http://informahealthcare.com/jmf ISSN: 1476-7058 (print), 1476-4954 (electronic) J Matern Fetal Neonatal Med, 2015; 28(2): 168–171 ! 2014 Informa UK Ltd. DOI: 10.3109/14767058.2014.907265

ORIGINAL ARTICLE

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Primary maternal cytomegalovirus infections during pregnancy: association of CMV hyperimmune globulin with gestational age at birth and birth weight Giovanni Nigro1, Ilaria Capretti1, Anne-Marie Manganello2, Al M. Best3, and Stuart P. Adler2 1

Pediatric Unit and School, University of L’Aquila, San Salvatore Hospital, L’Aquila, Italy, 2Department of Microbiology and Immunology, Virginia Commonwealth University, Medical College of Virginia Campus, Richmond, VA, USA, and 3School of Dentistry, Virginia Commonwealth University, Medical College of Virginia Campus, Richmond, VA, USA Abstract

Keywords

Background: Cytomegalovirus (CMV) hyperimmune globulin (HIG) may be helpful after a primary maternal CMV infection during pregnancy as a therapy for infected fetuses or to prevent maternal-to-fetus transmission of CMV. Although immunoglobulins administered during pregnancy appear safe, previous studies have not monitored HIG for a possible effect on duration of gestation and birth weight. Methods: We used clinical data on 358 women with a primary CMV infection during pregnancy, 164 of whom received one or more infusions of HIG. Results: The average birth weight of the 358 infants was 3076 g and the average gestational age at delivery for 351 women was 38.2 weeks. After adjusting for potential confounding variables, the only factor associated with low birth weight and the duration of gestation was the presence of symptoms at birth. The receipt of HIG was not associated with either a diminished birth weight or a reduced duration of pregnancy. The receipt of multiple doses of HIG (range 1–8) was significantly correlated with an increase in birth weight (p ¼ 0.006) and gestational age at delivery (p ¼ 0.014). This correlation was also significant for all asymptomatic infants and for infants whose mothers received multiple doses of HIG to prevent fetal infection. Conclusion: HIG administration during pregnancy is not associated with either diminished gestation or decreased birth weight and may enhance these parameters among women who receive multiple doses starting in early gestation.

Cytomegalovirus, immunoglobulin, pregnancy

Introduction Annually in Europe and the United States an estimated 80 000 pregnant women acquire a primary cytomegalovirus (CMV) infection (seroconvert) during pregnancy. For women who seroconvert the mother-to-fetus transmission rate increases from 33% when seroconversion is in early gestation to 75% when serconversion is in late gestation. Of congenitally infected newborns, disease occurs in approximately 50% if maternal infection occurs during the first half of pregnancy [1,2]. Long-term disease in newborns includes severe permanent neurologic damage comprised of impaired development, mental retardation and neurosensory hearing deficit. Several studies suggest that CMV hyperimmune globulin (HIG) when administered to women with a primary CMV infection during pregnancy is effective for either treating

Address for correspondence: Stuart P. Adler, Department of Microbiology and Immunology, Virginia Commonwealth University, 1101 East Marshal Street, Richmond, VA 23298, USA. Tel: 804-8281807. Fax: 804-827-0575. E-mail: [email protected]

History Received 3 March 2014 Accepted 19 March 2014 Published online 25 April 2014

a CMV infected fetus or for preventing maternal-to-fetal transmission of CMV [2–6]. Although due to a lack of randomized trials, HIG is not approved by any regulatory agency for use during pregnancy, HIG is often administered off-label during pregnancy. Since the 1950s, immune globin has been safely administered to pregnant women during pregnancy but large studies on the safety of HIG have not been reported. CMV causes low birth weight due to placental dysfunction with intrauterine hypoxia and malnutrition even in asymptomatic infants [7,8]. In our previous studies we observed no maternal or fetal adverse events associated with HIG administration during pregnancy [2,4]. The birth weight data were analyzed but we did not report the possible effects of HIG administration during pregnancy on duration of pregnancy and birth weights. In part, this was because a larger sample size was needed to control for the confounding effects of CMV congenital infection on birth weights. We now report a retrospective observational study with a larger sample size that assessed the association between receipt of maternal HIG and prematurity and birth weights.

