Introduction: We aimed to evaluate the neuroimaging findings and long-term neurodevelopmental outcomes of fetuses and children following intrauterine blood transfusion (IUT) for parvo B19 infection-induced anemia compared to those with RBC alloimmunization. Methods: We conducted a retrospective cohort study including women who underwent an IUT due to fetal anemia between 2006 and 2019 in a tertiary, university-affiliated medical center. The cohort was divided into two groups: a study group – fetuses affected by congenital parvo B19 infection; and a control group – fetuses affected by RBC alloimmunization. Retrospective data such as antenatal sonographic evaluations, fetal brain MRI results, and short-term fetal and neonatal outcomes were collected. All children underwent a neurodevelopmental evaluation after birth using a Vineland questionnaire. Primary outcome was defined as the presence or absence of neurodevelopmental delay. Secondary outcome was defined as the presence of abnormal fetal neuroimaging findings such as cerebellar hypoplasia, polymicrogyria, intracranial hemorrhage, or severe ventriculomegaly. Results: Overall, 71 fetuses requiring at least one IUT were included in the study. Of these, 18 were affected by parvo B19 infection and 53 by RBC alloimmunization with various associated antibodies. Fetuses in the parvo B19 group presented at an earlier gestational age (22.91 ± 3.36 weeks vs. 27.37 ± 4.67 weeks, p = 0.002) and were more affected by hydrops (93.33% vs. 16.98%, p < 0.001). Three fetuses out of the 18 (16.67%) fetuses in the parvo B19 group died in utero following the IUT. Abnormal neuroimaging findings were detected in 4/15 (26.7%) of the parvo B19 survivors versus 2/53 (3.8%) of fetuses affected by RBC alloimmunization (p = 0.005). There was no difference in long-term neurodevelopmental delay rates between the children in the study and control groups, as assessed at the average age of 3.65 and 6.53 years, accordingly. Conclusion: Fetal anemia due to parvo B19, treated with IUT, might be associated with increased rates of abnormal neurosonographic findings. The correlation between those findings and long-term adverse neurodevelopmental outcomes requires further investigation.

Mini-Summary

  • What does this study add to current knowledge?

    • This study compares neurodevelopmental outcomes between two groups of fetuses undergoing an IUT. The study shows that there is a higher rate of abnormal fetal neuroimaging findings in the parvo B19 population, but the long-term significance of those findings is not clear.

  • What are the main clinical implications?

    • Patients diagnosed with intrauterine parvo B19 infection should be followed up closely with neuroimaging studies, as there are higher rates of abnormal fetal neuroimaging findings in those fetuses.

Human parvo B19 is a single-stranded DNA virus that causes the “fifth disease” in school-aged children, including decreased erythrocyte production and subsequent anemia [1]. About 40% of women in the childbearing years are seronegative to parvo B19. Approximately 2.4% of seronegative pregnant women will get infected [2], and vertical transmission to the fetus will occur in 33–51% of those women [3, 4]. Vertical transmission to the fetus usually resolves with no symptoms, but in rare cases may result in severe anemia, high output cardiac failure, hydrops fetalis, and even fetal loss [1].

The overall rate of fetal loss is estimated at about 10% of the affected fetuses [5, 6]. In those affected by severe anemia and hydrops, mortality rate is higher and varies between 30 and 50% without an intrauterine blood transfusion (IUT) [1, 4, 7‒12]. IUT significantly reduces the morbidity and mortality of fetuses affected by parvo B19 infection. The perinatal survival rates vary between 67 and 85% for fetuses who undergo an IUT for parvo B19 infection [12, 13].

Data regarding the long-term neurodevelopmental outcomes of children born after an IUT are limited. For alloimmunization, long-term neurodevelopmental outcome is overall favorable, with a risk of 5% for neurodevelopmental impairment [14‒17]. However, data regarding neurodevelopmental impairment and neurosonographic findings in survivors of IUT for congenital parvo B19 infection are scarce and based on a few small studies [10, 11, 18‒21]. Neurodevelopmental impairment in survivors of intrauterine parvo B19 infection might be attributed to various reasons. Severe anemia presenting early in pregnancy accompanied by hydrops is one of them, but a direct viral effect on the developing brain, might be another.

Studies conducted on animals have suggested that parvo B19 has affinity to neuronal cells. However, this theory has not been thoroughly studied in humans [22, 23]. Some studies have also reported fetal prenatal stroke associated with parvo B19 infection, while others have associated it mostly with cerebellar lesions [24‒27].

Therefore, the objective of our study was to evaluate neuroimaging findings and short- and long-term neurodevelopmental outcomes of fetuses and children treated with an IUT for fetal anemia due to parvo B19 infection.

This was a retrospective cohort study of all women with singleton gestations who underwent an IUT for fetal anemia between the years 2006 and 2019 in a tertiary, university-affiliated medical center. Patients were allocated into two groups according to the underlying cause of fetal anemia: (1) fetuses who underwent an IUT due to congenital parvo B19 infection (study group); and (2) fetuses who underwent an IUT due to RBC alloimmunization (control group).

