Congenital cytomegalovirus infection following ... - Wiley Online Library

DOI: 10.1111/j.1471-0528.2007.01651.x

Fetal medicine

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Congenital cytomegalovirus infection following primary maternal infection in the third trimester L Gindes,a M Teperberg-Oikawa,b D Sherman,c J Pardo,d G Rahave a Department

of Obstetrics and Gynecology and b Central Virology Laboratory, Chaim Sheba Medical Center, Tel Hashomer, Israel of Obstetrics and Gynecology, Assaf-Harofe Medical Center, Zerifin, Israel d Department of Obstetrics and Gynecology, Rabin Medical Center, Petach Tiqwa, Israel e Department of Clinical Microbiology and Infectious Diseases, Hadassah Medical Center and School of Medicine, The Hebrew University, Ein-Kerem, Jerusalem, Israel Correspondence: Dr L Gindes, Department of Obstetrics and Gynecology, The Chaim Sheba Medical Center, 52621, Tel Hashomer, Israel. Email [email protected] c Department

Accepted 2 December 2007. Published OnlineEarly 11 February 2008.

Objective To determine the effect of primary cytomegalovirus

(CMV) infection in the third trimester on fetal outcome. Design Observational study. Setting Four perinatal departments in tertiary hospitals in Israel. Population Twenty-eight women with primary CMV infection

acquired after 25 weeks of gestation. Methods Prenatal evaluation included amniocentesis and ultrasonographic examinations. Maternal infection was determined from seroconversion and presence of low avidity anti-CMV immunoglobulin G after 25 weeks of gestation. Fetal CMV infection was diagnosed from CMV isolated or CMV DNA amplified from the amniotic fluid. Neonatal infection was established from CMV presence in their urine or anti-CMV IgM was in their peripheral blood immediately after birth. All liveborn neonates underwent cerebral ultrasonography, hearing assessment,

and psychomotor development evaluation. Infected neonates were followed up for a median of 36 months (range 6–36 months). Main outcome measures Intrauterine CMV infection and neonatal CMV disease throughout follow up. Results Vertical transmission of CMV was documented in 21 (75%) of the 28 pregnancies. None of the 20 live infected newborn had symptomatic congenital infection. One pregnancy was terminated at 34 weeks following evidence of prenatal infection. Most of the patients (75%) had CMV serology test due to clinical signs of CMV disease. Conclusions Although CMV infection during the third trimester of

pregnancy is highly transmissible, sequelae were not found among infected offspring. Keywords Cytomegalovirus, fetus, third trimester.

Please cite this paper as: Gindes L, Teperberg-Oikawa M, Sherman D, Pardo J, Rahav G. Congenital cytomegalovirus infection following primary maternal infection in the third trimester. BJOG 2008;115:830–835.

Introduction Cytomegalovirus (CMV) is the most common cause of congenital viral infection, occurring in approximately 1% of all newborns.1 Primary CMV infection occurs during pregnancy in 2% of women, with intrauterine transmission in approximately 40% of the cases. Approximately 10% of the infected liveborn neonates have symptomatic disease at birth. In addition, between 10 and 15% of the asymptomatic newborns develop late sequelae, particularly sensorineural hearing loss

The first five affiliations are affiliated with the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

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and neurodevelopmental disorders.2–4 CMV infections acquired early and late in gestation have similar rates of in utero transmission,5 but little is known about the relationship between the gestational age at the primary maternal infection and the outcome of the fetal infection. It is presumed that infections acquired in late pregnancy present with less prominent signs in the neonates because neuronal growth and migration are completed at about 26 weeks of gestation, and therefore, they are not affected by late pregnancy infections.6 Primary CMV infections during pregnancy are generally asymptomatic, and therefore, it is difficult to define the time of onset of maternal infection.2 In recent years, supplementary serologic assays, such as the immunoglobulin G (IgG)

ª 2008 The Authors Journal compilation ª RCOG 2008 BJOG An International Journal of Obstetrics and Gynaecology

Third-trimester CMV infection

avidity test, have been demonstrated as helpful in determining the onset of infection.7 Congenital CMV infection is relatively a common cause of hearing loss and mental retardation, and its antenatal diagnosis and prevention is a major challenge in perinatology. Because the relationship between timing of maternal CMV infection and fetal outcome has not been clearly delineated, the prenatal counselling of women with evidence of primary CMV infection is complicated. Therefore, the objective of our study was to determine how primary CMV infection in the third trimester of pregnancy affects fetal outcome.

