Keywords
adverse perinatal outcomes - chronic maternal hypertension - HDFN - hemolytic disease
- neonatal jaundice - obstetrical care - preterm birth
Hemolytic disease of the fetus and newborn (HDFN) is a rare but serious condition
caused by maternal alloimmunization against fetal red blood cells during pregnancy.[1] In the United States, the prevalence of HDFN ranges from 3/100,000 to 80/100,000
pregnancies annually.[2] Although HDFN incidence is declining with the availability of RhD immunoglobulins
and the implementation of antibody screening programs,[3]
[4] HDFN continues to affect pregnancies in many developing nations and under-resourced
settings that do not have universal screening and/or infrastructures, such as laboratory
testing or advanced fetal monitoring systems, which are required to identify and manage
HDFN.[5]
[6]
[7]
Identification of HDFN during pregnancy is crucial so pregnant patients can be provided
with proper clinical management and treatment.[8] Without proper screening and treatment, maternal antibodies can attack fetal red
blood cells, leading to hemolysis and anemia. Therefore, severe HDFN cases can present
antenatally as severe anemia, resulting in hydrops fetalis, and postnatally as hyperbilirubinemia.[1] Potential risk factors associated with HDFN include advanced maternal age at delivery,[9] non-Hispanic White race/ethnicity,[10] and a history of HDFN in a previous pregnancy.[11]
Interventions for severely anemic fetuses include intrauterine blood transfusions
(IUTs), which have significantly improved perinatal outcomes for decades.[12] However, IUTs are invasive procedures and have been associated with fetal morbidity,
including posttransfusion cord bleeding, fetal bradycardia, premature rupture of membranes,
emergency cesarean section, and fetal vascular accidents.[13] Since IUTs before the gestational age of 20 to 22 weeks are technically challenging
to perform and increase the likelihood of these complications, clinicians may opt
to administer intravenous immunoglobulin (IVIg) to delay or replace early IUT procedures.[14]
Due to its rarity, HDFN has not been the subject of many studies; therefore, there
is limited knowledge about its epidemiology and postnatal complications in the United
States. Our objective was to evaluate the maternal and child demographic, medical,
and obstetrical characteristics of pregnancies with HDFN compared with those without
HDFN in a large, integrated health care delivery system in Southern California.
Materials and Methods
Study Setting
Data were extracted from the Kaiser Permanente Southern California (KPSC) electronic
health records (EHRs). KPSC, a large, integrated health care system providing service
to >4.8 million members across Southern California,[15]
[16]
[17] is broadly representative of the demographic and socioeconomic diversity of those
living in Southern California.[15] KPSC EHRs contain detailed data for members, covering visits across all health care
settings. Clinical care of KPSC members provided by external contracted providers
(<3%) is captured in EHRs through insurance claim requests. The ethics committee of
the Institutional Review Board of KPSC approved the study with an exemption for patient
informed consent.
Study Population
This was a population-based, retrospective cohort study of pregnant patients who received
obstetrical care at the KPSC health care system from January 1, 2008, to June 30,
2022. We excluded pregnancies that (1) did not have membership at the start of the
pregnancy (index date), (2) had an elective abortion outcome, and (3) had an ABO alloimmunization
of the newborn alone without an HDFN diagnosis. After exclusions, we had 464,711 pregnancies
eligible for the study. The study cohort composition is illustrated as a flowchart
in [Fig. 1].
Fig. 1 Hemolytic disease of the fetus and newborn (HDFN) cohort composition flowchart. Includeda three twin pregnancies: five babies with HDFN babies and one baby without HDFN.
Outcome: Identification of HDFN
The primary outcome, HDFN, was identified from KPSC EHRs based on an algorithm that
was previously validated.[18] Briefly, the algorithm used “International Classification of Diseases, Ninth/Tenth
Revisions, Clinical Modification” (ICD-9/10-CM) codes/clinical notes to identify potential
pregnancies with a diagnosis of HDFN.[18] Then, the trained chart abstractors reviewed these records, examining structured
(procedural/diagnostic codes) and unstructured data (clinical notes in the EHR for
the mother or the infant), to confirm whether each record was a case with HDFN. Cases
with HDFN had (1) mothers with antibodies demonstrating alloimmunization, (2) infants
with positive direct antibody test (DAT) results, and (3) infants who received treatments
such as phototherapy for jaundice, blood transfusion, or IVIg for anemia or infants
with abnormal hemoglobin, hematocrit levels, or reticulocytes count results. HDFN
was also marked where infants had negative DAT results but the mother received several
IUTs. Unclear cases were adjudicated by our maternal-fetal medicine specialist (MJF).
