Chlamydial Infection In Pregnancy
Professor David Taylor-Robinson MD MRCP FRCPath
Until retirement in 1996, he was Head of the MRC's Sexually
Transmitted Diseases(STD) Research Group at St. Mary's
Hospital Medical School, and Professor of Genitourinary,
Microbiology and Medicine. His extensive research interests
include aetiology of acute and chronic non-gonococcal urethritis, epidydimitis, chronic prostatitis and pelvic inflammatory disease (PID); improved methods of detection for
Chlamydia trachomatis infection; seroepidemiology and prevention of STDs; Bacterial vaginosis; and pathogenesis of
Mycoplasma infections.
Introduction
The genus Chlamydia comprises at least four species.
Chlamydia trachomatis contains 15 serovars of which serovars A-C
cause trachoma and, rarely, sexually related infection, whereas
serovars D-K seem not to be associated with trachoma but cause
paratrachoma and a variety of genital-tract diseases. Serovars L1L3 are responsible for lymphogranuloma venereum (LGV). C.
pecorum causes pneumonia and diarrhoea in cattle and sheep and
C. psittaci causes disease in birds and animals and respiratory disease (psittacosis) in humans. C. pneumoniae is the binomial designation for strains which originally were termed TWAR. It also
causes human respiratory disease and, in addition, has been associated with atherosclerosis.
Chlamydiae are recognised as bacteria because they possess
peptidoglycan cell wall material, contain RNA and DNA and are
sensitive to a wide variety of broad-spectrum antibiotics.
However, the size of the infectious particles (elementary bodies:
EBs) is about that of large viruses (300 nm) and, like viruses, they
have an obligate intracellular existence. During the intracellular
reproductive cycle EBs are converted into metabolically active
reticulate bodies, which increase in number by binary fission,
reorganise themselves in inclusions into new EBs that are released
from the cell after 36-48 hours. Recognition of inclusions by staining techniques forms the basis of chlamydial detection in cell culture. Detection of EBs by the use of fluorescent monoclonal antibodies is another approach to diagnosis
Prevalence of C. trachomatis infection in
pregnancy
Prevalence rates for C. trachomatis genital tract infection, varying from 2% to 37%, have been reported for asymptomatic woman
in the United States1,2. A similar range has been recorded for
pregnant women, but overall it has been estimated that the prevalence rate in the United States is about 5% 3, 4.
The chlamydial prevalence rate for pregnant women in the
UK, based on the results of several studies5-8 in the past 15 years,
varies from 7% to 15%. In fact, as expected, the range is in keeping with that for asymptomatic non-pregnant women attending
general practice clinics for routine cervical cytology, gynaecology
clinics and colposcopy units. It has to be recognised, however,
that chlamydial prevalance rates for both pregnant and non-pregnant women are based largely on the use of relatively insensitive
tests, such as culture and enzyme immunoassays. It is to be
expected that the rates will be higher when populations are
examined by means of the more sensitive molecular techniques
(PCR or LCR).
The main demographic risk factors for chlamydial cervical
infection occurring in pregnant women are similar to those for
non-pregnant women9 and include age less than 20 years, single
marital status, the presence of mucopurulent cervicitis, abacteriuric pyuria and late antenatal booking4. It is not clear, however,
whether oral contraceptive usage prior to pregnancy affects the
rate of infection with C. trachomatis in pregnancy.
Clinical aspects of complications in pregnancy
Infection with C. trachomatis can occur at any time during
pregnancy and in the postpartum period, the consequence
depending on the trimester in which it occurs.
Infection by C. trachomatis in the first trimester of
pregnancy
Approximately 20% of patients with C. trachomatis infection
prior to surgical termination have developed salpingitis10,11 and
screening for C. trachomatis to avoid this iatrogenically induced
pathology has been advocated (see below). In contrast to induced
abortion, it is not known whether infection with C. trachomatis
predisposes to spontaneous abortion, since the high background
rate of both C. trachomatis and spontaneous abortion make an
aetiological association difficult to prove.
Infection by C. trachomatis in the second and third
trimesters of pregnancy
C. trachomatis has rarely been isolated from amniotic fluid and
infrequently from the placenta or membranes. In various
prospective studies of pregnant women, most of whom were
enrolled in the third trimester, no association of chlamydial infection with prematurity was demonstrated12-14. However, in a study
in which women were enrolled at 19 weeks of gestation, a highly
significant association was found between infection with C. trachomatis and stillbirth, premature birth and prenatal death from
prematurity15. In another study16, no association overall was shown
between C. trachomatis infection and any of the poor outcomes of
pregnancy, but in a subgroup of women in whom infection was
detected by culture and by having serum IgM chlamydial antibody (24% of those infected with C. trachomatis), the infection was
associated with low-birth-weight infants and with premature rupture of the membranes. Thus, although opinions about the effect
of a chlamydial infection have varied, the impression is that the
infection in the second rather than the third trimester may lead
to poor outcome.
