Incidence of HDFN during pregnancy was stable in Israel at an incidence rate ranging between 0.4-1 per 10,000 pregnancies during most of the study period. The incidence of HDFN diagnosed in newborns is higher compared to the incidence of HDFN diagnosed during pregnancy and has declined from 1.8 (95% CI 0.9–3.4) in 1998 to 1.1 (95% CI 0.4–2.5) in 2021 per 10,000 newborns (p < 0.001, Fig. 1).
A total of 76 pregnancies with an HDFN diagnosis were identified in 70 women, 73 (96%) of them with medical information regarding their pregnancy course and outcome. Alloantibodies were confirmed in 27 women during or before 28 pregnancies, representing 38.4% of all HDFN pregnancies (Fig. 2).
During the same 24-year study period, 395 additional newborns, who had not been identified during pregnancy because their mothers were not diagnosed during pregnancy (72%) or because their mothers were not included in the MHS database, were diagnosed postnatally with HDFN. Out of the 57 newborns born to HDFN diagnosed mothers, 55 were found in the MHS database and added to the HDFN newborn cohort. Therefore, in total, 450 HDFN newborns were identified and confirmed to have HDFN during their first year of life. Of the 450 HDFN newborns, 66 (14.7%) were confirmed to have HDFN during their first year of life based om maternal alloimmunization (Fig. 2).
Pregnancy and prenatal outcomes of HDFN
The average maternal age of 73 women diagnosed with HDFN at the time of diagnosis was 31.4+-5.8 years old. Frequency of comorbidities were low and included diabetes (2.7%), cardiovascular disease (4.1%) and hypertension (6.8%). The majority (54.8%) of women had never smoked. (Supplementary Table 3).
The average gravidity at which HDFN was diagnosed among the 73 pregnancies was 3.4 +- 1.8, diagnosis tended to occur during the fourth pregnancy (41.1%). HDFN was diagnosed at an average of 23.4 +- 9.3 weeks of gestation. Late onset (diagnosed after 24 weeks of gestation) HDFN was diagnosed in 38 (52.1%) pregnancies. Three pregnancies were treated with IVIg; two required at least one IUT following IVIg. Twelve additional pregnancies not treated with IVIg required at least one IUT. Hydrops was diagnosed in 8 pregnancies (Table 1). Of the 73 pregnancies with a diagnosis of HDFN, 22 were severe i.e., 14 were treated by intrauterine transfusion, 8 were diagnosed with fetal hydrops, 6 were induced pre-term and 1 resulted in an intrauterine death. The average gestational age (GA) of severe HDFN diagnosis was 24.5 +- 8.0 weeks (Table 1). The majority of cases of severe HDFN in pregnancy required at least one IUT (14, 63.6%).
Table 1 Pregnancy characteristics and outcomes of prenatal diagnosed HDFN
|
Mean +- SD/ N (%)
|
Pregnancy cohort
|
Alloantibody confirmed pregnancy cohort
|
Parameter
|
Procedure/
|
Total N=73
|
Severe N=22
|
Total N=28
|
Severe N=11
|
Category
|
Pregnancy Characteristics
|
GA at HDFN diagnosis
|
|
23.4 +- 9.3
|
24.5 +-8.0
|
23.9 +-9.5
|
24.5 +-6.6
|
Gravidity
|
|
3.4 +-1.8
|
4.1 +-1.9
|
4.1 +-1.5
|
4.7 +-1.6
|
Pregnancy number category at diagnosis
|
1
|
12 (16.4)
|
2 (9.1)
|
1 (3.6)
|
0
|
2
|
9 (12.3)
|
2 (9.1)
|
1 (3.6)