We also examined the frequency of IUTs among HDFN cases, calculating the proportion
of pregnancies requiring IUTs. Additionally, we analyzed the timing and number of
IUTs stratified by etiologic antibody to assess patterns in treatment. The secondary
outcomes investigated in the study included fetal death, APGAR score <7 at 5 minutes,
birth asphyxia, hypoxic-ischemic encephalopathy, neonatal jaundice, kernicterus, and
cerebral palsy.
Characteristics
Maternal characteristics evaluated in this study were age at index year, race/ethnicity
(non-Hispanic White [White], non-Hispanic Black [Black], Hispanic, Asian/Pacific Islander,
other/multiple, or unknown), household income (<$30,000, $30,000–49,999, $50,000–69,999,
$70,000–89,999, ≥$90,000, or missing), and insurance type (Medicaid, commercial, private,
or other). We also examined smoking, alcohol, or illicit drug use during pregnancy
(yes/no), parity, gravidity, and prepregnancy body mass index (BMI; kg/m2). For clinical characteristics, we examined gestational weight gain (lbs), medical
(asthma, chronic hypertension, pregestational diabetes, renal disease, and autoimmune
disease), and obstetrical (preterm premature rupture of membranes) comorbidities.
For the child characteristics, we reported frequencies for the baby's sex, birth weight
(g), gestational age at birth (weeks), head circumference (cm), preterm birth, fetal
death, APGAR score of <7 at 5 minutes, birth asphyxia, hypoxic-ischemic encephalopathy,
neonatal jaundice, kernicterus, and cerebral palsy.
Statistical Analysis
We examined the distribution of maternal and child characteristics by HDFN status.
For categorical variables, frequencies and percentages were estimated for each level
and the distribution of each variable was compared using a chi-square test. For continuous
variables, the means and standard deviations (SDs) were estimated and compared using
t-tests. p-Values were 2-sided, and statistical significance was set at p <0.05. Logistic regression analysis was conducted to estimate the crude and adjusted
odds ratios (aORs) for associations between maternal/fetal/infant characteristics
and HDFN risk, reported as point estimates with 95% confidence intervals (CIs). We
applied Firth's bias-reduced logistic regression for rare events. Statistical analysis
was performed using SAS version 9.4 (SAS Institute, Cary, NC).
Results
Of 464,711 KPSC pregnancies eligible for this study, a total of 136 pregnancies (29.3
cases per 100,000) with 138 births (n = 137 live births; n = 1 stillbirth) were identified with HDFN ([Fig. 1]). In the HDFN and non-HDFN groups, the mean (SD) ages were 31.8 (5.3) and 29.8 (5.7)
years, respectively ([Table 1]). Compared with non-HDFN pregnancies, HDFN pregnancies were more likely among older
mothers (aged ≥30 years), patients of non-Hispanic White race/ethnicity, Medicaid-only
insured patients, multipara patients, and multigravida patients. The HDFN group was
composed of 38.2% (n = 52) non-Hispanic White, 41.9% (n = 57) Hispanic, 12.5% (n = 17) Asian/Pacific Islander, and 7.4% (n = 10) non-Hispanic Black patients. Among the HDFN group, there was a higher proportion
of patients with chronic hypertension, renal disease, and a prepregnancy BMI of 30.0
to 34.9 kg/m2 compared with the non-HDFN group.