Effect of previous or chronic C. trachomatis on future pregnancies
Chlamydial infection may cause tubal infertillity through damage to the fallopian tubes and increase the chance of ectopic
pregnancy in those women who become pregnant,. While
attempts to isolate C. trachomatis from the fallopian tubes of
women with ectopic pregnancy have produced conflicting results,
reflecting possibly differences between acute and chronic salpingitis, the association has been seen best serologically. Thus, significantly greater titres of chlamydial IgG antibody occur in
patients with ectopic pregnancy than in those without17,18.
Postpartum C. trachomatis infection
Chlamydial endometritis may be asymptomatic or patients
may present with secondary postpartum haemorrhage, fever,
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Chlamydial Infection In Pregnancy
lower abdominal pain and/or vaginal discharge. Postpartum
endometritis may be subdivided into early (within the first 48
hours after birth) and late (3 days to 6 weeks after birth), chlamydial postpartum endometritis tending to fall into the late category with an onset usually 2 to 6 weeks after birth. Chlamydial postpartum endometritis tends to be associated with vaginal delivery.
In one study of women with late postpartum endometritis after
vaginal delivery, 23% had C. trachomatis detected in the
endometrium and a further 37% had C. trachomatis detectable in
the cervix, and the majority of those with endometritis were
afebrile and not seriously ill19.
The effect of C. psittaci and C. pneumoniae on pregnancy
C. pneumoniae is known to escape from the respiratory tract
and to lodge in the atheromatous plaques of major arteries20.
However, so far there is no evidence that such dissemination has
had any effect on pregnancy. In contrast, it is known that in the
UK and France, pregnant women have aborted after exposure to
C. psittaci-infected sheep during the lambing season21-25.
Chlamydiae have been isolated from placental samples of
women, usually sheep farmers’ wives, who had been in contact
with aborting ewes, and the women also exhibited antibody
responses. Showing that strains isolated from human fetuses and
placentae were of bovine origin has been helpful in clinching the
diagnosis26.
The pathological features of human disease are those of
severe acute placentitis27. Although the exact mechanism of placental involvement and abortion is unknown, the pathological
features suggest the likely course of events. C. psittaci organisms
acquired presumably through the respiratory rather than the genital route, escape into the maternal circulation and invade the placenta because of a predilection for the human trophoblast. There
they multiply rapidly, and are released into the intervillous spaces
and spread to other chorionic villi, including an intense acute
inflammatory response, the considerable tissue damage causing
placental insufficiency and fetal anoxic death. The maternal disseminated intravascular coagulation/shock syndrome is probably
due to the destruction of trophoblastic tissue releasing large
amounts of thromboplastic material and/or chlamydial endotoxin
into the maternal circulation.
While the events described above are dramatic, it is important to get the situation in perspective. It is noteworthy that the
prevalance of C psittaci antibodies in sera collected from workers
on farms in northern England, where chlamydial ovine abortion
occurred, was low and that antibody was detected no more frequently in farmers and their wives than in the non-farming adult
community28. Indeed, as indicated above, only a few cases of
human abortion arising in the way described have been recorded. Nevertheless, it is clearly prudent to advise pregnant women
to avoid contact with sheep, especially in the lambing season.
C. trachomatis infection in the newborn
Intrauterine infection with C. psittaci, as described, or with C.
trachomatis is a rare event. The major risk to the infant of acquiring a C. trachomatis infection and developing disease, as
described below, is from passing through an infected cervix.
Clearly, the frequency with which this occurs depends entirely on
38
the prevalence rate of cervical infection which as indicated previously, varies widely.
Conjunctivitis
The results of various studies indicate that between one-fifth
and one-half of infants exposed to C. trachomatis infecting the
cervix develop conjunctivitis29. The disease is seen usually from 1
to 3 weeks after birth and is characterised by a mucopurulent discharge and occasionally by pseudomembrane formation.
Although it may be quite severe, corneal ulceration and follicle
formation are rare and the disease is usually self-limiting, resolution occurring without visual impairment. If complications should
arise, however, they tend to do so in untreated infants.
