Health Outcomes of 215 Mothers of Children With Autoimmune Congenital Heart Block: Analysis of the French Neonatal Lupus Syndrome Registry

DISCUSSION

We report short- and long-term data on maternal disease progression in 215 mothers of children with CHB after a median follow-up of 11 years (range: 21 days to 54 years). We found that 52 (24%) mothers had a diagnosis of autoimmune disease at CHB diagnosis (6 more were diagnosed with such a disease during the index pregnancy). This finding is important for making recommendations about CHB monitoring during subsequent pregnancies because, in the absence of generalized anti-SSA antibody screening, three-quarters of the women whose fetus will develop CHB will not have access to specific follow-up to detect it.¹⁹ This finding is consistent with a previous systematic review of the literature on underlying maternal autoimmune diseases. It included 856 mothers of children with CHB—greater than half were classified as asymptomatic carriers of anti-SSA and anti-SSB antibodies, with nearly 14% of cases classified as incomplete or undifferentiated autoimmune disease.¹

After a median follow-up of 11 years (range: 21 days to 54 yrs), 77 of the 157 (49%) mothers with no initial diagnosis of SAID had developed such a disease. The review by Brito-Zerón et al includes no data on this point.¹ Our results are consistent with the 2 largest studies on this topic, 1 from the US including 229 mothers of children with NLS⁶ and the other from Finland, covering 83 mothers of children with autoimmune CHB.¹² In these 2 studies, 25 of 51 (49.0%) and 10 of 23 (43.5%) mothers asymptomatic at enrollment remained asymptomatic after a mean follow-up of 4.1 years (range 0.5-9.0) and 9.6 years (range 0.0-21.0), respectively. The low number of asymptomatic mothers in the US study by Rivera et al might be explained by the frequency of the pauci-UCTD group, which the authors defined by the presence of up to 2 of the following symptoms: arthralgia, oral or nasal ulcers, photosensitivity, lymphopenia, RP, dry eyes or dry mouth, or parotid swelling.⁶

Our analysis of the 215 women included in our registry showed that 135 had a SAID at last follow-up: 72 had SS (33%) and 54 had SLE (25%). Maternal disease was severe in only 3 women (lupus nephritis [LN] and/or neurolupus) and required immunosuppressive drugs, mainly MTX, in 6. None had died from a SAID. The literature on the diagnoses of diseases developed after the birth of a child with CHB is sparse. The Finnish study reported that mothers of children with CHB had clinical and immunologic characteristics more closely related to primary SS than to SLE.¹² Thus only 9 had SLE (11%) whereas 33 (39.8%) had primary SS after a mean follow-up of 9.9 ± 9 years, and severe manifestations of the disease were rare.¹² In the US study, among 229 mothers, 70 had SLE at enrollment and 24 additional mothers had developed SLE at the end of follow-up. Only 4 had developed LN (class IV in 2, class II/III and class II in 1 each).⁶ Among these 24 women, 5 were initially asymptomatic, 12 had undifferentiated autoimmune syndrome, and 7 had SS.⁶ Eight women who developed SS were initially asymptomatic, 13 had undifferentiated autoimmune syndrome, and 2 had SLE.⁶ An asymptomatic mother had an 18.6% probability of developing SLE within 10 years, and a 27.9% probability of probable/definite SS⁶ compared with 12.7% and 28.1%, respectively, in our study. Of note, the influence of ethnicity on the phenotypic expression of SAIDs has previously been described, with less favorable outcomes in non-White populations, especially in SLE.^20-22 Thus, we could not rule out the possibility that SLE and SS phenotypes were less severe than in previous studies, given that non-White women accounted for only 37% of our cohort.

We found no statistically significant difference between mothers with anti-SSA/Ro only and those who also had anti-SSB antibodies in terms of risk of developing a SAID (32/63 [51%] vs 45/93 [48%], P = 0.77). In contrast, the US study reported that significantly more mothers with only anti-SSA/Ro remained asymptomatic or did not progress beyond pauci-UCTD, compared with mothers with both antibodies (24/27 [89%] vs 13/24 [54%], P = 0.01).⁶ We found that arthralgia and myalgia (P < 0.001), dry mouth and/or eye syndrome (P = 0.01), and parotid swelling (P = 0.05) best predicted the development of a SAID (Table 2). These symptoms were unsurprising given that this progression was mainly toward SS. Finally, while SLE used to be considered the key maternal autoimmune disease related to CHB onset,^23,24 we, like others, found that SS was more prevalent in our cohort.^6,12,24

The principal limitation of our study is its retrospective nature and the absence of a standardized evaluation of SAID. It is therefore possible that we missed some diagnoses. Most symptomatic patients had mild CTDs, and their classification as SLE, SS, and especially UCTD might have changed if they had undergone thorough investigations at each timepoint. In addition, comparison with the US study by Rivera et al is difficult because we chose to apply international classification criteria for CTDs, including UCTD, whereas they defined a group called “pauci-CTD”.⁶ It is also difficult to compare various studies from the literature, since some included isolated cutaneous NLS,⁶ while others included patients negative for anti-SSA or anti-SSB antibodies.⁹ To overcome this issue, we chose to describe a homogeneous and well-defined group (ie, high-degree CHB only and positive for anti-SSA antibodies). We recognize that this prevented us from analyzing non-CHB NLS cases, but these will be the subject of future studies. In addition, we cannot exclude an immortal person–time bias as a result of inclusion of follow-up time preceding enrollment for some women, nor the possibility that the estimates of autoimmune disease diagnoses in the mothers included in our cohort is inflated, because CHB cases may have been more frequently reported for women already followed for an autoimmune disease, and because women not lost to follow-up may be more likely to develop such a disease. Another limitation is that we did not have detailed information on when medications were introduced, especially HCQ in pauci-symptomatic women, as this could have affected the development of overt CTD. Finally, the specificity of anti-SSA antibodies was not always available and we could not analyze the respective effect of anti-SSA52 and anti-SSA60 antibodies.

In conclusion, one-quarter of the women had a diagnosis of SAID at diagnosis of fetal CHB. Nearly half of the mothers with no initial diagnosis progressed toward a SAID during follow-up, most developing only mild symptoms. SS was more frequent than SLE. Severe diseases such as LN were rarely seen, and immunosuppressive drugs were rarely required. These women should receive regular follow-up to monitor symptom onset. In addition, ocular and salivary gland function tests could be routinely performed, as with minor salivary gland biopsy when required.