Data Collection

Data were collected from the hospital’s comprehensive computerized medical records. At our center, the Sheba Medical Center in Israel, all IUT procedures are recorded on a dedicated file. We searched for the diagnosis of IUT in our database and cross-matched it with the dedicated file. We then went over the patients’ records and manually collected comprehensive maternal, fetal, and neonatal data into an Excel file. The following data were recorded: maternal age and parity; gestational age at 1st IUT; presence of hydrops fetalis; fetal hemoglobin, hematocrit, and platelet levels prior to and at completion of the IUT; number of IUTs required; gestational age at delivery; indication for delivery; mode of delivery; and neonatal gender. Hydrops fetalis was defined as fluid accumulation in at least two body compartments, including skin edema, ascites, pericardial effusion, or pleural effusion. Antenatal follow-up results such as brain neurosonogram, brain MRI, fetal cardiac imaging, routine ultrasound scans, and genetic investigations were recorded as well. Short-term neonatal outcome measures were recorded, including birthweight, Apgar scores, cord blood gases, admission to NICU, neonatal complications, and neonatal cranial imaging results. Initial neonatal cranial imaging was conducted in the first week of life and prior to hospital discharge. The children’s long-term neurodevelopmental outcome was evaluated by the Vineland adaptive questionnaire. The questionnaire was conducted by a trained research assistant and filled out together with the children’s legal guardians.

Procedures and Definitions

Gestational age was calculated according to the last menstrual period and confirmed by a 1st trimester fetal crown-rump length sonographic measurement. Fetuses born to mothers with known RBC alloimmunization were followed up by serial ultrasounds and middle-cerebral artery peak systolic velocity (MCA-PSV) measurements every 2–4 weeks, starting from 16 to 18 weeks of gestation. Fetuses affected by parvo B19 infection were usually diagnosed based on an incidental finding of hydrops fetalis or knowledge of maternal exposure and serology indicating maternal seroconversion. Severe anemia prompting cord blood sampling and an IUT was suspected when MCA-PSV was >1.55 MoM [28, 29]. In cases of parvo B19, fetal infection was confirmed by PCR from fetal blood. After the initial IUT, fetuses in both groups were followed up every 2 weeks by an ultrasound scan including a biophysical profile (BPP), estimated fetal weight (EFW) measurement, and a neurosonogram. All fetuses in the study group underwent fetal cardiac echo and a brain MRI. Timing of subsequent IUT was determined according to MCA-PSV measurements, with the last IUT performed up to and not beyond 35+0 weeks of gestation. Genetic investigation including karyotype and chromosomal microarray analysis (available from 2012) was offered to all mothers undergoing IUT.

Outcome Measures

We assessed fetal and neonatal neurosonographic findings and long-term neurodevelopment in all surviving fetuses. All fetuses were assessed by a bi-weekly neurosonogram following an IUT. A routine brain MRI at 28–32 weeks of gestation was conducted for the parvo B19 group alone, followed by additional MRIs as indicated. Presence of postnatal brain injury on neonatal cerebral imaging (cranial ultrasound, computed tomography scan [CT], or magnetic resonance imaging [MRI]) was recorded if available. Diagnoses of cerebral palsy or other neurological adverse outcomes were assessed according to standard procedures and recorded as well [30]. These data were retrospectively collected from the patients’ charts.

To assess long-term neurological outcomes, all children underwent a developmental and intelligence evaluation adjusted to their age at testing. This part was accomplished by conducting a dedicated questionnaire by one of our research assistants with one of the children’s guardians. The Vineland adaptive behavioral scale questionnaire was used for this purpose [31]. According to the Vineland adaptive behavioral scale, five performance levels were addressed. These included high ≥98th percentile; moderately high = 84th-97th percentile; adequate = 18th–83rd percentile; moderately low = 3rd–17th percentile; and low ≤2nd percentile. Short- and long-term outcomes were compared between the groups.

Primary outcome was defined as the presence or absence of neurodevelopmental delay. Secondary outcome was defined as the presence of abnormal fetal or neonatal neuroimaging findings such as cerebellar hypoplasia, polymicrogyria, intracranial hemorrhage, or severe ventriculomegaly.

Statistics

Statistical analysis was performed using the SAS software (Version 9.4, SAS Institute, NC, USA). Continuous variables were compared using Student’s t test or Mann-Whitney U-test, and categorical variables were compared using χ2 test or Fisher’s exact test, as appropriate. A probability value <0.05 was considered statistically significant.

Ethics

This study protocol was reviewed and approved by the SHEBA Medical Center REB Committee, approval number 6076-19-SMC. Informed verbal consent was obtained to participate in the study from all participants’ parents or legal guardian or next of kin. This was done after sending preliminary notifying letters regarding a potential phone interaction. Verbal consent was specifically approved by the SHEBA Medical Center REB Committee, approval number 6076-19-SMC.

A total of 71 patients underwent an IUT due to fetal anemia between January 2006 and November 2019. Of these, 18 were affected by parvo B19 (study group) and 53 by RBC alloimmunization (control group). Three cases in the study group were complicated by intrauterine fetal demise.

Thus, 15 cases in the study group and 53 cases in the control group were eligible for short-term analysis. Of these, 14 in the study group and 45 in the control group were eligible for the long-term analysis due to loss to follow-up (Fig. 1). The demographic and clinical characteristics of both groups are presented in Table 1.

Fig. 1.

Study group design. Neurological outcomes of fetuses surviving parvo B19 intrauterine blood transfusion.

Fig. 1.

Study group design. Neurological outcomes of fetuses surviving parvo B19 intrauterine blood transfusion.

Close modal
Table 1.

