This study provides a comparison of the etiology and perinatal outcomes of fetuses diagnosed with NIHF. This is the first study known in the literature on the etiology and perinatal outcomes of early and late-onset NIHF. The most important finding of this study was that the fetuses diagnosed with early-onset NIHF were also born early, that is, in the first 24 weeks. In addition, live birth rates were higher in fetuses diagnosed with late-stage NIHF.
In a meta-analysis of 6361 patients, cardiovascular disease (21.7%) and chromosomal abnormalities (13.4%) were reported as the most common abnormalities in NIHF patients [2]. According to a recent study, the etiology was unknown in 46% (30/65), suspected in 9.2% (6/65), and confirmed in 44.6% (29/65). Of the confirmed cases, 11 resulted from aneuploidy, seven from fetal structural abnormalities, 2 each from fetal arrhythmias, Noonan syndrome, generalized lymphocytic dysplasia, and one from arthrogryposis, parvovirus, neonatal alloimmune thrombocytopenia, fetal goiter, and Kasabach-Merritt syndrome [10]. In our study, similar to the literature, these were the most common anomaly groups. Although the most common anomaly groups in our study were identical to those in the literature, there was no statistically significant difference between these groups in terms of early and late onset of NIHF (Table 2).
According to a retrospective study, the mean week of diagnosis of patients referred with a diagnosis of NIHF was 29.1 ± 4.4, whereas the mean week of delivery of live fetuses was 34.3 ± 2.7 [11]. However, all patients included in this study were those diagnosed with hydrops in the third trimester. According to another study, 31.7% of patients diagnosed with NIHF were born before 32 weeks of gestation, and 9.4% were born below 28 weeks, and 77.7% of NIHF pregnancies were associated with preterm birth [12]. However, in these two studies, the week in which patients were diagnosed with NIHF was not reported. 66.7% of NIHF cases with early onset were born under 24 weeks, and 50% of NIHF cases with late onset were born after 37 weeks (Table 2). Our study differs from the literature in this regard.
According to one study, 33.3% of patients diagnosed with NIHF in the previous pregnancy also developed NIHF in the subsequent pregnancy, and 36% of them were diagnosed with lysosomal storage disease [13]. In our study, 16.7% of our patients confirmed that NIHF had complicated their previous pregnancies. Although not statistically significant, the fact that patients with a history of hydrops had more late-stage NIHF than early-stage NIHF could be due to late hospitalization because of problems with previous pregnancies. Future screening of these recurrent NIHF cases for lysosomal storage disorders may be useful.
The consanguinity rate in our country was reported to be 8.4% [14]. Because a high risk of developing autosomal recessive genetic diseases is associated with consanguineous ancestry, screening for NIHF cases is essential. In our study, seven patients (15.2%) had a consanguineous ancestry. We believe that consanguineous ancestry is necessary for the pathophysiology of NIHF and should be questioned.
The prognosis of NIHF depends on the underlying etiology, gestational and birth week, and neonatal status. Even in the absence of chromosomal abnormality, survival rates of less than 50% have been reported in the literature [15, 16]. In our study, the neonatal mortality rate was low compared to the literature [17]. However, intrauterine mortality was still higher, supporting the "all or nothing" rule in first trimester obstetric practice [18].
Our study has some limitations. First, our study is a case-control study with a limited number of patients rather than a prospective study. Most patients did not give consent for invasive prenatal testing. It is difficult to confirm the diagnosis of hydrops in fetuses from terminated pregnancies. Because none of the parents consented to autopsy and postpartum genetic testing, we had to limit our diagnosis and confirmation of abnormalities to ultrasonography. In a study of tauopathies in hydrops patients, new-generation rasopathy genes were found in 56% of 26 patients with hydrops fetalis. It has been reported that testing these genes is beneficial in such patients [19]. However, in our country, these genes cannot yet be studied in the perinatal period.
Consequently, fetuses diagnosed with NIHF at an early stage may have a more severe course. Although there is no significant difference in etiology between trimesters, cardiac abnormalities should be more common in patients with late-onset NIHF. The high intrauterine mortality rate suggests that further studies and new genetic testing are needed to improve treatment and prognosis.