Methods All cases of primary CMV infection acquired during the third trimester of pregnancy, which were referred to the prenatal or infectious diseases clinics in four tertiary hospitals in Israel from 1998 to 2005, were enrolled in this cohort observational study. Approval of the Institutional Ethics Committee was obtained. Criterion for inclusion was maternal primary infection during the third trimester, evidenced by seroconversion later than 25 weeks of gestation. Demographic, clinical and pregnancy-related information was obtained. Clinical CMV was diagnosed when woman developed prolonged fever >38C, liver function tests abnormalities, and lymphocytosis with atypical lymphocytes. Serum CMV-specific IgG and IgM were measured by enzyme immunoassay (ImX; Abbott Laboratories, North Chicago, IL, USA or Eti-Cytok IgM; Sorin Biomedica, Vercelli, Italy). An IgG avidity assay (CMV IgG avidity EIA; Radim, Rome, Italy) was used, and avidities of less than 25% indicated recent infection that has developed in the past 12 weeks. In all cases where first positive serological test demonstrated positive IgM and negative IgG, subsequent tests demonstrated positive IgG. Fetal diagnosis was made by amniocentesis 6 weeks or more after the maternal seroconversion. Amniotic fluid samples were inoculated into shell vials containing MRC5 monolayers for isolation of CMV.8 Polymerase chain reaction amplification of CMV DNA in the amniotic fluid samples was also performed.9 A detailed ultrasonographic examination was performed on each woman after seroconversion and every 2 weeks thereafter. Elective terminations of pregnancy required evaluation and approval by an external committee. Each neonate was evaluated by a neonatologist. Neonatal evaluations included physical examination, testing of urine for CMV by 2 weeks of age, blood cell and platelet count, measurement of liver enzymes, bilirubin, and anti-CMV IgM. The newborns underwent ophthalmoscopy, cerebral and abdominal ultrasonography, and brain-stem auditory evoked responses. Among fetuses with suspected neurological involvement, cerebrospinal fluid was obtained and electroencephalography, cerebral

computed tomography, and magnetic resonance imaging were performed. Symptomatic congenital CMV disease was defined by fetal or infant death or by neurological involvement, including microcephaly, periventricular calcifications, cerebral dysplasias, seizures in an infant with CMV DNA in cerebrospinal fluid, ventricular and subependymal abnormalities, chorioretinitis, or auditory impairment. Intrauterine growth restriction was defined by head and abdominal circumferences that were below the 10th percentile for fetuses of similar age. Infected neonates were followed up for a mean of 32 months (range 6–36 months). CMV disease at 2–3 years of age was defined by mental retardation (IQ below 70) or motor delay, auditory or visual impairment. The Bayley Scale for Infant Development, 2nd edn (BSID-II), and the Wechsler Preschool and Primary Scale of Intelligence, 3rd edn (WPPSI-III) were used for evaluation. During the first 2 years of life, the children’s hearing was assessed by brain-stem auditory evoked responses. The threshold for normal hearing was defined as 0–20 dB. Abnormal responses were defined as mild (threshold, 21–45 dB), moderate (threshold, 46–70 dB), or severe (threshold, at least 71 dB). Odds ratios and their 95% CIs were calculated and were compared by the Fisher’s exact test

Results Twenty-eight pregnant women were eligible and enrolled in the study (Table 1). Twenty-one (75%) underwent serologic tests following clinical signs of CMV disease, which included fever, lymphadenopathy, and disturbed liver functions. Symptoms began between 25 and 37 weeks of pregnancy (mean 28.9 weeks). Five seronegative women underwent serial CMV serology testing that had been performed on a monthly basis, and two seronegative women were tested due to exposure to a sick household. The median gestational age upon seroconversion was 30 weeks (26–37 weeks). None of our cases was diagnosed due to ultrasonographic findings suggestive of congenital CMV infection. Fourteen women underwent amniocentesis, while 14 elected to deliver without further testing. Vertical transmission was detected in 21 of the 28 pregnancies (75%): in 12 of the 14 women who underwent amniocentesis (85.7%) and in 9 of the 14 who elected to deliver without amniocentesis (64%) (OR 4.5, P = 0.065, 95% CI 0.93–42.8). Twenty-seven women elected to continue their pregnancies and delivered at term or near term (36–42 weeks). One woman elected to terminate her pregnancy in week 34 following detection of CMV DNA in the amniotic fluid. All women delivered healthy infants without CMV disease during the follow-up period (average 33 months, median 36 months). All had normal hearing and developmental evaluations. Two women with evidence of vertical transmission had abnormal ultrasound findings. One had oligohydramnios at


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832

Yes

Yes

Yes

Yes

Yes

Yes

No

No

No

No

No

Yes

Yes

Yes

2

3

4

5

6

7

8

9

10

11

12

13

14

Clinical CMV*

1

No.