Demographic and clinical characteristics of both groups

Study group (n = 15, 22.1%)Control group (n = 53, 67.9%)p value
Maternal age, years 30.33±4.51 33.94±4.58 0.005 
Primiparity 1 (6.67) 3 (5.66) 1.0 
GAa at 1st IUTb, weeks 22.91±3.36 27.37±4.67 0.002 
Hydrops at 1st IUT 14 (93.33) 9 (16.98) <0.001 
HBc at 1st IUT 3.19±2.76 6.39±2.84 0.001 
PLTd at 1st IUT 45.09±30.58 146.50±33.65 0.02 
HB after 1st IUT 15.52±2.78 14.50±2.18 0.08 
No. of IUTs, total 1.20±0.41 2.38±1.29 0.001 
Study group (n = 15, 22.1%)Control group (n = 53, 67.9%)p value
Maternal age, years 30.33±4.51 33.94±4.58 0.005 
Primiparity 1 (6.67) 3 (5.66) 1.0 
GAa at 1st IUTb, weeks 22.91±3.36 27.37±4.67 0.002 
Hydrops at 1st IUT 14 (93.33) 9 (16.98) <0.001 
HBc at 1st IUT 3.19±2.76 6.39±2.84 0.001 
PLTd at 1st IUT 45.09±30.58 146.50±33.65 0.02 
HB after 1st IUT 15.52±2.78 14.50±2.18 0.08 
No. of IUTs, total 1.20±0.41 2.38±1.29 0.001 

Continuous variables are presented as mean ± SD and categorical variables as number and (percentage).

Neurological outcomes of fetuses surviving parvo B19 intrauterine blood transfusion.

aGA, gestational age.

bIUT, intrauterine blood transfusion.

cHB, hemoglobin.

dPLT, platelets.

Fetuses affected by parvo B19 presented for their first IUT at an earlier gestational age (22.91 ± 3.36 vs. 27.37 ± 4.67 weeks, respectively, p = 0.002), with higher rates of hydrops (93.33% vs. 16.98%, respectively, p < 0.001) and significantly lower hemoglobin (3.19 ± 2.76 vs. 6.39 ± 2.84 gr/dL, respectively, p = 0.001) and platelet levels (45.09 ± 30.58 vs. 146.50 ± 33.65 per microliter, respectively, p = 0.02), in comparison to the control group. As expected, fetuses in the control group required a higher number of IUTs than those in the study group (2.38 ± 1.29 vs. 1.20 ± 0.41, p = 0.001). The fetal and neonatal short- and long-term outcomes are presented in Table 2.

Table 2.

Fetal, perinatal, and long-term outcomes of both groups

Study group (n = 15, 22.1%)Control group (n = 53, 77.9%)p value
Abnormal fetal brain imaging findingsa 4 (26.67) 2 (3.77) 0.005 
Abnormal neonatal brain imaging findings 1 (6.67) 1 (1.89) 0.92 
Total Vineland score, percentile (range) 31.00 (9.0–91.0) 51.5 (6.0–97.0) 0.18 
 Loss to follow-up, n (%) 1 (6.67) 8 (15.10) 0.67 
 Age at follow-up, years (range) 3.65 (1.5 m-14 y) 6.53 (4 m-14 y) 0.004 
 Vineland low, n (%) 0 (0) 0 (0)  
 Vineland moderately low, n (%) 3 (21.43) 7 (15.56) 0.462 
 Vineland adequate, n (%) 9 (64.28) 35 (77.78) 0.462 
 Vineland moderately high, n (%) 2 (14.28) 3 (6.67) 0.462 
 Vineland high, n (%) 0 (0) 0 (0)  
GAb at delivery, weeks 38.20±3.55 35.43±1.75 <0.001 
Early preterm birth <34 weeks 1 (6.67) 6 (11.32) 1.0 
Vaginal delivery 11 (73.33) 21 (39.62) 0.07 
Cesarean section 4 (26.67) 32 (60.38) 0.034 
 Previous cesarean section 1 (25.0) 12 (37.5) 0.27 
 NRFHRc 2 (50.0) 16 (50) 0.48 
 Non-vertex 1 (25.0) 3 (9.37) 0.42 
 Other 0 (0.0) 1 (3.13) 0.68 
BWd, grams 2,775.46±765.55 2,621.80±523.52 0.45 
APGAR 5 min <7 0 (0.0) 2 (3.77) 1.0 
pH <7.2 0 (0.0) 3 (5.66) 0.82 
NICUe 3 (21.43) 24 (53.33) 0.01 
Study group (n = 15, 22.1%)Control group (n = 53, 77.9%)p value
Abnormal fetal brain imaging findingsa 4 (26.67) 2 (3.77) 0.005 
Abnormal neonatal brain imaging findings 1 (6.67) 1 (1.89) 0.92 
Total Vineland score, percentile (range) 31.00 (9.0–91.0) 51.5 (6.0–97.0) 0.18 
 Loss to follow-up, n (%) 1 (6.67) 8 (15.10) 0.67 
 Age at follow-up, years (range) 3.65 (1.5 m-14 y) 6.53 (4 m-14 y) 0.004 
 Vineland low, n (%) 0 (0) 0 (0)  
 Vineland moderately low, n (%) 3 (21.43) 7 (15.56) 0.462 
 Vineland adequate, n (%) 9 (64.28) 35 (77.78) 0.462 
 Vineland moderately high, n (%) 2 (14.28) 3 (6.67) 0.462 
 Vineland high, n (%) 0 (0) 0 (0)  
GAb at delivery, weeks 38.20±3.55 35.43±1.75 <0.001 
Early preterm birth <34 weeks 1 (6.67) 6 (11.32) 1.0 
Vaginal delivery 11 (73.33) 21 (39.62) 0.07 
Cesarean section 4 (26.67) 32 (60.38) 0.034 
 Previous cesarean section 1 (25.0) 12 (37.5) 0.27 
 NRFHRc 2 (50.0) 16 (50) 0.48 
 Non-vertex 1 (25.0) 3 (9.37) 0.42 
 Other 0 (0.0) 1 (3.13) 0.68 
BWd, grams 2,775.46±765.55 2,621.80±523.52 0.45 
APGAR 5 min <7 0 (0.0) 2 (3.77) 1.0 
pH <7.2 0 (0.0) 3 (5.66) 0.82 
NICUe 3 (21.43) 24 (53.33) 0.01 

Continuous variables are presented as mean ± SD and categorical variables as number and (percentage).

aAbnormal fetal brain imaging findings include cerebellar hypoplasia, ventriculomegaly, and intracranial hemorrhage.

bGA, gestational age.

cNRFHR, non-reassuring fetal heart rate.

dBW, birthweight.

eNICU, neonatal intensive care unit.