|
0
|
3
|
12 (16.4)
|
2 (9.1)
|
8 (28.6)
|
2 (18.2)
|
4+
|
30 (41.1)
|
12 (54.5)
|
17 (60.7)
|
9 (81.8)
|
Unknown
|
10 (13.7)
|
4 (18.2)
|
1 (9.1)
|
0
|
Twins
|
|
2 (2.7)
|
0
|
0
|
0
|
Late onset HDFN at 24 GA or later
|
|
38 (52.1)
|
12 (54.5)
|
17 (60.7)
|
6 (54.5)
|
Any IVIg
|
|
3 (4.1)
|
2 (9.1)
|
2 (7.1)
|
2 (18.2)
|
Any Intrauterine transfusion
|
|
14 (19.2)
|
14 (63.6)
|
9 (32.1)
|
9 (81.8)
|
Hydrops
|
|
8 (11.0)
|
8 (36.4)
|
2 (7.1)
|
2 (18.2)
|
Pregnancy Outcomes
|
Outcome
|
Live Birth
|
57 (78.1)
|
16 (72.7)
|
24 (85.7)
|
9 (81.8)
|
Miscarriage
|
9 (12.3)
|
6 (27.3)
|
3 (10.7)
|
2 (18.2)
|
Unknown
|
7 (9.6)
|
0
|
1 (3.6)
|
0
|
GA at delivery
|
|
37.6 +-3.1
|
34.9 +- 3.2
|
36.2 +-2.8
|
34.9 +-2.9
|
GA at miscarriage
|
|
18.2 +- 7.0
|
19.9 +- 6.9
|
13.9 +-9.6
|
20.7*
|
Birthweight (g)
|
|
2964.2 +- 710.9
|
2464.8 +- 560.5
|
2750.9 +-687.5
|
2702.3 +-747.8
|
Type of miscarriage
|
IUFD
|
1 (11.1)
|
1 (16.7)
|
0
|
0
|
Spontaneous
|
2 (22.2)
|
0
|
1 (33.3)
|
0
|
Induced
|
6 (66.7)
|
5 (83.3)
|
2 (66.7)
|
2 (100.0)
|
Induced preterm labor
|
|
6 (31.6)
|
6 (46.2)
|
5 (33.3)
|
5 (71.4)
|
Preterm labor
|
|
19 (33.3)
|
13 (81.3)
|
15 (62.5)
|
7 (77.8)
|
Preterm Category
|
Extreme preterm (<28 GA)
|
0
|
0
|
0
|
0
|
Very preterm (28-31+6 GA)
|
3 (15.8)
|
3 (23.1)
|
2 (13.3)
|
2 (28.6)
|
Moderate preterm (32-33+6 GA)
|
3 (15.8)
|
1 (7.7)
|
2 (13.3)
|
0
|
Late preterm (34-36+6 GA)
|
13 (68.4)
|
9 (69.2)
|
11 (73.3)
|
5 (71.4)
|
GA - gestational age; late onset defined as onset after 24 weeks of gestation
Among the subgroup of 28 pregnancies in the alloantibody confirmed cohort (N = 28), the average gravidity at which a woman was diagnosed with HDFN was 4.1+-1.5 and the majority (60.7%) were late onset HDFN. Eleven of these pregnancies were severe. A total of 9 pregnancies (32.1%) required at least one IUT. Two of the pregnancies were administered IVIg and both did require at least one IUT. Hydrops was diagnosed in two pregnancies. No cases of intrauterine death were reported.
Among the 73 pregnancies with HDFN, 57 (78.1%) resulted in live births, 9 in miscarriages and 7 had unknown outcomes. Of the 57 live births, 19 (33%) were preterm of which 6 were induced. The majority of these were late preterm (68.4%). Overall, the average birthweight was 2964.2+-710.9 grams (Table 1). Miscarriages included 1 intrauterine death at 28 gestational age (GA), 6 induced terminations of pregnancy at 15.8 GA (± 7.2) on average and 2 spontaneous miscarriages at 19.4 GA (± 3.7).
Pregnancy outcomes in 22 severe HDFN pregnancies included 16 (72.7%) live births; 13 (81.3%) of these were preterm. Of the preterm births, 3 were very preterm between 28–32 weeks of gestation, 1 moderate preterm between 32–34 weeks of gestation and 9 late preterm between 34–37 weeks of gestation. Of the remaining six cases of severe HDFN, there were 5 induced miscarriages and 1 intrauterine fetal death (IUFD). Out of the 7 preterm deliveries among the severe HDFN alloantibody confirmed pregnancies, 5 were induced labors. Characteristics and outcomes of early and late onset HDFN pregnancies are presented in Supplementary Tables 4 and 5.