26

28

27

26

27

28

29

30

32

37

Week of symptoms during pregnancy

11

11

12

28

18

26

25

25

27

24

25

27

32

27

Week of last negative serology

27–29

26–27

29–30

26

28

31

34

30

26

28

30

31

33

37

Week of seroconversion**

Table 1. Detailed information of each case participates in the study

26

28

31

34

35

31

27

30

28

32

30

31

33

37

Week of first positive serology

IgG negative IgM positive

IgG positive IgM positive IgG positive IgM positive

IgG positive IgM positive Avidity 18% IgG positive IgM positive Avidity 23% IgG positive IgM positive

IgG positive IgM positive Avidity 13% IgG negative IgM positive IgG positive IgM positive IgG positive IgM positive Avidity 9% IgG positive IgM positive Avidity 13% IgG negative IgM positive IgG positive IgM positive Avidity 21% IgG positive IgM positive

Results of first positive serology***

Positive

ND

ND

Positive

ND

Positive

ND

Positive

Positive

ND

Positive

Positive

ND

ND

Amniocentesis

Positive

Negative

Negative

TOP

Positive

Positive

Positive

Positive

Positive

Negative

Positive

ND

Positive

Negative

CMV in neonatal urine

Negative

Negative

Positive

TOP

Positive

ND

Positive

ND

ND

ND

ND

ND

Negative

Negative

Neonatal CMV IgM

(continued)

Routine follow-up serology for seronegative

Exposure to a child with CMV at 30 weeks


Routine follow-up serology for seronegative, fatigue at 26 weeks Routine follow-up serology for seronegative

Comments

Gindes et al.



Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

No

No

15

16

17

18

19

20

21

22

23

24

25

26

27

28

25–26

25

26

33

30

30

29

27

28

29

30

30

Week of symptoms during pregnancy

28

Pregestation

Pregestation

Pregestation

Pregestation

Pregestation

Pregestation

Pregestation****

5

8

8

8

8

10

Week of last negative serology

29–32

27

27

27

34

31

32

33

26

28

28

30

31

31

Week of seroconversion**

34

28

27

28

35

31

32

33

26

32

30

30

31

33

Week of first positive serology

IgG positive IgM positive

IgG positive IgM positive Avidity 7% IgG positive IgM positive IgG positive IgM positive Avidity 5% IgG negative IgM positive IgG positive IgM positive IgG negative IgM positive IgG negative IgM positive IgG negative IgM positive IgG positive IgM positive Avidity 9% IgG positive IgM positive IgG positive IgM positive IgG positive IgM positive IgG positive IgM positive

Results of first positive serology***

ND

Positive

Negative

Positive

ND

ND

ND

ND

Positive

Positive

ND

Negative

ND

Positive

Amniocentesis

Negative

Positive

Negative

Positive

Positive

Negative

Negative

Negative

Positive

Positive

Positive

ND

Positive

Positive

CMV in neonatal urine

ND, not done; TOP, termination of pregnancy. *Clinical CMV: prolonged fever .38C, hepatitis, lymphocytosis with atypical lymphocytes. **Seroconversion is the appearance of IgM followed by that of IgG. The avidity assist in the calculation of the timing of seroconversion. ***In all cases where first positive serological test demonstrated positive IgM and negative IgG, subsequent tests demonstrated positive IgG. ****Pregestational serology was performed before current pregnancy.

Clinical CMV*

No.

Table 1. (Continued)

Positive

Positive

Negative

Positive

Negative

Positive

Negative

Negative

ND

ND

Negative

Negative

Negative

Negative

Neonatal CMV IgM


Exposure to husband with CMV at 26 weeks

Comments


833

Gindes et al.

36 weeks of gestation and delivered a healthy infected child 2 weeks later. Another woman, who had CMV disease at week 26, had false-positive ultrasonographic features compatible with microcephaly that disappeared on follow-up evaluation and gave birth to a healthy newborn that developed uneventfully during the follow-up period.