CMV hyperimmune globulin and birth weight

DOI: 10.3109/14767058.2014.907265

Methods

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Patients The patients comprised 358 women who had primary CMV infection (304 seroconverted and 54 had positive IgM and low CMV IgG avidity) during pregnancy and delivered an infant with a recorded birth weight. 320 women were evaluated in Italy and of these 221 were included in one prospective study and one retrospective study previously reported [2,4]. Other patients from Italy were referred to one of us (GN). Thirty-eight patients with complete recorded data were from the United States and were enrolled in the National CMV Registry for Pregnant women (CMVregistry.org). Comprehensive case report data were available on each patient. Using an intent-to-treat philosophy, all patients are included in the analysis here even if incomplete information was available. The case report data used in this study were maternal age at conception, gestational age at the time of maternal CMV infection, the viral load in amniotic fluid if performed, if treated with HIG, the gestational age at the first dose and the number of subsequent doses, estimated gestational age at delivery as obtained from the medical record using the LMP method, and if the infant had symptoms at birth. Symptoms at birth excluded birth weight but included ventriculomegaly, periventricular cysts or calcifications, cerebral atrophy, optic atrophy, microcephaly, leukoencephalopathy, mild-to-severe hearing loss in one or both ears, and thrombocytopenia. Gestational ages were clinical estimates made by the patient’s obstetrician. The gestational age at maternal infection was estimated after maternal seroconversion and defined as half way between the last seronegative serum and the first seropositive serum. For 54 women the first sera was seropositive with low IgG avidity for CMV. For these women the time of maternal infection was defined as the first serum with low avidity.

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The dose of Cytotect in Italy was either 100 units/kg or 200 units/kg of maternal weight as previously reported [2]. In the US, Cytogam was used at 150–200 mg/kg of maternal weight. All studies were IRB approved in the US and by the local Ethical Committees in Italy. All patients provided written consent permitting use of their medical records for research purposes. Statistical methods All statistical analyses were done using JMP software version 10 (SAS Institute Inc., Cary, NC). To determine which characteristics may be associated with the outcomes of interest – birth weight and gestational age at delivery – univariate tests were first used to screen the characteristics. Continuous characteristics were tested for a non-zero correlation and groups were compared using a t-test. Those characteristics whose unadjusted p were below 0.2 were included in a multiple regression analysis. Difference between correlations was tested using an interaction test in the multiple regression analysis. Significance was declared at p50.05.

Results The average birth weight of the 358 infants was 3076 g (SD ¼ 629), significantly less than the average birth weight of 3400 g for developed countries (t ¼ 9.7, p50.0001). The average gestational age at delivery for 351 women was 38.2 weeks (SD ¼ 2.3), also significantly less than the 40 weeks of the average pregnancy (t ¼ 15, p50.0001). To determine possible reasons for these lower than normal values we sought associations between a variety of factors and birth weights and gestational ages at delivery. Table 1 shows that the following characteristics were individually related to birth weight: maternal age at diagnosis, congenital infection,

Table 1. Association of birth weight with maternal and infant characteristics. Univariate analysis Characteristics Maternal age in years at diagnosis Gestational age in weeks at the time of seroconversion Gestation age in weeks when first treated with HIG Copy number of CMV DNA in AF

Number

Mean ± SD

228 287

30.3 ± 4.77 15.8 ± 7.51

161

22.4 ± 6.07

59

833 951

Range

1 462 941

t ratio

p value

15 to 41 2 to 34

1.61 1.02

10 to 37 500 to 7 210 854

Adjusted analysis t ratio

p value

0.1082 0.3090

1.14 Not done

0.2564 Not done

0.84

0.4025

Not done

Not done

0.78

0.4396

Not done

Not done

Birth weight (g) Congenital infection Yes No Maternal HIG Yes No Symptoms at birth Yes No Location Italy US

267 89

3013 3258

623 619

770 to 4750 822 to 4900

3.22

0.0014

1.49

0.1374

164 194

3179 2990

628 619

822 to 4900 770 to 4750

2.85

0.0046

1.55

0.1223

77 278

2784 3162

681 585

770 to 3880 1072 to 4900

4.83

50.0001

3.38

0.0009

320 38

3088 2975

612 760

770 to 4900 822 to 4536

1.04

0.2992

Not done

Not done

Correlation was used to test for a relationship with continuous characteristics and a t test was used to test for group differences. Those factors passing the univariate screening (p50.2) were included in a multiple regression analysis for final testing (p50.05).

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G. Nigro et al.

