elevated viral antibody titres in spontaneous abortion

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FEMS MicrobiolosyImmunology 64 0990) 23-28 23 Published by Elsevier FEMSIM00096 Research Papers Elevated viral antibody titres in spontaneous abortion L.M. Irvine 1, R.Tavorath 2, p. Lindsay 1, P.M.S. O'Brien 1, and P. Griffiths 2 s Academic Department of Obstetrics and Gynaecology, The Royal Free Hospital Medical School, London, U.K., and z Department of Virology, The Royal Free Hospital Medical School, London, U.K. Received 7 August1989 Accepted21 September1989 Key words: Spontaneous abortion; Virus; High antibody level 1. SUMMARY To assess the possible role of virus infections in spontaneous abortion we undertook a prospective study of three groups of patients: women who had a spontaneous abortion; women seen in the ante- natal booking clinic; and those undergoing ther- apeutic termination of pregnancy. Venous blood was taken for antibody detection, cervical swabs for virus isolation, and in the cases of spontaneous and therapeutic abortion products of conception were sent for virus culture. The infectious agents studied were influenza A and B, adenovirus, re- spiratory syncytial virus, measles, psittacosis, Varicella zoster, and mumps virus. Statistical anal.. ysis revealed that women in the spontaneous abor- tion group has a higher incidence of antibodies against respiratory ryncytial virus (P < 0.01), and mumps virus (P < 0.01). Among women seroposi- five for each virus, higher titres were found only for respiratory syncytial virus (P < 0.05) in cases rather than controls. These results could be ex- plained if viruses such as respiratory syncytial Correspcm&,nce to: L.M. lrvine, AcademicDepartment of Ob- steUics and Gynaeeology,The Royal Free Hospital Medical School, Pond Street, Hampstead, London NW3 2QG, U.IC virus caused abortion or if women having a spon- taneous abortion mount exaggerated immune re- sponses to fetal and viral infections, and the former altered immune response is associated with spon- taneous abortion. 2. INTRODUCTION Spontaneous abortion occurs commonly; it has been estimated by Warburton and Fraser [I] that approximately 15~ of clinically confirmed preg- nancies end in this way. This figure has been confirmed by more recent work by Miller et al. [2]. These figures are probably an underestimate as some women may not consult their doctor, or the doctor may manage the patient at home. The incidence of spontaneous abortion prior to clinical recognition varies according to the criteria used to diagnose pregnancy, but Edmonds et al. [3] have estimated it to be as high as 58~$. Despite the high incidence of spontaneous abortion the aefiology is nnknown in many cases, although numerous causes have been postulated. Chromosomal abnormalities have been found in the products of conception in up to 55~ of cases of first trimester abortions according to Lauritsen [4], and these were commonly autosomal ~omy 0920-8534/90/$03.50 @1990 Federation of European Microbiological Societies

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Page 1: Elevated viral antibody titres in spontaneous abortion

FEMS Microbiolosy Immunology 64 0990) 23-28 23 Published by Elsevier

FEMSIM 00096

R e s e a r c h P a p e r s

Elevated viral antibody titres in spontaneous abortion

L.M. I rvine 1, R .Tavora th 2, p. Lindsay 1, P.M.S. O 'Br ien 1, and P. Gr i f f i ths 2

s Academic Department of Obstetrics and Gynaecology, The Royal Free Hospital Medical School, London, U.K., and z Department of Virology, The Royal Free Hospital Medical School, London, U.K.

Received 7 August 1989 Accepted 21 September 1989

Key words: Spontaneous abortion; Virus; High antibody level

1. SUMMARY

To assess the possible role of virus infections in spontaneous abortion we undertook a prospective study of three groups of patients: women who had a spontaneous abortion; women seen in the ante- natal booking clinic; and those undergoing ther- apeutic termination of pregnancy. Venous blood was taken for antibody detection, cervical swabs for virus isolation, and in the cases of spontaneous and therapeutic abortion products of conception were sent for virus culture. The infectious agents studied were influenza A and B, adenovirus, re- spiratory syncytial virus, measles, psittacosis, Varicella zoster, and mumps virus. Statistical anal.. ysis revealed that women in the spontaneous abor- tion group has a higher incidence of antibodies against respiratory ryncytial virus ( P < 0.01), and mumps virus ( P < 0.01). Among women seroposi- five for each virus, higher titres were found only for respiratory syncytial virus ( P < 0.05) in cases rather than controls. These results could be ex- plained if viruses such as respiratory syncytial

Correspcm&,nce to: L.M. lrvine, Academic Department of Ob- steUics and Gynaeeology, The Royal Free Hospital Medical School, Pond Street, Hampstead, London NW3 2QG, U.IC

virus caused abortion or if women having a spon- taneous abortion mount exaggerated immune re- sponses to fetal and viral infections, and the former altered immune response is associated with spon- taneous abortion.