Discussion In the present study, we found a transmission rate of 75% following third-trimester CMV infection without any sequelae in the infected offspring. In previous studies, a definite association was noted between the gestational age of maternal infection and the outcome of the fetus—almost all infants with symptomatic congenital infection were exposed in the first half of pregnancy.5,10–12 However, few cases of congenital disease were reported following third-trimester maternal infection, presenting mainly with hearing loss.11,13 Severe neurological damage following maternal infection in the third trimester was described in seven infants.14 The authors assumed that these children were infected in the third trimester of gestation, but all children were referred for investigation of neurological and developmental problems when they were between 10 months and 11 years old. In only one child, serological evidence of intrauterine CMV infection at gestational week 27 existed, but information on the exact timing of seroconversion during pregnancy was missing. Contrary to our findings, Stagno et al.5 found no difference in the transmission rate when they compared pregnancies where maternal CMV infection occurred at between weeks 4 and 22, 16 and 27, and 23 and 40. Others reported transmission rates between 58 and 77% in late gestational periods.12,15,16 It is difficult to study the effect of gestational age on the outcome of congenital CMV because it is often impossible to time the onset of the maternal infection. When the first test is performed at week 28, IgM antibodies against CMV could indicate first-, second- or third-trimester infection. To evaluate the effect of genuine third-trimester CMV infection, only women with documented clinical disease or a precise date of IgG CMV seroconversion were included in our study; this accounts for the small number of women enrolled. Seventy-five percent of our cohort had clinical disease, much higher than the reported rate of 5%.10,17,18 Due to insistence of pregnant women and the fear of litigation, most obstetricians test pregnant women for CMV during the first trimester. Testing for CMV during the third trimester, however, is usually performed only after suspected clinical signs of disease. Half of the women underwent amniocentesis, but although infection was demonstrated in 85.7% of them, all but one elected to continue their pregnancy. Israeli law does not entirely prevent abortion at any stage of pregnancy, but the

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degree of permissiveness differs between trimesters of pregnancy (Ministry of Justice, 1977). Until week 23, elective termination of pregnancy is permissible if one or more of the following conditions is present: the pregnant woman is a teenager, over 40 years, or not married; the woman has severe emotional problems; the woman’s health is at risk; or there is evidence of fetal abnormalities. The decision to terminate pregnancy is made by hospital committees composed of a social worker and a gynaecologist. However, after week 23 of pregnancy, the regulation of pregnancy termination becomes more restrictive, and termination is limited to medical reasons when approaching the third trimester. The Israeli Ministry of Health has authorised six hospitals to create high committees for the elective termination of late pregnancy. These committees are larger and multidisciplinary and are made up of the highest level administrators: the director of the Medical Centre, the director of the Obstetrics and Gynaecology Department, the director of the Neonatal Department, the director of the Genetic Counselling Department, and the director of the Social Work Department. Nevertheless, the rate of late termination of pregnancy in Israel is 5–10 times higher than that reported for countries such as Denmark, the UK, Canada, and the USA, where policies are relatively more restrictive.19 Ultrasonography has limited sensitivity in detection of fetal infection.20 Furthermore, since ultrasonographic abnormalities develop dynamically several weeks after the viral transmission,21 the yield of such tests in third-trimester infections is low. Interestingly, in our study, the CMV intrauterine transmission rate seemed to increased with advancing stage of pregnancy, which is in accordance with the data by Revello and Gerna22 who reported transmission rates of 45.4% (49/108), 45.6% (21/46), and 78.6% (11/14) following primary infections in the first, second and third trimesters, respectively. Higher rates of CMV transmission during late gestation were also reported by Daiminger et al.12 and by Bodeus et al.16 An increase in congenital infection rates with advancing pregnancy is known for acute maternal infection with rubella virus, varicella-zoster virus, and Toxoplasma gondii when increased placental blood flow facilitates inoculation of the placenta. In contrast, the severity of congenital disease is related inversely to gestational age and is much greater when infections occur in the first trimester. Sequelae of fetal infection are worse during organogenesis. As the duration of pregnancy increases, fetal infections are less likely to cause congenital malformations.22 Although passive immunisation may alter the natural course of CMV during pregnancy,23 the possible efficacy of hyperimmune globulin therapy for maternal infection in the last trimester is uncertain. The major limitation of this study is the small number, so it may not be adequately powered to detect low rates of neonatal consequences of CMV infection. However, the exact timing of seroconversion during the third trimester was possible only in



those with symptomatic CMV disease during the third trimester or among those who performed serology every 2–3 weeks, causing diminution of the group.