J Matern Fetal Neonatal Med, 2015; 28(2): 168–171

receipt of maternal HIG and neonatal symptoms at birth but that when all of these were included in a multiple regression analysis (p50.0001), only symptoms at birth were related to birth weight (p50.001). Those with symptoms at birth were 378 g smaller (95% CI ¼ 163–618 g) than those without symptoms. Receipt of maternal HIG was not associated with low birth rate (p40.1) and, in fact, those receiving HIG had nominally higher birth weights. Additionally, since maternal age was missing in 130 cases and it was not significant in the multiple regression, the analysis was repeated without this predictor using all of the patients and the results were identical; that is, symptoms were significant (p40.0001) and HIG was not (p ¼ 0.0641). Table 2 shows the results for the 351 patients where gestational age at delivery was recorded. In the preliminary analyses, the following characteristics passed the screening (p50.2): gestational age when first treated with HIG, congenital infection and symptoms at birth. Using these factors in multiple regression, only symptoms at birth remained significant (p ¼ 0.0029). Additionally, since gestational age when first treated with HIG is relevant only for those receiving a dose, removing it from the model yielded identical results; that is, that symptoms were significant (p ¼ 0.0003) and an additional test of maternal HIG was not significant (p40.8). The receipt of at least one maternal dose of HIG was associated with a significantly reduced risk for CMV infection at birth. In the 162 women receiving HIG, 59 (36%) delivered uninfected newborns compared to 30 of 194 (15%) in those not receiving HIG (OR ¼ 0.32, 95% CI ¼ 0.19 to 0.53, p50.001). For those who received HIG, the median number of doses per woman was two and 29% received one dose. One woman received eight infusions and 13 received 6 doses. Given this and the above observations we sought to determine if the number of maternal doses of HIG received correlated with birth weight or diminished duration of pregnancy. For both parameters, for all newborns, there was an increase in gestational age at delivery and birth weight that correlated significantly with the number of maternal doses of HIG

received (slopping black line, Figure 1). Although there was no significant difference in correlation for symptomatic infants (p40.3), this correlation was also significant for asymptomatic infants at birth (slopping blue line, Figure 1).

Discussion Immunoglobulins have been used safely in pregnancy since the 1950s, primarily to treat blood group incompatibilities but also for passive immunization against rubella, hepatitis A and B, varicella and measles [9]. Adverse events specific to pregnancy have not been reported. Nevertheless, there are no large case series that specifically address all aspects of immunoglobulin safety for the mother and fetus. In our previous studies we did not observe adverse events associated with maternal HIG during pregnancy but the number of patients was relatively small and HIG effects could have been masked by the effects of CMV on the placenta and fetus which frequently leads to low birth weight [7]. In this large cohort of patients we asked specifically if maternal HIG during pregnancy was associated with a shortened gestation or low birth weights. Although we did observe that primary maternal CMV infection was significantly associated with both diminished birth weights and a shorter duration of pregnancy than anticipated, we did not find an association of these factors and the receipt of maternal HIG. We did observe that multiple doses of maternal HIG were significantly correlated with both increasing birth weights and longer gestation but only for infants born asymptomatic. One to three HIG doses were used to treat a fetal CMV infection diagnosed by ultrasound abnormalities or testing of amniotic fluid for CMV and monthly doses to prevent fetal infection among women infected too early in pregnancy for amniocentesis [2]. Of the women we studied, approximately half received HIG for treatment and half for prevention of fetal infection. Thus, the increasing gestational age at delivery was correlated with the increasing number of HIG infusions that were limited to the prevention group. The association of multiple monthly doses of HIG and increasing birth weights and gestational ages at delivery is

Table 2. Association of gestational age at birth with maternal and infant characteristics.

Characteristics Maternal age in years at diagnosis Gestational age in weeks at the time of seroconversion Gestation age in weeks when first treated with HIG Copy number of CMV DNA in AF

Univariate analysis

Adjusted analysis

Number

Mean ± SD

Range

t ratio

p value

t ratio

p value

225 282 158 59

30.3 ± 4.68 15.9 ± 7.41 22.5 ± 6.08 833 951 1 462 941

17 to 41 2 to 34 10 to 37 500 to 7 210 854

0.58 0.50 1.57 0.01

0.5626 0.6168 0.1177 0.9896

Not done Not done 0.68 Not done

Not done Not done 0.4951 Not done

1.88

Gestational at birth (weeks) Congenital infection Yes No Maternal HIG Yes No Symptoms at birth Yes No Location Italy US

261 88

38.0 ± 2.41 38.9 ± 1.82

19 to 42 29 to 42

3.21

0.0015

161 190

38.3 ± 1.87 38.1 ± 2.62

29 to 42 19 to 42

0.73

0.4667

76 273

37.3 ± 3.38 38.4 ± 1.81

19 to 41 28 to 42

3.72

0.0002

317 34

38.2 ± 2.25 37.7 ± 2.81

19 to 42 29 to 41

1.27

0.2039

0.0611

Not done Not done 3.00

0.0029

Not done Not done

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DOI: 10.3109/14767058.2014.907265