Table 1
Distribution of maternal demographic, medical, and obstetrical characteristics based
on hemolytic disease of the fetus and newborn (HDFN) status
|
Characteristic
|
Total (n = 464,711)
|
HDFN status
|
|
HDFN (n = 136)
|
Non-HDFN (n = 464,575)
|
p-Value
|
|
Age at index date, y
|
|
Mean (SD)
|
29.8 (5.7)
|
31.8 (5.3)
|
29.8 (5.7)
|
<0.0001[a]
|
|
Age at index date, y, n (%)
|
|
< 20
|
21,437 (4.6)
|
3 (2.2)
|
21,434 (4.6)
|
0.0030[b]
|
|
20–29
|
193,523 (41.6)
|
40 (29.4)
|
193,483 (41.6)
|
|
30–34
|
152,571 (32.8)
|
51 (37.5)
|
152,520 (32.8)
|
|
≥35
|
97,180 (20.9)
|
42 (30.9)
|
97,138 (20.9)
|
|
Race/ethnicity, n (%)
|
|
Non-Hispanic White
|
126,026 (27.1)
|
52 (38.2)
|
125,974 (27.1)
|
0.0121[b]
|
|
Non-Hispanic Black
|
36,344 (7.8)
|
10 (7.4)
|
36,334 (7.8)
|
|
Hispanic
|
213,525 (45.9)
|
57 (41.9)
|
213,468 (45.9)
|
|
Asian/Pacific Islander
|
62,045 (13.4)
|
17 (12.5)
|
62,028 (13.4)
|
|
Other/multiple
|
5,794 (1.2)
|
0 (0.0)
|
5,794 (1.2)
|
|
Unknown
|
20,977 (4.5)
|
0 (0.0)
|
20,977 (4.5)
|
|
Household income, USD, n (%)
|
|
< $30,000
|
17,307 (3.7)
|
4 (2.9)
|
17,303 (3.7)
|
0.8428[b]
|
|
$30,000–$49,999
|
113,957 (24.5)
|
29 (21.3)
|
113,928 (24.5)
|
|
$50,000–$69,999
|
135,554 (29.2)
|
42 (30.9)
|
135,512 (29.2)
|
|
$70,000–$89,999
|
96,346 (20.7)
|
27 (19.9)
|
96,319 (20.7)
|
|
≥$90,000
|
100,388 (21.6)
|
34 (25.0)
|
100,354 (21.6)
|
|
Missing
|
1,159 (0.2)
|
0 (0.0)
|
1,159 (0.2)
|
|
Insurance type, n (%)
|
|
Medicaid
|
44,583 (9.6)
|
22 (16.2)
|
44,561 (9.6)
|
0.0351[b]
|
|
Commercial
|
386,724 (83.2)
|
101 (74.3)
|
386,623 (83.2)
|
|
Private
|
27,385 (5.9)
|
11 (8.1)
|
27,374 (5.9)
|
|
Other/unknown
|
6,019 (1.3)
|
2 (1.5)
|
6,017 (1.3)
|
|
Smoking during pregnancy, n (%)
|
|
No
|
453,040 (97.5)
|
132 (97.1)
|
452,908 (97.5)
|
0.7487[b]
|
|
Yes
|
11,671 (2.5)
|
4 (2.9)
|
11,667 (2.5)
|
|
Alcohol use during pregnancy, n (%)
|
|
No
|
403,999 (86.9)
|
120 (88.2)
|
403,879 (86.9)
|
0.6528[b]
|
|
Yes
|
60,712 (13.1)
|
16 (11.8)
|
60,696 (13.1)
|
|
Illicit drug use during pregnancy, n (%)
|
|
No
|
446,864 (96.2)
|
131 (96.3)
|
446,733 (96.2)
|
0.9207[b]
|
|
Yes
|
17,847 (3.8)
|
5 (3.7)
|
17,842 (3.8)
|
|
Parity, n (%)
|
|
Multiparous
|