2. I N T R O D U C T I O N

Spontaneous abortion occurs commonly; it has been estimated by Warburton and Fraser [I] that approximately 15~ of clinically confirmed preg- nancies end in this way. This figure has been confirmed by more recent work by Miller et al. [2]. These figures are probably an underestimate as some women may not consult their doctor, or the doctor may manage the patient at home. The incidence of spontaneous abortion prior to clinical recognition varies according to the criteria used to diagnose pregnancy, but Edmonds et al. [3] have estimated it to be as high as 58~$.

Despite the high incidence of spontaneous abortion the aefiology is nnknown in many cases, although numerous causes have been postulated. Chromosomal abnormalities have been found in the products of conception in up to 55~ of cases of first trimester abortions according to Lauritsen [4], and these were commonly autosomal ~ o m y

0920-8534/90/$03.50 @ 1990 Federation of European Microbiological Societies

Page 2: Elevated viral antibody titres in spontaneous abortion

or monosomy X. Uterine abnormalities have also been impficated, uterine septum or abnormalities of the uterine artery such as two ascending branches on one side have been shown to be associated with recurrent abortion by Burchell et al. [5]. Cervical incompetence, either congenital as described by Jeunings [6] or more commonly acquired, is a recognised cause of spontaneous abortion and may be diagnosed on the history and confirmed at hysterosalpingogram. Incompetent cervix, however, usually results in a mid-trimester spontaneous abortion. Other causes suggested in- dude infections, but these are only anecdotal re- ports, Herpes simplex [7], Cytomegalovirus [8], Listeriosis [9], Poliovirus [10], and Mumps [11].

The immune system has been implicated in spontaneous abortion. Mowbrey et al. [12] found that couples who suffered from recurrent sponta- neous abortion shared more HLA antigens than the general population. In order to induce a pre- stunably protective immune response they injected pooled lymphocytes into the woman and reported a number of successful pregnancies following such uncontrolled treaunent.

In an attempt to clarify the role of virus infec- tion in spontaneous abortion we undertook the present prospective study. Our hypothesis was that maternal infection might precede the clinical pre- sentation with miscarriage by several weeks, by which time the acute maternal humoral immune response would already have passed. We did not therefore look for evidence of rising titres of IgG antibodies or of specific IgM antibodies which can measure acute infection. Instead, we looked at the prevalence and titre of IgG antibodies against a variety of viruses and related the found results to a comparable control group of women whose pregnancies were uneventful.

3. PATIENTS AND METHODS

Three groups of patients were recruited. The cases comprised those admitted with spontaneous first-ttimester abortion in whom products of con- ception and serology were examined. There were two control groups: a group of antenatal booking patients to provide control serology, and a group

of patients undergoing therapeutic termination of pregnancy to provide control products of concep- tion for virus isolation.

3.1. Group I (spontaneous abortions) Women who presented with a missed or incom-

plete first uimester abortion were recruited. Pa- tients with a history suggestive of cervical incom- petence were excluded from the study. A full history was taken of any recent "Flu" like ill- nesses or skin rash, and a detailed past-obstetric history including details of any other spontaneous abortions. Venous blood, vaginal swabs, and prod- ucts of conception were taken for virus isolation.

3.2. Group 2 (therapeutic termination) Women undergoing therapeutic termination of

pregnancy were recruited and venous blood, vagi- nal swabs and products of conception were taken.

3.3. Group 3 (women booking in the antenatal clinic) Venous blood was taken from these patients,

and vaginal swabs taken during a routine specu- lum examination. Outcome of the pregnancy was determined in the booking control group.

3. 4. Laboratory methods All the pathological samples were assayed for

complement-fixing antibodies against the follow- ing infectious agents: influenza A, influenza B, adenovirus, respiratory syncytial virus (RSV), measles, varicella zoster, mumps, and a Chlamydia, psittacosis.

3.5. Statistical analysis The Student's t-test was used to compare age

and gestation, and the Chi-square test with Yates correction was used to compare the incidence of antibodies between cases and controls.