Overall, the parvo B19 group had higher rates of abnormal fetal brain imaging findings, including cerebellar hypoplasia and intracranial hemorrhage, compared to the control group (26.67% vs. 3.77%, p = 0.005). There was one case of myocarditis in the parvo B19 group that resolved following the acute phase of the infection. Patients with RBC alloimmunization were delivered at an earlier gestational age (35.43 ± 1.75 vs. 38.20 ± 3.55 weeks, respectively, p < 0.001), had higher rates of cesarean deliveries (60.38% vs. 26.67%, respectively, p = 0.034), and higher rates of NICU admission (53.33% vs. 21.43%, respectively, p = 0.01), most probably due to late prematurity.

The study and control groups did not differ in the rates of abnormal neonatal neuroimaging findings and in the rates of long-term neurodevelopmental impairment, as shown by their Vineland score results (21.43% vs. 15.56%, p = 0.462). Of note, the rates of neurodevelopmental impairment in the study and control groups were higher compared to the general population (21.43% and 15.56% vs. 10.6%) [32].

A multivariable analysis controlling for confounders such as gestational age at 1st IUT, hydrops presentation at 1st IUT, number of IUTs overall, and gestational age at delivery revealed that fetuses in the Parvo B19 group had an aOR of 6.23 (95% CI of 0.35–112.51) for neurodevelopmental delay and an aOR of 3.12 (95% CI 0.08–125.33) for abnormal fetal neuroimaging findings in comparison to fetuses in the RBC alloimmunization group (online suppl. Table 1; for all online suppl. material, see https://doi.org/10.1159/000530993; Table 2). Fetuses with abnormal neuroimaging findings and/or abnormal Vineland scores, from both groups, are presented in Table 3.

Table 3.

Short- and long-term outcomes of neonates with abnormal brain imaging findings and/or low Vineland scores

Presentation at 1st IUTGA at 1st IUTGeneticsFetal brain imaging findings*Neonatal brain imaging findingsGA at deliveryBirthweight, g, %tileVineland Score**NDI diag
Case#2 (Study) Hydrops 23+5 Normal TCD <3%tile TCD <3%tile 36+1 2,526; AGA Normal None 
Case#5 (Study) Hydrops 21+6 Normal TCD <3%tile Normal*** 39+5 4,000; LGA Normal None 
Case#6 (Study) Hydrops 22+4 N/A TCD <5%tile Normal 39+2 2,700; AGA Low None 
Case#12 (Study) Severe anemia 32+4 N/A Normal Not indicated 39+2 3,606; AGA Low None 
Case#15 (Study) Hydrops 22+5 Normal Intraventricular hemorrhage Normal 38+1 2,835; AGA Low None 
Case#3 (Control) Hydrops 22+5 N/A Normal Not indicated 30+5 1,925; AGA Low None 
Case#6 (Control) Severe anemia 29+3 Normal Normal Not indicated 35+4 2,680; AGA Low None 
Case#19 (Control) Severe anemia 30+6 N/A Normal Not indicated 34+5 3,000; AGA Low None 
Case#36 (Control) Severe anemia 22+4 Normal Normal Not indicated 37+0 2,955; AGA Low None 
Case#40 (Control) Hydrops 27+0 Normal Normal Not indicated 36+1 2,140; SGA Low None 
Case#42 (Control) Hydrops 19+3 Normal Ventriculomegaly Normal 34+0 2,135; AGA Normal None 
Case#44 (Control) Severe anemia 22+4 Normal Normal Not indicated 27+1 1,100; AGA Low CP 
Case#45 (Control) Severe anemia 16+1 Normal Intraventricular hemorrhage Intracranial hemorrhage 36+2 3,042; AGA Low Autism 
Presentation at 1st IUTGA at 1st IUTGeneticsFetal brain imaging findings*Neonatal brain imaging findingsGA at deliveryBirthweight, g, %tileVineland Score**NDI diag
Case#2 (Study) Hydrops 23+5 Normal TCD <3%tile TCD <3%tile 36+1 2,526; AGA Normal None 
Case#5 (Study) Hydrops 21+6 Normal TCD <3%tile Normal*** 39+5 4,000; LGA Normal None 
Case#6 (Study) Hydrops 22+4 N/A TCD <5%tile Normal 39+2 2,700; AGA Low None 
Case#12 (Study) Severe anemia 32+4 N/A Normal Not indicated 39+2 3,606; AGA Low None 
Case#15 (Study) Hydrops 22+5 Normal Intraventricular hemorrhage Normal 38+1 2,835; AGA Low None 
Case#3 (Control) Hydrops 22+5 N/A Normal Not indicated 30+5 1,925; AGA Low None 
Case#6 (Control) Severe anemia 29+3 Normal Normal Not indicated 35+4 2,680; AGA Low None 
Case#19 (Control) Severe anemia 30+6 N/A Normal Not indicated 34+5 3,000; AGA Low None 
Case#36 (Control) Severe anemia 22+4 Normal Normal Not indicated 37+0 2,955; AGA Low None 
Case#40 (Control) Hydrops 27+0 Normal Normal Not indicated 36+1 2,140; SGA Low None 
Case#42 (Control) Hydrops 19+3 Normal Ventriculomegaly Normal 34+0 2,135; AGA Normal None 
Case#44 (Control) Severe anemia 22+4 Normal Normal Not indicated 27+1 1,100; AGA Low CP 
Case#45 (Control) Severe anemia 16+1 Normal Intraventricular hemorrhage Intracranial hemorrhage 36+2 3,042; AGA Low Autism 

IUT, intrauterine blood transfusion; GA, gestational age; Genetics: K, karyotype; CMA, chromosomal microarray analysis.