264,887 (57.0)
|
120 (88.2)
|
264,767 (57.0)
|
<0.0001[b]
|
|
Nulliparous
|
140,722 (30.3)
|
11 (8.1)
|
140,711 (30.3)
|
|
Unknown
|
59,102 (12.7)
|
5 (3.7)
|
59,097 (12.7)
|
|
Gravidity, n (%)
|
|
Multigravida
|
326,956 (70.4)
|
126 (92.6)
|
326,830 (70.4)
|
<0.0001[b]
|
|
Nulligravida
|
136,049 (29.3)
|
10 (7.4)
|
136,039 (29.3)
|
|
Unknown
|
1,706 (0.4)
|
0 (0.0)
|
1,706 (0.4)
|
|
Prepregnancy BMI, kg/m2, n (%)
|
|
< 18.5
|
9,302 (2.0)
|
2 (1.5)
|
9,300 (2.0)
|
0.0505[b]
|
|
18.5–24.9
|
172,300 (37.1)
|
49 (36.0)
|
172,251 (37.1)
|
|
25.0–29.9
|
121,422 (26.1)
|
28 (20.6)
|
121,394 (26.1)
|
|
30.0–34.9
|
68,732 (14.8)
|
25 (18.4)
|
68,707 (14.8)
|
|
≥35.0
|
54,829 (11.8)
|
12 (8.8)
|
54,817 (11.8)
|
|
Missing
|
38,126 (8.2)
|
20 (14.7)
|
38,106 (8.2)
|
|
Gestational weight gain, lbs
|
|
Mean (SD)
|
27.5 (15.88)
|
25.6 (15.73)
|
27.5 (15.88)
|
0.0376[a]
|
|
Asthma, n (%)
|
|
No
|
440,344 (94.8)
|
131 (96.3)
|
440,213 (94.8)
|
0.4122[b]
|
|
Yes
|
24,367 (5.2)
|
5 (3.7)
|
24,362 (5.2)
|
|
Chronic hypertension, n (%)
|
|
No
|
455,405 (98.0)
|
130 (95.6)
|
455,275 (98.0)
|
0.0449[b]
|
|
Yes
|
9,306 (2.0)
|
6 (4.4)
|
9,300 (2.0)
|
|
Pregestational diabetes, n (%)
|
|
No
|
458,543 (98.7)
|
136 (100.0)
|
458,407 (98.7)
|
0.1761[b]
|
|
Yes
|
6,168 (1.3)
|
0 (0.0)
|
6,168 (1.3)
|
|
Renal disease, n (%)
|
|
No
|
456,372 (98.2)
|
128 (94.1)
|
456,244 (98.2)
|
0.0003[b]
|
|
Yes
|
8,339 (1.8)
|
8 (5.9)
|
8,331 (1.8)
|
|
Autoimmune disease, n (%)
|
|
No
|
463,441 (99.7)
|
135 (99.3)
|
463,306 (99.7)
|
0.3020[b]
|
|
Yes
|
1,270 (0.3)
|
1 (0.7)
|
1,269 (0.3)
|
|
PPROM, n (%)
|
|
No
|
458,085 (98.6)
|
133 (97.8)
|
457,952 (98.6)
|
0.4428[b]
|
|
Yes
|
6,626 (1.4)
|
3 (2.2)
|
6,623 (1.4)
|
Abbreviations: BMI, body mass index; PPROM, preterm premature rupture of membranes;
SD, standard deviation; USD, United States dollar.
a Kruskal–Wallis p-values.
b Chi-square p-values.
Compared with infants born without a diagnosis of HDFN, infants born with a diagnosis
of HDFN were more likely to be male, to be born preterm (delivery at <370/7 weeks gestation), to have low birth weight (<2,500 g), to have a smaller head circumference,
and to develop neonatal jaundice ([Table 2]).