4. RESULTS

None of the cases or control patients reported a history of a rash or flu-like illness in the 2 weeks prior to recruitment. In only one patient was virus isolated from a high vaginal swab. This patient was seen in the booking clinic at 22 weeks. At

Page 3: Elevated viral antibody titres in spontaneous abortion

Table 1

Patient Num- Mean age Mean gestation group bet :i: SD 5: SD

Oears) (weeks)

Spontaneous abortion 33 31.2 + 7.0 12.5 + 4.7

Therapeutic abortion controls 8 25 .1+6 .6 12.0+2.8

Antenatal controls 69 28.55:2.2 14.5+4.5

scan she was found to have a missed abortion and the high vasinal swab grew herpes simplex virus. Another patient from the booking control group subsequently had a still birth at thirty four weeks for which no cause was found at postmortem. These cases were excluded from the control group due to the adverse outcome of the presnancy. The 69 women in the bookin 8 group delivered live infants of mean gestation 39.2 + 1.6 SD, and there were no perinatal deaths (Table 1).

Using an unpaired Student's t-test we found no significant difference between cases and controls Influenza A in respect of age or gestation at which they were virus included in the study. Antibodies against each of the eight infective agents were assessed (Table 2). Influenza B Using the Chi square test with Yates correction we virus found that cases had slgnificandy higher incidence of mumps and respiratory syacytial virus antibod- Adenovirus ies when compared to the control cases ( P < 0.01).

Table 3 shows the distribution of antibody titres among cases and controls for each of infectious Respiratory agents studied. It can be seen that the cases had a syncytial

virus significantly higher antibody titre against respira- tory syncytial virus. Measles

virus

5. DISCUSSION . . Psittacosis

Early fetal loss is a common occurrence, and in most cases the reasons are obscure. We have shown varicella

that of the eight infectious agents studied mumps zoster virus

and RSV antibodies were found more commonly in those women who had a spontaneous abortion. Mumps Infection with mumps has been suggested as a virus cause of spontaneous abortion by Kurtz et al. [13]

who isolated mumps virus from the tissue of a fetus aborted at 10 weeks, 4 days after the preg- nant woman had developed mumps clinically. We also found that women who had a spontaneous abortion had higher titres of RSV antibodies than the controls. It is possible that the higher titres of antibody may be due to recent infectious, but it is not possible to tell when the infections with the different agents occurred.

The mechanism by which infectious agents cause spontaneous abortion is not clear. In some diseases such as rubella or syphilis the agent actu- ally infects the conceptus, and can be cultured from the products of conception, a direct effect. We did not isolate any viruses from the products of conception studied. Virus~ might also cause spontaneous abortion by an indirect effect by

Table 2

Proportions of cases anc controls with antibodies detectable against each of the eight infectious agents

Infectious Antibody Cases Con- To- X 2 P agent present troll tals

Yes 24 42 66 No 6 27 33 2.63 NS Totals 30 69 99

Yes 22 52 74 No 8 17 25 0.05 NS Totals 30 69 99

Yes 15 33 48 No 15 36 51 0.04 NS Totals 30 69 99

Yes 21 27 48 No 8 42 50 7.77 < 0.01 Totals 29 69 98

Yes 25 65 90 No 5 4 9 1.82 NS Totals 30 69 99

Yes 9 26 35 No 20 43 63 0.39 NS Totals 29 69 98

Yes 27 52 79 No 2 17 19 3.05 NS Totals 29 69 98

Yes 29 48 77 No 1 20 21 6.93 < 0.01 Totals 30 68 98

Page 4: Elevated viral antibody titres in spontaneous abortion

26

Table 3 Distmbutions of antibody titres among cases and controls with detectable levels of antibodies against each of the eight infectious agents

Antibody levels 0o82)

3 4 5 6 7 n ~ SD t P

Influenza A Ca 8 11 5 24 3.875 0.741 1.31 NS virus C 23 13 5 1 42 3.619 0.795

Influenza B Ca 14 8 22 3.364 0.492 0.79 NS virus C 33 15 2 2 52 3.481 0.754

Adenovirus Ca 8 6 1 15 3.533 0.640 0.38 NS C 21 10 1 1 33 3.455 0.711

Respiratory Ca 11 8 2 21 3.571 0.676 2.08 < 0.05 syncytial C 21 6 27 3.22 0.424 virus

Measles Ca 3 9 8 4 1 25 4.640 1.036 1.20 NS virus C 12 26 2C 6 1 65 4.354 0.943

Psittacosh Ca 5 3 1 9 3.667 1.000 1.11 NS C 21 4 1 26 3.269 0.667

Varicella Ca 9 15 3 27 3.778 0.641 1.11 NS zoster virus C 15 26 9 2 52 3.962 0.791

Mumps virus Ca 11 11 7 29 3.862 0.789 0.19 NS C 13 28 6 1 48 3.896 0.692

Abbreviations: Ca, cases; C, controls; NS, not significant.

changes in maternal metabolism. Maternal pyrexia has been postulated as a possible cause of sponta- neous abortion by an undefined constitutional ef- fect on maternal metabolism. However, in situa- tions where the body temperature is artifically elevated by saunas taken in pregnancy, as in Sweden, there is no higher incidence of sponta- neous abortion. This does not, however, exclude a possible indirect effect of lymphokines causing the pyrexia and precipitating an abortion. Conversely the pyrexial patient may take proprietory medica- tions which could potentially damage the fetus, though in our study no such history was obtained. Griffiths and Baboonian [14] found a seven-fold increase in early fetal loss in women who had CMV infection when compared to conuols. In the same study they demonstrated no histological evi- dence of CMV infection in any of the specimens they e g a m i n ~ and thus concluded tha t the fetal loss may not have resulted from the direct effect of interuterine infection.

