADs in order to provide adequate counselling and preventative strategies (Andreoli, Ann Rheum Dis 2017).

The transplacental passage of maternal aPL does not generally produce any thrombotic complication in the neonate. The registry of infants born to mothers with APS, started by the European Forum on aPL in 2003, is collecting precious information for the assessment of neonatal outcome and subsequent development. The exposure to maternal aPL was linked to learning disabilities (LD) in children born to both mothers with SLE and with APS, based on the experimental observation that aPL can affect neural cells functioning. A recent study on the long-term neurodevelopment of children exposed in utero to aPL was reassuring for a normal neurological functioning and intelligence level, but found a higher rate of LD as compared to the general population (19% vs 3%) (Nalli, Lupus 2017). These affected children were all born at term to triple aPL positive mothers.

Although systemic autoimmune diseases are not hereditary, newborns may receive from the mother a genetic background that may predispose to the emergence of autoimmunity and, possibly, of related symptoms. However, the incidence of autoimmune diseases in the offspring was rather low (1%) among 269 children with a mean age of 15 years collected in the previously cited survey of Italian Rheumatology Centers.