TCD, trans-cerebellar diameter; CHF, congenital heart failure; BW, birthweight; ICH, intracranial hemorrhage; NDI, neurodevelopmental impairment; CP, cerebral palsy.

*Abnormal fetal brain imaging findings included neurosonographic images confirmed by MRI findings of cerebellar hypoplasia, intracranial hemorrhage, or ventriculomegaly.

**Low Vineland scores are defined as moderately low = 3rd–17th percentile and low ≤2nd percentile.

***Patient completed a neonatal neurosonogram but declined a neonatal MRI.

In the parvo B19 group, 4 fetuses (case#2, case#5, case#6 and case#15) had abnormal fetal brain imaging studies (3 cases of cerebellar hypoplasia and 1 case of intracranial hemorrhage). Only one of those abnormal findings (case#2) was supported in the neonatal life, showing persistent cerebellar hypoplasia on postpartum brain ultrasound.

Conversely, in the RBC alloimmunization group, only 2 fetuses (control#42 and control#45) had abnormal brain imaging studies (1 control with mild ventriculomegaly and 1 control with intracranial hemorrhage). Only one of these findings (control#45) was supported by neonatal brain imaging, showing persistent intracranial hemorrhage. Interestingly, there was no concordance between abnormal neuroimaging findings and abnormally low Vineland scores (Table 3).

Principal Findings

Our study indicates that fetuses affected by parvo B19 who required IUT, had higher rates of abnormal fetal neuroimaging findings, such as cerebellar hypoplasia and intracranial hemorrhage, compared to the RBC alloimmunization group, but this difference did not persist into the neonatal life. We demonstrated comparable rates of long-term neurodevelopmental impairment in the two groups (study and control), that were much higher (in both) than in the general population [32].

A multivariable analysis accounting for potential differences between the groups as gestational age at 1st IUT, presenting with hydrops at 1st IUT, number of IUTs overall, and gestational age at delivery demonstrated higher rates of adverse outcomes in the parvo B19 group, but due to a very small sample size and very wide confidence intervals, these data should be interpreted with caution.

Results in the Context of Other Studies and Clinical Implications

To date, only a few studies examining short-term neuroimaging findings and long-term neurodevelopmental outcomes after an IUT for parvo B19 infection have been published. There is an ongoing debate in the literature regarding the direct viral effect on the developing fetal brain and regarding its short- and long-term clinical significance.

There are reports suggesting that premature fetal blood vessels permit infection by parvo B19, causing perivascular inflammatory changes in the developing fetal brain [25, 33‒35]. Studies focusing on neuroimaging in neonates following intrauterine parvo B19 infection suggest that the virus may have neurotropic characteristics and therefore may cause cerebellar and/or cerebral injury [24, 35], specifically correlating with the parvo B19 viral load.

However, the significance or the persistence of those findings into neonatal life and childhood is unclear, as there are numerous studies to support brain plasticity, recovery, and regeneration, from multiple types of injury inflicted in fetal life [36‒38]. Of note, fetal neuroimaging finding of isolated cerebellar hypoplasia has a wide differential diagnosis and resultant prognoses. Cerebellar hypoplasia should not be diagnosed prior to 24 weeks of gestation due to inaccurate measurements prior to this gestational age [39]. When properly and definitively diagnosed, cerebellar hypoplasia, if persistent, can be associated with various other brain anomalies, aneuploidy, infections, ischemic insults, and metabolic disorders. If truly isolated, it can be a normal variant, although reports of long-term outcomes are sparse [40‒42].

Data on long-term neurodevelopmental outcomes after an IUT for any indication are limited and are especially scarce for parvo B19 IUT survivors. According to some studies, there is an increased rate of neurodevelopmental impairment following an IUT for parvo B19 infection, while according to others, there is not.

A review by Lindenburg et al. [43] pointed out that severe neurodevelopmental impairment after an IUT for parvo B19 infection in pregnancy is not rare and may occur in up to 12.5% of the survivors. Two other studies by De Jong et al. [20] and Nagel et al. [19] observed increased abnormal neurodevelopmental outcomes in survivors of IUT for parvo B19 infection.

De Jong et al. [20] reported severe developmental delay and cerebral palsy in 11% and 4% of the 28 fetuses who underwent an IUT for parvo B19 infection, a rate much higher compared to the Dutch general population. Nagel et al. [19] evaluated long-term outcomes in 16 hydropic fetuses with parvo B19 infection treated with an IUT and reported a 30% rate of developmental delay. Of note, 5 of the children included in the study were younger than 18 months of age at the time of testing, and the diagnosis was reversed at re-testing at an older age in 3 cases.

In contrast to the above, other studies suggested normal long-term neurological outcome following an IUT for fetal hydrops due to parvo B19 infection. Dembinski et al. [21] reported normal neurodevelopment in 20 survivors of an IUT following parvo B19 infection. No independent effect on developmental or intelligence outcomes was observed, even after stratifying for fetal hemoglobin levels, number of IUTs, or gestational age at delivery. However, this study was limited by a high loss-to-follow-up rate [35%].