Table 2
Distribution of child characteristics and perinatal outcomes[c] based on hemolytic disease of fetus and newborn (HDFN) status
|
Characteristic
|
Total (n = 446,499)
|
HDFN status
|
|
HDFN (n = 138)
|
Non-HDFN (n = 446,361)
|
p-Value
|
|
Sex, n (%)
|
|
Female
|
216,646 (48.5)
|
59 (42.8)
|
216,587 (48.5)
|
0.3061[a]
|
|
Male
|
228,476 (51.2)
|
79 (57.2)
|
228,397 (51.2)
|
|
Missing
|
1,377 (0.3)
|
0 (0.0)
|
1,377 (0.3)
|
|
Birth weight, g, n (%)
|
|
< 1,500
|
5,982 (1.3)
|
4 (2.9)
|
5,978 (1.3)
|
0.0003[a]
|
|
1,500–2,499
|
25,780 (5.8)
|
18 (13.0)
|
25,762 (5.8)
|
|
2,500–3,999
|
366,607 (82.1)
|
110 (79.7)
|
366,497 (82.1)
|
|
≥4,000
|
38,773 (8.7)
|
4 (2.9)
|
38,769 (8.7)
|
|
Missing
|
9,357 (2.1)
|
2 (1.4)
|
9,355 (2.1)
|
|
Gestational age at birth, wk, n (%)
|
|
< 28
|
3,763 (0.8)
|
2 (1.4)
|
3,761 (0.8)
|
<0.0001[a]
|
|
28–32
|
6,270 (1.4)
|
3 (2.2)
|
6,267 (1.4)
|
|
33–34
|
8,765 (2.0)
|
12 (8.7)
|
8,753 (2.0)
|
|
35–36
|
25,320 (5.7)
|
24 (17.4)
|
25,296 (5.7)
|
|
≥37
|
402,381 (90.1)
|
97 (70.3)
|
402,284 (90.1)
|
|
Head circumference, cm
|
|
Mean (SD)
|
34.0 (2.7)
|
33.5 (2.3)
|
34.0 (2.7)
|
0.0332[b]
|
|
Fetal death, n (%)
|
|
No
|
444,315 (99.5)
|
137 (99.3)
|
444,178 (99.5)
|
0.6917[a]
|
|
Yes
|
2,184 (0.5)
|
1 (0.7)
|
2,183 (0.5)
|
|
APGAR score <7 at 5 min, n (%)
|
|
No
|
435,606 (97.6)
|
135 (97.8)
|
435,471 (97.6)
|
0.3404[a]
|
|
Yes
|
6,083 (1.4)
|
3 (2.2)
|
6,080 (1.4)
|
|
Missing
|
4,810 (1.1)
|
0 (0.0)
|
4,810 (1.1)
|
|
Birth asphyxia, n (%)
|
|
No
|
446,441 (100.0)
|
138 (100.0)
|
446,303 (100.0)
|
0.8935[a]
|
|
Yes
|
58 (0.0)
|
0 (0.0)
|
58 (0.0)
|
|
Hypoxic-ischemic encephalopathy, n (%)
|
|
No
|
445,887 (99.9)
|
138 (100.0)
|
445,749 (99.9)
|
0.6634[a]
|
|
Yes
|
612 (0.1)
|
0 (0.0)
|
612 (0.1)
|
|
Neonatal jaundice, n (%)
|
|
No
|
283,942 (63.6)
|
48 (34.8)
|
283,894 (63.6)
|
<0.0001[a]
|
|
Yes
|
162,557 (36.4)
|
90 (65.2)
|
162,467 (36.4)
|
|
Kernicterus, n (%)
|
|
No
|
446,494 (100.0)
|
138 (100.0)
|
446,356 (100.0)
|
0.9686[a]
|
|
Yes
|
5 (0.0)
|
0 (0.0)
|
5 (0.0)
|
|
Cerebral palsy, n (%)
|
|
No
|
446,277 (100.0)
|
138 (100.0)
|
446,139 (100.0)
|
0.7933[a]
|
|
Yes
|
222 (0.0)
|
0 (0.0)
|
222 (0.0)
|
Abbreviation: SD, standard deviation.
a Chi-square p-value.
b Kruskal–Wallis p-value.
c Unit of analysis = live births and stillbirths.
Among the 136 pregnancies with HDFN, 17 (12.5%) required IUTs, while 117 (86.0%) did
not require IUTs. The majority of IUTs were performed for cases with anti-D antibodies,
with a mean gestational age of 27.6 weeks for the first transfusion ([Supplementary Table S1], available in the online version only). The distribution of antibodies among HDFN
cases with IUTs is shown in [Supplementary Fig. S1] (available in the online version only).
Hispanic race/ethnicity was associated with a lower likelihood of HDFN diagnosis (aOR:
0.63; 95% CI: 0.43, 0.93) than non-Hispanic White race/ethnicity ([Table 3]). Maternal characteristics associated with an increased risk for HDFN were maternal
age of ≥35 years (aOR: 1.74; 95% CI: 1.13, 2.67), chronic hypertension (aOR: 2.07;
95% CI: 0.96, 4.50), renal disease (aOR: 3.43; 95% CI: 1.75, 6.70), and multipara
(aOR: 4.95; 95% CI: 2.73, 8.95).
