# High Rate of Severe Fetal Outcomes Associated with Maternal Parvovirus B19 Infection in Pregnancy

Authors: Richard H. Beigi; Harold C. Wiesenfeld; Daniel V. Landers; Hyagriv N. Simhan
Journal: Infectious Diseases in Obstetrics and Gynecology
 (2008)

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## Abstract

Objective. To augment the understanding of parvovirus B19 infection in pregnancy with respect to maternal characteristics and their corresponding fetal outcomes.
Study Design. Retrospective case-series of all women referred to Magee-Women_s Hospital with serologically-documented parvovirus B19 infection during pregnancy from 1998–2001.
Results. All 25 cases that are available for analysis occurred from January through June. The frequency of cases varied substantially from year to year, with 14 cases in 1998, 0 cases in 1999 and 2000, and 11 cases in 2001. In contrast to previous reports, the minority of women [4/25(16%)] experienced symptoms attributable to parvovirus B-19 infection although 3 of 25 (12%) fetuses developed hydrops fetalis and 4/25 (16%) suffered an intrauterine of fetal death.
Conclusions. These findings suggest that parvovirus B19 infection in pregnancy follows seasonal and annual trend variation, may produce a lower frequency of maternal symptoms and a higher fetal loss rate than previously reported. Synopsis.
Maternal parvovirus B19 infection follows seasonal and annual variation is often asymptomatic and may have higher fetal loss rates than previously reported. Continued surveillance is warranted.


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## Body

## 1. Introduction

Parvovirus B19 is
a small, nonenveloped DNA virus that exclusively infects humans. After
infection, parvovirus B19 replication occurs primarily in erythrocytes and
erythroblasts which can lead to anemia in predisposed individuals. Children who
are infected with parvovirus B19 typically develop erythema infectiosum (fifth
disease) which is characterized by a “slapped-cheek” rash, low-grade fever, and
mild influenza-like symptoms [1]. Infected healthy adults
generally have mild constitutional symptoms only. In contrast,
immune-compromised individuals including fetuses can develop severe chronic
anemia requiring directed therapies [1]. Transmission occurs via respiratory
secretions, and typically occurs in outbreak fashion in the spring in childcare
facilities or schools, although outbreaks may occur sporadically
year-round.Infection transmitted
in utero from a susceptible
mother to the immune-incompetent fetus is recognized as an infrequent cause of
fetal morbidity and mortality.  Risk
factors for maternal infection have been described in a Danish population, and
include large number of children in the household and
occupational exposure (such as teacher or day-care worker) [2, 3].
Although adult disease is generally mild, fetal parvovirus B19 infection can
cause spontaneous abortion in the early part of pregnancy and aplastic anemia, nonimmune
hydrops fetalis and in utero fetal demise [4].The exact
frequency of these negative outcomes in
utero is unclear and there currently is no uniform consensus in the
obstetrical community as to the indications for conservative versus aggressive
management of maternal parvovirus B-19 infection [5]. The largest cohort of 618
parvovirus-exposed pregnant women described by Harger et al. has suggested that
perinatal morbidity and mortality is rare among pregnancies complicated by parvovirus
B19 infection [6]. Among 52 documented maternal seroconversions, they reported
that there were no cases of nonimmune hydrops fetalis or fetal death. In
addition, the majority of these women had symptoms attributable to parvovirus
infection, making clinical identification easier.We describe a more
recent series of women from the same institution to highlight alternative clinical
findings and higher rates of severe fetal outcomes from previous reports,
highlighting the need for continued surveillance of this potentially
devastating infectious disease in pregnancy.


## 2. Material and Methods

This was a retrospective
case-series of all gravid women referred to our hospital for possible parvovirus
B19 exposure between 1998 and 2001. Magee-Women’s is a large tertiary-care
maternity hospital that serves as a referral center for the entire western Pennsylvania, eastern Ohio and northern West Virginia
region. This study was approved by the Magee-Women’s Hospital institutional
review board.Demographic,
medical, occupational, and outcome information from pregnant women referred to
the Maternal-Fetal Medicine Division at Magee-Women’s Hospital for evaluation
of possible exposure to parvovirus B19 (as well as specific information
regarding the nature of the exposure) was collected using a standardized
questionnaire. Other clinical and obstetric outcome
information was obtained using a computerized perinatal database maintained at
our institution. All patients with suspected exposure to parvovirus B19 had
serial antibody titers to parvovirus B19
drawn to verify infection and were followed
with the protocol outlined in Figure1. For women with documented maternal
infection (seroconversion of IgM), the fetus underwent serial ultrasound
evaluation weekly, and a cordocentesis was offered when the ultrasound
demonstrated evidence of fetal hydrops or if the middle cerebral artery peak
systolic velocity values suggested severe anemia (middle cerebral artery peak
systolic velocity, >1.50 multiples of the median) as per our divisional
guidelines for practice.Figure 1
Diagnostic and
therapeutic protocol for evaluation of possible parvovirus B19 exposure in
pregnancy.Categorical data
were evaluated using descriptive statistics with the assistance of Stata 7.0 for Windows (Stata Corp., College
Station, Tex, USA)