Similarly, normal neurodevelopmental outcome of all 129 parvo B19 intrauterine infection-surviving infants was reported by Miller et al. [9]. But only 3 of the 129 examined survivors had developed fetal hydrops and required an intrauterine intervention. The evidence to support or dispute delayed neurodevelopment in long-term parvo B19 survivors is limited by studies of a small sample size that lack structured long-term follow-up and by the fact that the underlying mechanism is still not fully understood.

One should bear in mind that cerebral injury and neurological impairment may be caused by hypoxic-ischemic injury due to severe fetal anemia and fetal hydrops. According to the LOTUS study [16], which investigated the long-term neurodevelopmental outcome of 291 children after IUT for RBC alloimmunization, several factors can be associated with increased risk for neurodevelopmental impairment, including severity of anemia and fetal hydrops. This observation is in line with the reported rates of neurodevelopmental impairment after an IUT for parvo B19-induced anemia and might be related to the earlier appearance of fetal anemia and the higher rates of hydrops fetalis at presentation in the parvo B19 group.

In our study, abnormal fetal neuroimaging findings were significantly higher in the parvo B19 group in comparison to the alloimmunization group, but long-term outcomes did not differ between the groups. These findings might be explained by direct viral effect on the developing brain but may be attributed even more to the presence of an early severe anemia and higher rates of hydrops fetalis.

Strengths and Limitations

Our study has several strengths. First, we reported on a relatively large cohort of fetuses treated at a single tertiary center. Second, to the best of our knowledge, this is the first study comparing the neurological findings and neurodevelopmental outcomes of fetuses undergoing an IUT due to fetal anemia resulting from parvo B19 infection versus RBC alloimmunization. We acknowledge the fact that anemia and hydrops resulting from RBC alloimmunization are pathophysiologically different in nature from those caused by parvo B19. One is driven by a hemolytic process, whereas the other by an aplastic crisis. Thus, with RBC alloimmunization, the effects on the developing brain can be further affected in the neonatal period by hemolytic effects, including hyperbilirubinemia and kernicterus. However, to overcome this, our analysis controlled for the effects of intrauterine blood transfusion, intrauterine hydrops, and severe anemia.

Our study is not without limitations. The retrospective nature of this study raises the possibility of biases inherent to such investigations. Since there was no strict control of all study aspects, we could not exclude the possibility that additional unknown factors (e.g., differential pediatric care, socioeconomic status) could explain the differences observed between the groups. Additionally, not all cases in the study population underwent an MRI, leading to subtle findings being misdiagnosed. However, abnormalities considered for the secondary outcome (cerebellar hypoplasia, intracranial hemorrhage, or severe ventriculomegaly) are well identifiable on fetal neurosonogram. Another limitation is the fact that in the study groups, the average child’s age was 3.65 years, which differs from the control group and might not be sufficient for the definition of long-term neurological follow-up. Lastly, another limitation is derived from using the Vineland questionnaires to examine the neurodevelopmental outcome of our participants, which could lead to some respondent biases.

To conclude, survivors of IUT for parvo B19-induced fetal anemia do not differ from those surviving an IUT due to RBC alloimmunization in rates of long-term neurodevelopmental delay. The higher rates of abnormal neuroimaging findings in fetal life, resolving after delivery, might be attributed to the parvo B19 infection itself or to presence of early anemia and the hydropic state. Further studies, preferably of a prospective nature, are needed to distinguish between the two possible underlying causes. These studies should include the complete fetal parvo B19 exposed population (asymptomatic and symptomatic women), controlling for degree of anemia, with standardized long-term longitudinal neurodevelopmental follow-up, including postnatal testing with imaging studies and neurodevelopmental evaluations. Therefore, following an IUT for fetal anemia due to parvo B19 infection, fetal neuroimaging should be considered, including brain neurosonogram and fetal brain MRI, with need for neurological long-term standardized follow-up for surviving children.

This study protocol was reviewed and approved by the SHEBA Medical Center REB Committee, approval number 6076-19-SMC. Informed verbal consent was obtained to participate in the study from all participants’ parents or legal guardian or next of kin. This was done after sending preliminary notifying letters regarding a potential phone interaction. Verbal consent was specifically approved by the SHEBA Medical Center REB Committee, approval number 6076-19-SMC.

The authors have no conflicts of interest to declare.

No funding was received in the preparation of this manuscript.

Alexandra Berezowsky contributed to design of work, analysis and interpretation of data, revision of manuscript, and final approval of the version to be published. Alyssa Hochberg contributed to interpretation of data, critical revision of manuscript, and final approval of the version to be published. Noam Regev contributed to the acquisition and analysis of data, manuscript drafting, and final approval of the version to be published. Boaz Weisz, Shlomo Lipitz, and Yoav Yinon contributed to the conception and design of the work, revision of manuscript, and final approval of the version to be published.