Table 3
Association between maternal characteristics and hemolytic disease of the fetus and
newborn diagnosis (2008–2022[a])
|
Characteristic
|
OR (95%CI)
|
|
Crude
|
Adjusted[b]
|
|
Age at index date,[c] y
|
|
< 20
|
0.77 (0.21, 2.77)
|
1.32 (0.38, 4.65)
|
|
20–29
|
1.00 (reference)
|
1.00 (reference)
|
|
30–34
|
1.47 (0.96, 2.27)
|
1.29 (0.84, 1.98)
|
|
≥35
|
2.15 (1.41, 3.28)
|
1.74 (1.13, 2.67)
|
|
Race/ethnicity
|
|
Non-Hispanic White
|
1.00 (reference)
|
1.00 (reference)
|
|
Non-Hispanic Black
|
0.69 (0.36, 1.35)
|
0.66 (0.34, 1.28)
|
|
Hispanic
|
0.65 (0.44, 0.94)
|
0.63 (0.43, 0.93)
|
|
Asian/Pacific Islander
|
0.68 (0.39, 1.16)
|
0.65 (0.38, 1.10)
|
|
Other/multiple
|
0.21 (0.01, 3.36)
|
0.21 (0.01, 3.03)
|
|
Unknown
|
0.06 (0.00, 0.93)
|
0.04 (0.00, 0.65)
|
|
Household income,[d] USD
|
|
< $30,000
|
0.76 (0.28, 2.02)
|
0.84 (0.32, 2.22)
|
|
$30,000–49,999
|
0.75 (0.46, 1.23)
|
0.85 (0.51, 1.41)
|
|
$50,000–69,999
|
0.91 (0.58, 1.43)
|
1.02 (0.65, 1.60)
|
|
$70,000–89,999
|
0.83 (0.50, 1.37)
|
0.89 (0.55, 1.46)
|
|
≥$90,000
|
1.00 (reference)
|
1.00 (reference)
|
|
Missing
|
1.26 (0.08, 20.47)
|
1.21 (0.08, 17.98)
|
|
Insurance type
|
|
Medicaid
|
1.20 (0.59, 2.45)
|
1.30 (0.64, 2.67)
|
|
Commercial
|
0.62 (0.34, 1.15)
|
0.70 (0.39, 1.28)
|
|
Private
|
1.00 (reference)
|
1.00 (reference)
|
|
Other/unknown
|
0.99 (0.25, 3.88)
|
1.22 (0.32, 4.61)
|
|
Smoking status during pregnancy, yes
|
1.32 (0.52, 3.38)[d]
|
1.41 (0.57, 3.48)
|
|
Alcohol consumption during pregnancy, yes
|
0.91 (0.54, 1.52)[d]
|
1.05 (0.63, 1.73)
|
|
Illicit drug use during pregnancy, yes
|
1.05 (0.45, 2.46)[d]
|
1.38 (0.60, 3.13)
|
|
Prepregnancy BMI, kg/m2
|
|
< 18.5
|
0.94 (0.26, 3.33)
|
1.06 (0.31, 3.62)
|
|
18.5–24.9
|
1.00 (reference)
|
1.00 (reference)
|
|
25.0–29.9
|
0.82 (0.52, 1.30)
|
0.76 (0.48, 1.20)
|
|
30.0–34.9
|
1.29 (0.80, 2.08)
|
1.16 (0.72, 1.88)
|
|
≥35.0
|
0.79 (0.43, 1.48)
|
0.70 (0.37, 1.29)
|
|
Missing
|
1.87 (1.12, 3.13)
|
2.18 (1.31, 3.61)
|
|
Gestational weight gain, lbs
|
0.99 (0.98, 1.00)
|
0.99 (0.98, 1.01)
|
|
Comorbidities[e]
|
|
Asthma
|
0.76 (0.32, 1.77)
|
0.75 (0.33, 1.70)
|
|
Chronic hypertension
|
2.44 (1.11, 5.36)
|
2.07 (0.96, 4.50)
|
|
Pregestational diabetes
|
Not estimated
|
Not estimated
|
|
Renal disease
|
3.62 (1.81, 7.25)
|
3.43 (1.75, 6.70)
|
|
Autoimmune disease
|
4.04 (0.81, 20.23)
|
3.88 (0.82, 18.27)
|
|
Parity
|
|
Nulliparous
|
1.00 (reference)
|
1.00 (reference)
|
|
Multiparous
|
5.57 (3.04, 10.20)
|
4.95 (2.73, 8.95)
|
|
Unknown
|
1.14 (0.41, 3.15)
|
1.14 (0.43, 3.03)
|
|
Gravidity
|
|
Nulligravida
|
1.00 (reference)
|
1.00 (reference)
|
|
Multigravida
|
5.01 (2.67, 9.41)
|
1.35 (0.53, 3.39)
|
|
Unknown
|
3.80 (0.22, 64.85)
|
2.88 (0.18, 45.30)
|
|
PPROM
|
1.81 (0.63, 5.24)
|
2.09 (0.75, 5.80)
|
Abbreviations: BMI, body mass index; CI, confidence interval; OR, odds ratio; PPROM,
preterm premature rupture of membranes; USD, United States dollar.