Among the subgroup of 28 alloantibody confirmed pregnancies, 24 (85.7%) resulted in live births, 2 induced abortions (1 at 20.7 GA and 1 at unknown GA), 1 spontaneous miscarriage at 7.1 GA and 1 unknown outcome. Of the 24 live births, 15 (62.5%) occurred preterm, most of which were late preterm (73.3%), and average birthweight was 2750.9 +-687.5 grams (Table 1).
The pregnancy cohort included 3 women each with 2 HDFN pregnancies in the study period. Pregnancy characteristics and outcomes for both pregnancies are presented in Supplementary Table 6. One woman delivered in both pregnancies, one woman delivered in the first pregnancy and had an induced miscarriage in the second pregnancy and one woman spontaneously miscarried in the first pregnancy and delivered very preterm in the second. There were no cases of hydrops or IUFD.
Postnatal outcomes of HDFN newborns
The median age at diagnosis of the 395 newborns diagnosed only postnatally was 2.7 weeks (IQR 0.7–5.7). The majority (58.2%) of all 450 HDFN newborns, including 55 born from HDFN pregnancies, were male.
Anemia and jaundice were the most common complications of HDFN during the first year of life. Both complications were diagnosed in over 30% of the full newborn cohort. Twelve percent of the newborn cohort (n = 54) had developmental disorders. Other complications included edema (5.1%), auditory dysfunction (3.3%), blood disorders (2.7%) and kernicterus (1.1%) as depicted in Table 2. Anemia was diagnosed in 63.6% and jaundice in 19.7% of the subgroup of the alloantibody confirmed newborn cohort; kernicterus was observed in 4 newborns (6.1%), edema in 4.5% and development disorders in 3.0%. Almost one third of alloantibody confirmed newborns underwent blood transfusions (31.8%) and 10.6% underwent phototherapy.
Table 2
Complications reported in newborns diagnosed postnatally with HDFN
Complication
|
Newborn cohort N = 450
|
Alloantibody confirmed newborn cohort N = 66
|
|
N (%)
|
Age at diagnosis (months)/
Mean +- SD
|
N (%)
|
Age at diagnosis (months)/
Mean +- SD
|
Anemia
|
158 (35.1)
|
1.9 +-2.4
|
42 (63.6)
|
1.6 +-2.2
|
Auditory Dysfunction/Deafness
|
15 (3.3)
|
3.8 +-3.5
|
0
|
NA
|
Development Disorder
|
54 (12.0)
|
6.5 +-3.3
|
2 (3.0)
|
3.6+-0.9
|
Edema
|
23 (5.1)
|
6.8 +-2.9
|
3 (4.5)
|
9.1 +-0.9
|
Jaundice
|
154 (34.2)
|
0.8 +-1.4
|
18 (27.3)
|
0.6 +-0.5
|
Kernicterus
|
5 (1.1)
|
0.2 +-0.1
|
4 (6.1)
|
0.3 +-0.1
|
Movement Disorder
|
1 (0.2)
|
7.3
|
0
|
NA
|
Oculomotor Impairments
|
4 (0.9)
|
5.9 +-4.1
|
0
|
NA
|
Blood Disorder (acidosis, calcemia)
|
12 (2.7)
|
1.9 +-2.0
|
0
|
NA
|
Other Blood Disorder (transient neonatal neutropenia)
|
13 (2.9)
|
3.4 +-3.8
|
1
|
0.2
|
Of the 450 newborns, 29% and 37% of newborns had complete blood count (CBC) results between 2–3 months of age and 10–12 months of age, respectively. Among the alloantibody confirmed newborns, CBC results were available for 40% of newborns up to 1 month old as well as in 10–12 month olds. Laboratory test results were comparable between the full newborn cohort and the alloantibody confirmed cohort (Supplementary tables 7,8). Mean hemoglobin and hematocrit values were low during the first 3 months of life; however, the mean values rose to normal levels by the age of one year (Supplementary Fig. 1).