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

1.
Enders
M
,
Weidner
A
,
Zoellner
I
,
Searle
K
,
Enders
G
.
Fetal morbidity and mortality after acute human parvovirus B19 infection in pregnancy: prospective evaluation of 1018 cases
.
Prenat Diagn
.
2004
;
24
(
7
):
513
8
.
2.
van Gessel
PH
,
Gaytant
MA
,
Vossen
ACTM
,
Galama
JMD
,
Ursem
NTC
,
Steegers
EAP
.
Incidence of parvovirus B19 infection among an unselected population of pregnant women in The Netherlands: a prospective study
.
Eur J Obstet Gynecol Reprod Biol
.
2006 Sep 1
128
1–2
46
9
.
3.
de Jong
EP
,
de Haan
TR
,
Kroes
ACM
,
Beersma
MFC
,
Oepkes
D
,
Walther
FJ
.
Parvovirus B19 infection in pregnancy
.
J Clin Virol
.
2006 May
36
1
1
7
.
4.
Corcoran
A
,
Doyle
S
.
Advances in the biology, diagnosis and host-pathogen interactions of parvovirus B19
.
J Med Microbiol
.
2004 Jun
53
Pt 6
459
75
.
5.
Gilbert
GL
.
Parvovirus B19 infection and its significance in pregnancy
.
Commun Dis Intell
.
2000 Mar
24
Suppl l
69
71
.
6.
Prospective study of human parvovirus [B19] infection in pregnancy public health laboratory service working party on fifth disease
.
BMJ
.
1990 May 5
300
6733
1166
70
.
7.
Chisaka
H
,
Morita
E
,
Yaegashi
N
,
Sugamura
K
.
Parvovirus B19 and the pathogenesis of anaemia
.
Rev Med Virol
.
2003
;
13
(
6
):
347
59
.
8.
Norbeck
O
,
Papadogiannakis
N
,
Petersson
K
,
Hirbod
T
,
Broliden
K
,
Tolfvenstam
T
.
Revised clinical presentation of parvovirus B19-associated intrauterine fetal death
.
Clin Infect Dis
.
2002 Nov
35
9
1032
8
.
9.
Miller
E
,
Fairley
CK
,
Cohen
BJ
,
Seng
C
.
Immediate and long term outcome of human parvovirus B19 infection in pregnancy
.
Br J Obstet Gynaecol
.
1998 Feb
105
2
174
8
.
10.
Cameron
AD
,
Swain
S
,
Patrick
WJA
.
Human parvovirus B19 infection associated with hydrops fetalis
.
Aust N Z J Obstet Gynaecol
.
1997
;
37
(
3
):
316
9
.
11.
Rodis
JF
,
Rodner
C
,
Hansen
AA
,
Borgida
AF
,
Deoliveira
I
,
Shulman Rosengren
S
.
Long-term outcome of children following maternal human parvovirus B19 infection
.
B19 Infect
.
1998
;
91
(
1
):
125
8
.
12.
Schild
RL
,
Bald
R
,
Plath
H
,
Eis-Hübinger
AM
,
Enders
G
,
Hansmann
M
.
Intrauterine management of fetal parvovirus B19 infection
.
Ultrasound Obstet Gynecol
.
1999 Mar
13
3
161
6
.
13.
Fairley
CK
,
Smoleniec
JS
,
Caul
OE
,
Miller
E
.
Observational study of effect of intrauterine transfusions on outcome of fetal hydrops after parvovirus B19 infection
.
Lancet
.
1995
;
346
(
8986
):
1335
7
.
14.
Sensorineural outcome at 2 Years for survivors of erythrobla: Obstetrics and Gynecology
.
15.
Harper
DC
,
Swingle
HM
,
Weiner
CP
,
Bonthius
DJ
,
Aylward
GP
,
Widness
JA
.
Long-term neurodevelopmental outcome and brain volume after treatment for hydrops fetalis by in utero intravascular transfusion
.
Am J Obstet Gynecol
.
2006 Jul
195
1
192
200
.
16.
Lindenburg
IT
,
Smits-Wintjens
VE
,
Van Klink
JM
,
Verduin
E
,
Van Kamp
IL
,
Walther
FJ
.
Long-term neurodevelopmental outcome after intrauterine transfusion for hemolytic disease of the fetus/newborn: the LOTUS study
.
Am J Obstet Gynecol
.
2012
206
2
141.e1
141.e8
.
17.
Van Klink
JMM
,
Koopman
HM
,
Oepkes
D
,
Walther
FJ
,
Lopriore
E
.
Long-term neurodevelopmental outcome after intrauterine transfusion for fetal anemia
.
Early Hum Dev
.
2011
;
87
(
9
):
589
93
.
18.
Perkin
MA
,
English
PMB
.
Immediate and long term outcome of human parvovirus B19 infection in pregnancy
.
BJOG
.
1998
;
105
(
12
):
1337
8
.
19.
Nagel
HTC
,
De Haan
TR
,
Vandenbussche
FPHA
,
Oepkes
D
,
Walther
FJ
.
Long-term outcome after fetal transfusion for hydrops associated with parvovirus B19 infection
.
Obstet Gynecol
.
2007
;
109
(
1
):
42
7
.
20.
De Jong
EP
,
Lindenburg
IT
,
Van Klink
JM
,
Oepkes
D
,
Van Kamp
IL
,
Walther
FJ
.
Intrauterine transfusion for parvovirus B19 infection: long-term neurodevelopmental outcome
.
Am J Obstet Gynecol
.
2012
206
3
204.e1
204.e5
.
21.
Dembinski
J
,
Haverkamp
F
,
Maara
H
,
Hansmann
M
,
Eis-Hübinger
AM
,
Bartmann
P
.
Neurodevelopmental outcome after intrauterine red cell transfusion for Parvovirus B19-induced fetal hydrops
.
BJOG
.
2002
;
109
(
11
):
1232
4
.
22.
Margolis
G
,
Kilham
L
.
Parvovirus infections, vascular endothelium, and hemorrhagic encephalopathy