a 2022 data were limited to 6 months.
b Adjusted for maternal race/ethnicity, age, household income, insurance type, prepregnancy
BMI, and parity.
c Index date refers to the earliest date of pregnancy start.
d Median household income was based on the 2010 census tract of residence information.
e Comorbidities diagnosed within 1 year prior to the index date.
Similarly, a fetal and infant characteristic associated with an increased risk for
HDFN was neonatal jaundice (aOR: 3.11; 95% CI: 2.20, 4.41). Compared with non-HDFN
pregnancies, HDFN pregnancies were more likely to deliver preterm at gestation 33
to 34 weeks (aOR: 5.72; 95% CI: 2.78, 11.78) and 35 to 36 weeks (aOR: 3.76; 95% CI:
2.38, 5.94) than at term gestation. Meanwhile, lower odds of HDFN were associated
with a birth weight ≥4,000 g compared with a normal weight (2,500–3,999 g; aOR: 0.36;
95% CI: 0.14, 0.90; [Table 4]).
Table 4
Association between fetal and infant characteristics and hemolytic disease of the
fetus and newborn diagnosis[a] (2008–2022[b])
|
Characteristic
|
OR (95% CI)
|
|
Crude
|
Adjusted[c]
|
|
Sex
|
|
Male
|
1.00 (Reference)
|
1.00 (Reference)
|
|
Female
|
0.79 (0.56, 1.10)
|
0.79 (0.57, 1.09)
|
|
Missing/unknown
|
Not estimated
|
Not estimated
|
|
Birth weight, g
|
|
< 1,500
|
2.50 (0.97, 6.41)
|
1.64 (0.39, 6.82)
|
|
1,500–2,499
|
2.38 (1.46, 3.90)
|
1.00 (0.53, 1.85)
|
|
2,500–3,999
|
1.00 (Reference)
|
1.00 (Reference)
|
|
≥4,000
|
0.38 (0.15, 0.99)
|
0.36 (0.14, 0.90)
|
|
Missing/unknown
|
0.89 (0.25, 3.11)
|
1.10 (0.33, 3.71)
|
|
Gestational age at birth, wks
|
|
< 28
|
2.74 (0.78, 9.63)
|
2.33 (0.42, 13.07)
|
|
28–32
|
2.30 (0.79, 6.69)
|
2.06 (0.55, 7.71)
|
|
33–34
|
5.89 (3.27, 10.62)
|
5.72 (2.78, 11.78)
|
|
35–36
|
4.00 (2.57, 6.22)
|
3.76 (2.38, 5.94)
|
|
≥37
|
1.00 (Reference)
|
1.00 (Reference)
|
|
Head circumference, cm
|
0.91 (0.85, 0.97)
|
0.97 (0.88, 1.07)
|
|
Fetal death
|
2.23 (0.45, 11.11)
|
1.55 (0.30, 8.03)
|
|
APGAR score <7 at 5 min
|
1.85 (0.64, 5.35)
|
1.25 (0.41, 3.86)
|
|
Birth asphyxia
|
Not estimated
|
Not estimated
|
|
Hypoxic-ischemic encephalopathy
|
Not estimated
|
Not estimated
|
|
Neonatal jaundice
|
3.26 (2.30, 4.62)
|
3.11 (2.20, 4.41)
|
|
Kernicterus
|
Not estimated
|
Not estimated
|
|
Cerebral palsy
|
Not estimated
|
Not estimated
|
Abbreviations: CI, confidence interval; OR, odds ratio.
a Estimates by HDFN status are presented using data on all births (live births and
stillbirths).
b 2022 data were limited to 6 months.
c Adjusted for maternal race/ethnicity, age, household income, insurance type, prepregnancy
BMI, parity, infant sex, birth weight, and gestational age at birth.