Finally, one might spec~ate that our results reflect not virus infections themselves but an indi- rect measure of maternal humoral responses. Thus, women with a genetic predisposition to mount heightened immune response 8~aingt any antigen, including those present on the fetus, may be at risk of having miscarriages. If this predisposition gave them higher than average ant ibody titres against certain viruses then this would explain our observed results. This is in contrast to the work of Tongio et al. [15] who found that the majority of women who had had a spontaneous abort ion did not have detectable cytotoxic antibodies against paternal lymphocytes, whereas normal multigravid women did. We have no results to support our suggestion, bu t in order to investigate the possibil- ity pat ients could be immunised between preg- nancies with non-replicatin 8 vaccines and the im- mune response could be compared between wo- men with and without a history of spontaneous abortion.

Page 5: Elevated viral antibody titres in spontaneous abortion

R E F E R E N C E S

[I] Warbarton, D. and Fraser, F.C. (1959) Genetic aspects of abortion. Clin. Obstet. GynaeenL 2, 22-35.

[2] Miller, J.F., Williamum, E., Glue, J., Gordon, Y.B., Gngl~nka~ J.G. and Sykes, A. (1980) Fetal loss after implantation: a prospective study. Lancet II, 554-556.

[3] Edmond& D.K., Lind.say, KS., Miller, J.F., W!lllam~on. E. and Wood, PJ. (1982) Early embryonic mortality in women. Fertil. Sterii. 38, 477.-453.

[4] Laufitsen, J.G. (1976) Aetiology of spontaneous abortion. Aceta Obstet Gynecol. Stand. suppl. 52,1-29.

[$] Burcbell, R.C., Creed, F., Rasoulpour, M. and Whit~omb, M. (1978) Vascular anatomy of the human uterus and pregnancy wastage. Br. J. Obstet. Gynaecol. 85, 698-706.

[6] Jennings, C.L. Jr. (1972) Temporary submuc.cf~ ce~clage for cervical incompetence: report of forty eight cases. An~ J. Obstet. Gyn¢~ol. 113:1097-1102.

[7] Nahmias, AJ., ~osey, W.E., l~aib, Z.M., Freeman, M.G., Fernandez, RJ. and Whecle, LH. (1971) Perinatai risk assodated with maternal geaital herpes. Am. J. Obstet. ~necoL 110, 825-837.

[8] Kriei, R.L., Getes, GJt., Wulff, H., Powell, N., Pollard, LD. and Chin, T.D. (1971) Cytomegalovirus isolation

associated with pregnant T wastage. Am. J. Obstet. C_~ne- col. 106, 885-889.

[9] Rappapurt, F., Rabinovitz~ M., Toaff, R. and l~ochik, N. (1960) Genital Listmwis as a cause of repeated abortion. Lancet I, 1273-1275.

[10] Horn, P. (1955) Poliomyelitis in pregnancy. A twenty year report from Los Pngeles County. Obstet. Gynecol. 5, 121-137.

[11] Siegal, M., Fuerst, H.T. and Petrels, N.S. (1966) Com- parative fetal mortality in maternal virus diseases, a pro- spoctive study of Rubella, Measles, Mumps, Chicken Pox end Hepatitis. N. Eng. J. Med. 274, 768-771.

[12] Mowbrey, J.F., Gibbings, C., Liddell, H., Reginald, P.W., Underwood, J.L. and Beard, R.W. (1985) Controlled trial of treatment of recurrent spontaneous abortion by im- manisation with paternal cells. Lancet I, 941-943.

[13] Kurtz, J.B., Tomlinson, A.H. and Pearson, J. (1982) Mumps virus isolated from a fetus. Br. Med. J. 284, 471.

[14] Griffiths, P.D. and Baboonian, C. (1984) A prospective study of primary Cytomegalovirus infection during preg. nancy: final report. Br. J. Obstet. Gynaecol. 91, 307-315.

[15] Tongio, M.M, Berrebi, A. and Mayer, S. (1972) A study of lymphocytotoxic antibodies in muitiparous women hav- ing had four pregnancies. Tissue Antigens 2, 378-388.