.
Lab Invest
.
1970
;
22
(
5
):
478
88
.
23.
Margolis
G
,
Kilham
L
.
Problems of human concern arising from animal models of intrauterine and neonatal infections due to viruses: a review
.
Prog Med Virol
.
1975
;
20
:
79
113
.
24.
Maisonneuve
E
,
Garel
C
,
Friszer
S
,
Pénager
C
,
Carbonne
B
,
Pernot
F
.
Fetal brain injury associated with parvovirus B19 congenital infection requiring intrauterine transfusion
.
Fetal Diagn Ther
.
2019 Jul 1
46
1
1
11
.
25.
Isumi
H
,
Nunoue
T
,
Nishida
A
,
Takashima
S
.
Fetal brain infection with human parvovirus B19
.
Pediatr Neurol
.
1999
;
21
(
3
):
661
3
.
26.
Kerr
JR
,
Barah
F
,
Chiswick
ML
,
McDonnell
GV
,
Smith
J
,
Chapman
MD
.
Evidence for the role of demyelination, HLA-DR alleles, and cytokines in the pathogenesis of parvovirus B19 meningoencephalitis and its sequelae
.
J Neurol Neurosurg Psychiatry
.
2002
;
73
(
6
):
739
46
.
27.
Rodeck
CH
,
Nicolaides
KH
,
Warsof
SL
,
Fysh
WJ
,
Gamsu
HR
,
Kemp
JR
.
The management of severe rhesus isoimmunization by fetoscopic intravascular transfusions
.
Am J Obstet Gynecol
.
1984 Nov 15
150
6
769
74
.
28.
Cosmi
E
,
Mari
G
,
Delle Chiaie
L
,
Detti
L
,
Akiyama
M
,
Murphy
J
.
Noninvasive diagnosis by Doppler ultrasonography of fetal anemia resulting from parvovirus infection
.
Am J Obstet Gynecol
.
2002 Nov
187
5
1290
3
.
29.
Delle Chiaie
L
,
Buck
G
,
Grab
D
,
Terinde
R
.
Prediction of fetal anemia with Doppler measurement of the middle cerebral artery peak systolic velocity in pregnancies complicated by maternal blood group alloimmunization or parvovirus B19 infection
.
Ultrasound Obstet Gynecol
.
2001 Sep
18
3
232
6
.
30.
Surveillance of Cerebral Palsy in Europe
.
Surveillance of cerebral palsy in Europe: a collaboration of cerebral palsy surveys and registers. Surveillance of Cerebral Palsy in Europe [SCPE]
.
Dev Med Child Neurol
.
2000 Dec
42
12
816
24
.
31.
Sparrow
SS
,
Cicchetti
DV
,
Balla
DA
Vineland-II survey forms manual [Vineland adaptive behavior scales]
.
2005
326
.
32.
ילדים עם מוגבלות בישראל
.
מחקר ארצי » Brookdale ברוקדייל : Brookdale ברוקדייל [Internet]
. [cited 2022 Nov 25]. Available from: https://brookdale.jdc.org.il/publication/children-with-disabilities-in-israel-a-national-study/.
33.
Mylonas
I
,
Gutsche
S
,
Anton
G
,
Jeschke
U
,
Weissenbacher
ER
,
Friese
K
.
Parvovirus B 19 infection during pregnancy
.
Z Geburtshilfe Neonatol
.
2007 Apr
211
2
60
8
.
34.
de Jong
EP
,
Walther
FJ
,
Kroes
ACM
,
Oepkes
D
.
Parvovirus B19 infection in pregnancy: new insights and management
.
Prenat Diagn
.
2011 May
31
5
419
25
.
35.
Pistorius
LR
,
Smal
J
,
De Haan
TR
,
Page-Christiaens
GCML
,
Verboon-Maciolek
M
,
Oepkes
D
.
Disturbance of cerebral neuronal migration following congenital parvovirus B19 infection
.
Fetal Diagn Ther
.
2008
;
24
(
4
):
491
4
.
36.
Kirton
A
,
Deveber
G
.
Stroke in the fetus and neonate
.
Future Cardiol
.
2006 Sep
2
5
593
604
.
37.
Thomason
ME
.
Development of brain networks in utero: relevance for common neural disorders
.
Biol Psychiatry
.
2020 Jul
88
1
40
50
.
38.
Anderson
AL
,
Thomason
ME
.
Functional plasticity before the cradle: a review of neural functional imaging in the human fetus
.
Neurosci Biobehav Rev
.
2013 Nov
37
9 Pt B
2220
32
.
39.
Malinger
G
,
Lev
D
,
Lerman-Sagie
T
The fetal cerebellum. Pitfalls in diagnosis and management
.
2009
. [cited 2023 Jan 22]; Available from: www.interscience.wiley.com.
40.
Garel
C
.
Posterior fossa malformations: main features and limits in prenatal diagnosis
.
Pediatr Radiol
.
2010 Jun
40
6
1038
45
.
41.
Poretti
A
,
Leventer
RJ
,
Cowan
FM
,
Rutherford
MA
,
Steinlin
M
,
Klein
A
.
Cerebellar cleft: a form of prenatal cerebellar disruption
.
Neuropediatrics
.
2008 Apr
39
2
106
12
.
42.
Atallah
A
.
Guibaud | laurent, gaucherand P, massardier | jerome, vincent des portes |, massoud M. Fetal and. perinatal outcome associated with small cerebellar diameter based on second-or third-trimester ultrasonography
.
Prenat Diagn
.
2019
;
39
:
536
43
.
43.
Lindenburg
ITM
,
van Klink
JM
,
Smits-Wintjens
VEHJ
,
van Kamp
IL
,
Oepkes
D
,
Lopriore
E
.
Long-term neurodevelopmental and cardiovascular outcome after intrauterine transfusions for fetal anaemia: a review
.
Prenat Diagn
.
2013
;
33
(
9
):
815
22
.