Our study of pregnancy and delivery outcomes among women with Fabry disease showed an increase of pain burden during pregnancy in women with moderate pain before pregnancy. The risk for miscarriage was not increased in Fabry disease. Preeclampsia occurred more frequently and neonates were more often preterm, had a lower birth weight, and were more commonly small for gestational age as compared to global data and the general population in Austria, respectively.

In a recent study from Spain, 83.5% of women showed signs and symptoms of Fabry disease, which compares well to the present cohort of 44 women of whom 86.4% reported Fabry disease related symptoms [11]. In our study, acroparesthesia, pain, and gastrointestinal symptoms were the most common disease manifestations. This did not differ between 32 women with a history of pregnancies as compared to 12 women without pregnancies. However, women with a history of pregnancy were older and presented more frequently with other signs and symptoms as outlined in Table 4. Thus, age is likely associated with both, the symptoms and the likelihood of having had a pregnancy.

Forty-three percent of all 44 women in our study received Fabry disease therapy with enzyme replacement or a chaperone. This observation is very similar to the 34% of treated patients in the Spanish study and analogical points to a shortfall of specific therapy in women with Fabry disease [11]. Only two patients received enzyme replacement therapy during pregnancy in our study. Regarding treatment during pregnancy the SmPC of agalsidase beta points out that agalsidase beta must not be used during pregnancy unless clearly necessary. In case of agalsidase alfa the SmPC mentions that only very limited data are available on agalsidase alfa-exposed pregnant women. For the use during pregnancy caution is advised. There is no clear recommendation for treatment during pregnancy with enzyme replacement therapy. At this point, it is worth mentioning that chaperone therapy is not licensed for use in pregnancy [12].

Only one previous study reported Fabry disease-related symptoms during pregnancy. Among these, acroparesthesia was reported in 31.3% and headaches in 22.5% [4]. However, changes in pain burden during pregnancy were not ascertained in that study. In contrast, our study employed a pain scale that clearly showed an increase in pain burden during pregnancy, primarily in women with moderate pain before pregnancy, whereas women with no or low pain burden before pregnancy did not experience a substantial change in pain during pregnancy.

The main maternal risk factors for poor pregnancy, delivery, and neonatal outcomes, still overrepresented in our cohort as compared to the general population, were hypertension, signs of chronic kidney disease, and smoking. These findings compare well with other cohorts of women with Fabry disease bearing children [3, 4].

Importantly, preeclampsia is a life-threatening disease of pregnancy and plays a decisive role in maternal and neonatal morbidity and mortality [13]. From a global perspective, the regional rates of preeclampsia vary between 1% and 5.6%, with 3.8% in the European region [10]. In our study, as well as in two other studies of Fabry disease, the prevalence of preeclampsia was 11.5% and 4.9% or 9.4%, respectively [3, 4]. Thus, the aforementioned studies emphasize a substantially increased risk for preeclampsia in Fabry disease.

Among pregnancy outcomes, the rate of successful pregnancies resulting in a live birth was 87.1% and the women enrolled in our study reported three induced abortions. Furthermore, the rate of miscarriages, 8.6% (n = 6), was similar to the study of Holmes and colleagues (11.8%) [4]. Contrary to the aforementioned studies, Bouwman et al. observed miscarriages in 25% of participants (not pregnancies) of their study. Through this, the rate of miscarriages of all pregnancies in this study remains elusive [3]. Notwithstanding, a recent study of the general population in Norway showed a miscarriage risk of around 10% in women aged 25–29, which rises rapidly after age 30, reaching 53% in women aged 45 and over [14]. Thus, we did not observe an overall increased risk of miscarriages in women with Fabry disease.

This first report on detailed delivery outcomes of pregnancies in women with Fabry disease disclosed a higher rate of preterm infants (20.3%) as compared to the Austrian population (7.3%). This is in line with the data provided by Holmes (18.5% of pregnancies) and Bouwman (19% of women) [3, 4]. In this context, a recent systematic review showed a preterm birth rate of 7.9% in developed countries in the year 2020 [15]. By way of contrast, the preterm birth rate in this analysis was highest in southern Asia (13.2%) [15]. Thus, prematurity in Fabry disease is even more frequent as compared to less developed countries and compares more or less to other hereditary disease such as complement mediated thrombotic microangiopathy [16].

The rate of C-sections was not different in women with Fabry disease as compared to the general population in Austria. Weight at birth of female and male infants was lower, with 20.3% of infants presenting with low birth weight and 28.1% of infants being small for gestational age compared to 9.3% of the Austrian population. Thus, it is tempting to speculate that Fabry disease manifestations of the mother, together with the consequences of glycosphingolipid deposits within multiple cell types of the placenta, cord, and membranes, are the culprits of the somewhat worse neonatal outcomes in Fabry disease [17].

Nevertheless, neonatal outcomes in our study were satisfactory. Follow-up of the offspring within this study showed 57.1% of genetically tested children harbouring an inherited variant in GLA. Among daughters and sons with Fabry disease, 29.4% (5 of 17) and 46.7% (7 of 15) received Fabry disease specific therapy by the end of this study.

The strengths of our study comprise the completeness of pregnancy and neonatal data accomplished by the Austrian Mother–Child Health Passport. Furthermore, data was also collected by structured personal interviews supported by a study-specific questionnaire. Of course, a recall bias regarding miscarriages and signs and symptoms of Fabry disease in previous pregnancies cannot be ruled out. Although the sample size is small, the results of this study in a rare disease should be considered generalizable to the population of patients with Fabry disease living in regions with advanced healthcare.