Conclusion Although third-trimester CMV infection carries a high transmission rate, it has no deleterious effect on the fetal outcome. Although the study is limited by its small size and its observational design, we think that performing amniocentesis for the diagnosis of third-trimester intrauterine CMV infection is an unnecessary invasive procedure.

Contribution to authorship L.G. collected all the information of the patients from medical files, interviewed the patients, analysed statistically, and wrote the paper. M.T.O. carried out the CMV laboratory tests, identified the patients suspected to have primary CMV infection during the third trimester. D.S. added information of his patients. J.P. added information of his patients. G.R. collected all the information of the patients from medical files, interviewed the patients, and assisted in writing the paper. j

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8 Lazzarotto T, Varani S, Gabrielli L, Spezzacatena P, Landini MP. New advances in the diagnosis of congenital cytomegalovirus infection. Intervirology 1999;42:390–7. 9 Nigro G, Mazzocco M, Anceschi MM, La Torre R, Antonelli G, Cosmi EV. Prenatal diagnosis of fetal cytomegalovirus infection following primary or recurrent maternal infection. Obstet Gynecol 1999;94: 909–14. 10 Ahlfors K, Forsgren M, Ivarsson SA, Harris S, Svanberg L. Congenital cytomegalovirus infection: on the relation between type and time of maternal infection and infant’s symptoms. Scand J Infect Dis 1983;15: 129–38. 11 Liesnard C, Donner C, Brancart F, Gosselin F, Delforge ML, Rodesch F. Prenatal diagnosis of congenital cytomegalovirus infection: prospective study of 237 pregnancies at risk. Obstet Gynecol 2000;95:881–8. 12 Daiminger A, Ba¨der U, Enders G. Pre- and periconceptional primary cytomegalovirus infection: risk of vertical transmission and congenital disease. BJOG 2005;112:166–72. 13 Pass RF, Fowler KB, Boppana SB, Britt WJ, Stagno S. Congenital cytomegalovirus infection following first trimester maternal infection: symptoms at birth and outcome. J Clin Virol 2006;35:216–20. 14 Steinlin MI, Nadal D, Eich GF, Martin E, Boltshauser EJ. Late intrauterine cytomegalovirus infection: clinical and neuroimaging findings. Pediatr Neurol 1996;15:249–53. 15 Revello MG, Sarasini A, Zavattoni M, Baldanti F, Gerna G. Improved prenatal diagnosis of congenital human cytomegalovirus infection by a modified nested polymerase chain reaction. J Med Virol 1998;56: 99–103. 16 Bodeus M, Hubinnont C, Goubau P. Increased risk of cytomegalovirus transmission in-utero during late gestation. Obstet Gynecol 1999;93: 658–60. 17 Griffiths PD, Baboonian C. A prospective study of primary cytomegalovirus infection during pregnancy: final report. Br J Obstet Gynaecol 1984;91:307–15. 18 Stagno S, Pass RF, Dworsky ME, Alford CA Jr. Maternal cytomegalovirus infection and perinatal transmission. Clin Obstet Gynecol 1982;25: 563–76. 19 Gross ML. After feticide: coping with late-term abortion in Israel, Western Europe, and the United States. Camb Q Healthc Ethics 1999;8:449–62. 20 Weiner CP, Grose CF, Naides SJ. Diagnosis of fetal infection in the patient with an ultrasonographically detected abnormality but a negative clinical history. Am J Obstet Gynecol 1993;168:6–11. 21 Watt-Morse ML, Laifer SA, Hill LM. The natural history of fetal cytomegalovirus infection as assessed by serial ultrasound and fetal blood sampling: a case report. Prenat Diagn 1995;15:567–70. 22 Revello MG, Gerna G. Pathogenesis and prenatal diagnosis of human cytomegalovirus infection. J Clin Virol 2004;29:71–83. 23 Nigro G, Adler SP, La Torre R, Best AM; Congenital Cytomegalovirus Collaborating Group. Passive immunization during pregnancy for congenital cytomegalovirus infection. N Engl J Med 2005;353: 1350–62.


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