CMV hyperimmune globulin and birth weight

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Figure 1. Correlation between the numbers of maternal doses administered and birth weight or gestational age at delivery, for symptomatic (red circle) or asymptomatic infants (blue triangle). Note that HIG dose values are jittered in order to more easily visualize each patient. For birth weight (left panel), for all infants (slopping black line), n ¼ 358, r ¼ 0.16, p ¼ 0.002 (slopping black line); for asymptomatic infants (slopping blue line), n ¼ 278, r ¼ 0.16, p ¼ 0.006; and for symptomatic infants (red flat line), n ¼ 77, r ¼ 0.002, p40.9. For gestational age at delivery (right panel) for all infants (slopping black line), n ¼ 351, r ¼ 0.13, p ¼ 0.014; for asymptomatic infants (slopping blue line), n ¼ 273, r ¼ 0.15, p ¼ 0.015; and for symptomatic infants (red flat line), n ¼ 76, r ¼ 0.02, p40.8.

consistent with our understanding of pathogenesis of fetal disease due to CMV. At birth, most of the symptoms of congenital CMV infection are likely due to an effect of the virus on the placental rather than the fetus. After a primary maternal CMV infection during pregnancy the placenta enlarges even among women whose fetuses never become infected with CMV [10]. The enlarged placenta decreases in size after HIG administration suggesting that immunoglobulin improves placental function [10,11]. Immunohistochemistry of placental specimens from women with untreated congenital infection, women who were treated with immunoglobulin and uninfected controls observed that treatment suppressed CMV replication and associated inflammation in the placenta and destruction of stromal villae [11]. Thus, the increasing birth weights and prolonged duration of gestation associated multiple HIG doses may reflect a sustained improvement in placental function throughout gestation and suggests there may be an improved outcome when HIG is started early in gestation. In summary, our data provide reassurance that HIG administration during pregnancy is not associated with either a diminished duration of gestation or decreased birth weight and adds to the evidence for the safety of immunoglobulin therapy during pregnancy.

Declaration of interest The authors report no conflicts of interest.

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2. Nigro G, Adler SP, La Torre R, Best AM. Passive immunization during pregnancy for congenital cytomegalovirus infection. N Engl J Med 2005;353:1350–4. 3. Visentin S, Manara R, Milanese L, et al. Early primary CMV infection in pregnancy: maternal hyperimmune globulin therapy improves children’s outcome at one year. Clin Infect Dis 2012;55: 497–503. 4. Nigro G, Adler SP, Parruti G, et al. Immunoglobulin therapy of fetal cytomegalovirus infection occurring in the first half of pregnancy: a case-control study of the outcome in children. J Infect Dis 2012;205:215–22. 5. Revello MG. Role of antibodies and CMI in preventing congenital CMV. The Development and Evaluation of Human Cytomegalovirus Vaccines, Public Workshop, 10 January 2012. The Food and Drug Administration(FDA) Center for Biologics Evaluation and Research (CBER), the National Institutes of Health, the National Institute of Allergy and Infectious Diseases (NIAID), the Centers for Disease Control and Prevention and the National Vaccine Program Office. Available from: http://videocast.nih.gov/pastevents.asp?c¼1 [last accessed 10 Jan 2012]. 6. Buxmann H, Stackelberg OM, Schlo¨ber L, et al. Use of cytomegalovirus hyperimmunoglobulin for prevention of congenital cytomegalovirus disease: a retrospective analysis. J Perinat Med 2012;40:439–46. 7. Berge P, Stagno S, Federer W, et al. Impact of asymptomatic congenital cytomegalovirus infection on size at birth and gestational duration. Pediatr Infect Dis J 1990;9:170–5. 8. Pereira L, Petitt M, Tabata T. Cytomegalovirus infection and antibody protection of the developing placenta. Clin Infect Dis 2013;57:S174–7. 9. Clark AL, Gall SA. Clinical uses of intravenous immunoglobulin in pregnancy. Am J Obstet Gynecol 1997;176:241–53. 10. La Torre R, Nigro G, Mazzocco M, et al. Placental enlargement in women with a primary maternal cytomegalovirus infection is associated with fetal and neonatal disease. Clin Infect Dis 2006;43: 994–1000. 11. Maidji E, Nigro G, Tabata T, et al. Antibody treatment promotes compensation for human cytomegalovirus-induced pathogenesis and a hypoxia-like condition in placentas with congenital infection. Am J Pathol 2010;177:1298–310.

Primary maternal cytomegalovirus infections during pregnancy: association of CMV hyperimmune globulin with gestational age at birth and birth weight.

Cytomegalovirus (CMV) hyperimmune globulin (HIG) may be helpful after a primary maternal CMV infection during pregnancy as a therapy for infected fetu...
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