## 3. Results

There were 25 cases of
serologically-documented parvovirus B19 infection during pregnancy from 1998
through 2001. There was clear seasonal variation in disease incidence, with all
cases occurring from January through June. The frequency of cases demonstrated
substantial yearly variation, with 14 cases in 1998, 0 cases in 1999 and 2000,
and 11 cases in 2001. The median age of the women in our cohort was 33
years (range, 16–39) and the
median number of children living at home with the women was 2 (range, 0–4). The median
gestational age at the time of diagnosis of maternal seroconversion among the
women was 222/7 weeks (range 2–41). In terms of
clinical findings, 19 (76%) of the women presented for evaluation because they
had a child at home with symptoms of pediatric parvovirus infection and only 4
(16%) of women were symptomatic (Table 1).Table 1
Occupation and clinical
characteristics of women.
CohortN=25OccupationN(%)Work
at home11
(44%)Business/office7
(28%)Health
care6
(24%)Student/teacher1
(4%)Clinical characteristicsN(%)Asymptomatic21
(84%)Polyarthralgia2
(8%)Rash4
(16%)Fever1
(4%)Pregnancy outcomesN(%)No.
of ultrasounds performed,
median
(range)6
(0–20)Hydrops
fetalis3
(12%)IUFD(a),4
(16%)(a) IUFD =
intrauterine fetal death.Pregnancy outcomes
are also described in Table1. Of significance, hydrops fetalis, and
intrauterine fetal demise occurred in 12% and 16% of our cohort, respectively.
Among the three fetuses noted to have hydrops fetalis, two were concomitantly diagnosed
with intrauterine fetal deaths. The third case of hydrops was noted in a living
fetus. Cordocentesis and intrauterine blood transfusion was offered to this
patient and she declined. On serial surveillance ultrasounds, this fetus was
noted to have recovery of hydrops over two weeks with concomitant improvement
of noninvasive assessments of fetal anemia using middle cerebral artery Doppler
velocimetry. Among the four fetal deaths, two were the aforementioned cases
with hydrops and two occurred without hydrops. Of these 4 fetal deaths, only 1
woman had symptoms potentially attributable to parvovirus B-19 infection
(rash).The median
gestational age at birth was 39 weeks (range, 14–42 weeks), median
birth weight was 3449 grams (range, 280–4210), and median
Apgar scores were 8 and 9 at 1 and 5 minutes, respectively.


## 4. Discussion

This investigation
found much higher frequencies of untoward in utero effects attributable to parvovirus B-19 infection than
previously reported. We report a frequency of 12% for hydrops fetalis and 16%
for in utero fetal demise. Reported frequencies from large studies and reviews in
the literature for hydrops fetalis and fetal demise are much lower, ranging
from 0–1.0% and 0–6.0%, respectively (1,6). We also found significant seasonal
variation in rates of perinatal complications from parvovirus B-19
infection.  Clinicians should be aware of
these findings and recognize that nonimmune hydrops fetalis or fetal demise is
a real possibility and appears to fluctuate based on seasonal and potential virulence
factors.Our data support
the notion that maternal symptoms in the setting of parvovirus B19 infection
during pregnancy are uncommon. This is in contrast to Harger’s series in that
the majority of those women (67.0%) had symptoms attributable to parvovirus
B-19 infection, and thus sought care. The majority of the women in our cohort
presented due to a child at home with symptoms of parvovirus infection. This
highlights the importance of educating women about the nature of parvovirus
infection in the pediatric setting. It is critical to note that the prenatal care
provider should test any potentially exposed pregnant woman for parvovirus
infection even if she is asymptomatic, given the relatively low frequency of
symptoms among women who acquired infection in this cohort. Moreover, only 1 of
4 infected women who later suffered a fetal demise reported symptoms,
highlighting the lack of correlation between maternal symptoms and untoward
fetal outcomes.Recent data
support the association of parvovirus B19 infection in pregnancy with
nonhydropic fetal death in the second and third trimesters [7]. Ascertainment
of our cohort was contingent upon the patient presenting for care after
referral based on a suspected exposure or (more rarely) symptoms of infection.
In fact, the reproductive burden of parvovirus B19 infection during pregnancy
may be greater than our estimates in this report. This investigation does not
include an estimate of the contribution of unrecognized maternal parvovirus B19
infection to spontaneous abortion, stillbirth, or other adverse pregnancy
outcomes.It is not readily
apparent why fetal outcomes and the maternal symptom complex are different in
this report compared with findings from the same institution over the previous
eight years. No women in our cohort had medical problems placing them at risk
for immune compromise. It is unclear if the differences in outcomes are mere
statistical  fluctuations or if there has
been a change in the virulence of parvovirus B-19. Changing seasonal virulence
patterns is a recognized phenomenon for other viral infections (influenza) and
is an equally viable explanation of our findings. It is also possible that
given our small sample size and the possibility of selection bias, our findings
are not generalizable to the obstetrical population at large and represent a
small window into the overall reproductive burden of parvovirus B-19 infection.When combining
previous reports and the current report the relationship between congenital parvovirus
B19 infection and adverse pregnancy outcome is clear, and may occur more
commonly than previously reported. One strategy that may be available in the
future for prevention of disease outbreaks is vaccination. A Phase I study of a
recombinant human parvovirus B19 vaccine suggests safety and immunogenicity
among 24 subjects [8]. Certainly, such an intervention is early in the
development phase, but hopefully will provide us with a solution to a
concerning problem. Until the development of such a vaccine, however, we are
obligated to maintain vigilance for this serious pathogen and counsel our
patients appropriately with respect to both prevention and management of this increasingly
recognized and potentially devastating congenital infectious disease.



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