Discussion
This population-based, retrospective cohort study reported the characteristics of
HDFN-affected pregnancies compared with non-HDFN pregnancies using 14 years of data
(January 1, 2008, to June 30, 2022) from KPSC hospitals. HDFN-affected pregnancies
were relatively rare, with a prevalence rate of 29.3 per 100,000, consistent with
previously reported rates.[2]
[19] While one study using the National Hospital Discharge Survey reported a higher prevalence[20]; however, that study examined HDFN among live births spanning from 1996 to 2010
and may not reflect the declining rates of HDFN over the last few decades.
Consistent with previous research,[11]
[20] non-Hispanic White patients had a higher proportion of HDFN pregnancies (38% of
HDFN cases) in our study. This is an important finding as the KPSC health care system
has a racially and ethnically diverse patient population.[15] Furthermore, our study demonstrated that advanced maternal age and multipara status
were associated with an increased risk of HDFN diagnosis. A previous case-control
study[9] in a Dutch population found the opposite, that younger patients were more likely
to have RhD immunization risk, but the authors noted that this was difficult to explain
and that it could have been an artifact of their study design. The higher rates of
HDFN among those with a higher prepregnancy BMI, chronic hypertension, and renal disease
in our study should be investigated further. Finally, HDFN pregnancies in our analysis
were associated with preterm birth and neonatal jaundice. This finding is also consistent
with prior studies.[21]
[22] Preterm delivery could also be a result of antenatal therapy due to HDFN identified
during pregnancy; it has been proposed that a medically indicated late preterm or
early-term birth could reduce the fetal risk of ongoing exposure to maternal autoantibodies.[21]
[22]
The study highlights the importance of monitoring pregnancies at risk for HDFN, particularly
among patients who are older, multipara, and living with chronic health conditions.
The association of HDFN with preterm birth and neonatal jaundice underscores the need
for targeted prenatal care and possible early intervention strategies. Our findings
indicate that while the majority (86.0%) of pregnancies affected by HDFN did not require
transfusion, those with certain alloantibodies, particularly anti-D, were more frequently
given IUTs. The mean timing of the first transfusion varied by antibody type. Further
research is needed to confirm these findings and establish comprehensive guidelines
for managing HDFN in diverse clinical settings. Additional studies should evaluate
the risk of subsequent HDFN in pregnancies previously affected by the condition and
explore underlying mechanisms. Future research should focus on the long-term outcomes
of infants born with HDFN and the effectiveness of different antenatal therapies in
reducing HDFN-related complications.
Strengths and Limitations
Strengths and Limitations
A major strength of this study was the ability to identify and examine 136 pregnancies
with HDFN, a rare disorder in the United States. HDFN was evaluated among a large
sample of a racially and ethnically diverse population, and HDFN cases were ascertained
with a validated algorithm that combined structured and unstructured EHR data and
confirmed them to be HDFN cases using chart review.[18] The use of KPSC EHRs allowed for the examination of comorbidities, and the linked
datasets between the mother and fetus/neonate allowed for a rich examination of the
distribution of HDFN compared with non-HDFN pregnancies among the mother and their
baby spanning over a decade.
This study had some limitations. First, due to the rarity of this condition, the sample
size after stratification was small for many characteristics. Thus, our point estimates
may be underpowered, reducing the chance of detecting a true effect. Second, those
who had a history of HDFN prior to receiving care at KPSC hospitals were not observed
in this study.
The findings of this study demonstrated that HDFN was more common among non-Hispanic
White patients, older mothers, multiparous patients, and those with chronic hypertension
or renal disease. Newborns with HDFN had higher rates of preterm delivery and neonatal
jaundice. These findings suggest that pregnancies affected by HDFN merit continued
clinical attention.
