| Research background Hydrops fetalis is a clinical symptom of fetal edema and fluid accumulation in the body cavity as demonstrated by prenatal ultrasound.According to the etiology,it can be divided into two types: immune hydrops fetalis and non-immune hydrops fetalis.With the widespread use of anti-D immunoglobulin,the incidence of immune hydrops fetalis has decreased significantly.Non-immune hydrops fetalis is a disease with a complex etiology.Abnormalities in the fetal heart,skeletal structure,blood and lymphatic system,and genetic disorders can all lead to the incidence of non-immune hydrops fetalis,and often result in a poor maternal and fetal prognosis.The detection of hydrops fetalis etiology,especially fetal genetics,based on ultrasound presentation,is the main diagnostic and treatment step.Objective The clinical data of cases of non-immune hydrops fetalis consulted in the prenatal diagnosis center of our hospital in the past four years were collected and reviewed,and their prenatal ultrasound characteristics,etiological findings and pregnancy outcomes were summarized to explore the correlation between clinical characteristics of non-immune hydrops fetalis and its etiology and prognosis,as well as the value of the utilization of whole exome sequencing tests.Materials and Methods 1 Research object The clinical data of 74 pregnant women who diagnosed as non-immune hydrops fetalis in The University of Hong Kong-Shenzhen Hospital from January 1st 2019 to December 31 st 2022 were analyzed,and the pregnancy outcomes were followed up.2 Methods 2.1 Data Collection 2.1.1 History and non-genetic laboratory tests Maternal age,obstetric history,previous medical history,family history,comorbidity and complications during pregnancy,infection-related tests,Kleihauer-Betke test,etc.2.1.2 Prenatal ultrasound sonography Week of gestation of the first episode of oedema,ultrasound presentation of hydrops fetalis,other abnormal structures,ultrasound Doppler.2.1.3 Genetic testing Selected samples of chorionic villi,amniotic fluid,cord blood and umbilical cord are taken for genetic testing such as karyotyping,multiplex-linked probe amplification(MLPA),chromosomal microarray analysis(CMA)and whole exome sequencing(WES).2.2 Additional whole exome sequencing in selected cases For some cases of NIHF with negative fetal chromosome tests,additional Trio/proband whole exome sequencing was performed with the consent of the couple.2.3 Pregnancy outcome and follow-up Record the week of gestation and fetal abnormalities for those requesting termination of pregnancy,and for those requesting continuation of pregnancy,record their gestation period,perinatal conditions,maternal and fetal pregnancy outcomes,and follow up live births with telephone or clinic visits.Results A total of 74 pregnant women were included in this study,of whom 49(66.2%)were primiparous,25(33.8%)were multipara.The diagnosis was consistent with typical non-immune hydrops fetalis in 59 cases and atypical in 15(20.3%)cases.The earliest week of gestation at which the sonogram of fetal oedema was first detected by ultrasound was 12 weeks,the latest was 35 weeks and the average was 19.6 weeks.The most common site of hydrops was pleural effusion in 51 cases(51/74,68.9%),followed by oedema of the skin(44/74,59.5%),peritoneal effusion(31/74,41.9%)and pericardial effusion(18/74,24.3%),placental thickening in 4(4/74,5.4%)cases in mid and late pregnancy,and in 9(9/74,12.2%)case polyhydramnios.Twenty-nine(40.5%)cases of NIHF were combined with fetal structural and/or soft marker,21 of which were single and 8 of which were multiple.The most common structural anomalies were cardiovascular(18/29,62.1%),followed by limb and skeletal(9/29,31.0%),central nervous system(5/29,17.2%),facial(4/29,13.8%),gastrointestinal and abdominal wall(2/29,6.9%),thoracic(2/29,6.9%)and urinary(1/29,3.4%).The etiology of NIHF was evaluated in 57 cases,genetic etiology accounted for 57.9%(33/57)of the diagnoses of non-immune hydrops fetalis,including chromosomal abnormalities in 33.3%(19/57),rare monogenic gene diseases in 19.3%(11/57)and severer alpha thalassaemia in 5.3%(3/57).Only three case was a nongenetic etiology-fetal-maternal transfusion syndrome,intrauterine infection of syphilis and fetal arrhythmia,respectively.The proportion of genetical abnormalities in typical and atypical non-immune hydrops fetalis was 62.7%(32/51)and 16.7%(1/6)respectively,without statistically significant difference between the two comparisons.Of the 34 cases with normal chromosomal testing,22 cases were followed up with Trio-WES and 20 cases were found to be pathogenic/likely pathogenic gene;two cases of proband-WES and found likely pathogenic gene.The pathogenic/likely pathogenic gene are PIEZO1、MAGEL2、FOXP3、PQBP1、PTPN11、CHRND 、SETD5、EPHB4 and GUSB.The additional diagnostic rate for whole exome sequencing was 19.3%(11/57)and the positivity rate was 50%(11/22).Forty-six of the 74 cases were terminated of pregnancy or induced by stillbirth.28 cases were continued pregnancy,27 cases delivered in third trimester,and one not yet delivered,all without intrauterine intervention.The live birth rate of NIHF was 36.5%(27/74).Fourteen live births of typical NIHF were followed up,one case was lost to follow-up,3 of the remaining babies died within one year of age,and there was no adverse prognosis at short-term follow-up of the other ten live births.No pregnancy-related complications such as hypertensive disorders of pregnancy and mirror syndrome occurred in any of the pregnancies.Conclusions 1.The week of gestation at which antenatal ultrasound first detects hydrops fetalis is suggestive of the etiology of NIHF.2.WES is recommended in cases of NIHF that have normal chromosomal testing,it can obtain 19.3% etiological diagnosis rate.3.In cases of NIHF without genetic abnormalities or significant fetal structural abnormalities,the prognosis is better. |
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