Respiratory tract infection
Overall, about 10-20% of exposed infants develop pneumonia30, that is about half of those who develop conjunctivitis.
However, pneumonia is not always preceded by conjunctivitis. A
history of recent conjunctivitis and bulging eardrums is found in
about half the cases. Chlamydial pneumonia occurs usually
between the fourth and eleventh weeks of life, preceded by upper
respiratory symptoms, and is characterised by an afebrile protracted course in which there is tachypnoea and a prominent stacatto-type cough. Generalised hyperinflation with bilateral, diffuse and symmetrical interstitial infiltration with scattered areas of
atelectasis are the radiographic findings. The occurrence of C.
trachomatis IgM antibody in the infant’s serum is a useful diagnostic marker.
The exact way in which pneumonia develops is unknown,
although a relative eosinophilia in some cases has suggested the
possibility of a hypersensitivity mechanism. However, whatever
the mechanism, the disease is not to be dismissed lightly because
there is evidence that it can lead to permanent lung damage.
Thus, children who have experienced a chlamydial infection during infancy are more likely to develop obstructive lung disease
and asthma than are those who have had pneumonia due to
other causes or healthy controls31-33.
Infection at other sites
Apart from the eyes and respiratory tract, the vagina and rectum may be colonised by C. trachomatis at birth3, although colonisation has apparently not been associated with clinical disease.
The possibility of chlamydiae causing gastroenteritis in infants has
been considered32, but it amounts to no more than speculation.
Management of C. trachomatis in pregnancy
Screening
Effective screening requires the availability of a sensitive and
specific test which is acceptable to patients, the existence of effective treatment in the event of a positive result, and that it be costeffective.
Although not all investigators agree, the number of organisms
shed by asymptomatic women, whether pregnant or not, is probably no fewer than by symptomatic ones34, which suggests that
asymptomatic chlamydial infection should be no more difficult to
diagnose. However, small numbers of chlamydia are shed by
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Chlamydial Infection In Pregnancy
about 40% of infected women, irrespective of symptoms35 and
most of these will be detected only by use of the most sensitive
methods. The problem is compounded in a low prevalence population in which the positive predictive value of a test, even one
with a relatively high specificity, is unacceptably low. Thus, in one
study36 in which an enzyme immunoassay was used to test asymptomatic women in whom the prevalence of chlamydial infection
was 6.7%, the positive predictive value was 57%. This means that
in a low risk population there may be more false-positive than
true-positive results, a situation that can be rectified only by using
tests of the greatest sensitivity and specificity.
It would seem reasonable, although not widely practiced, to
screen patients who have had a previous spontaneous pre-term
rupture of the membranes at less than 37 weeks of gestation for
infection, including that by C. trachomatis. Whether to screen for
C. trachomatis in pregnancy routinely should be based on local
prevalence rates, with the knowledge that insensitive tests which
constitute the majority, will provide false-negative results and
reduce the cost-effectiveness of screening. Certainly, with prevalence rates of 5-7% in the United States and Sweden, antenatal
screening programmes have been regarded as cost-effective3,37,38
and in view of the high morbidity associated with chlamydial
infection in pregnant women, particularly infection of the newborn, the prevalence rate at which screening becomes cost-effective is almost certainly lower than for non-pregnant women.
Nevertheless, in the UK, a routine screening programme in pregnancy has never been instituted, either because of apathy or
because evidence that C. trachomatis causes damage to the fetus
during pregnancy is not strong. Furthermore, in high-risk population early screening would provide the opportunity for maternal infection to occur between screening and delivery. On the
other hand, screening and treating later in pregnancy, for example in the thirty-sixth week, to prevent infection of the newborn
is, as indicated above, worthwhile in a high-risk population. In
addition, screening of women who are to have a termination of
pregnancy would seem entirely justified in view of the greater
risk to chlamydia-positive women. This becomes even more rational now that highly sensitive tests are available.
Treatment of the mother
Tetracylines are generally considered to be the drugs of first
choice for treating chlamydia-infected, non-pregnant women.
Other choices are the 4-fluoroquinolones (such as ofloxacin and
ciprofloxacin), co-trimoxaole and broad-spectrum penicillins such
as pivampicillin. The choice is more restricted in pregnant
women, who are found to be infected with chlamydiae as a result
of a screening programme or otherwise. The use of tetracylines
is precluded since they cross the placenta and may cause skeletal
growth retardation and permanent discolouration of the teeth.
The 4 fluoroquinolones are not advocated because they have
caused arthropathy in immature animals and, furthermore, they
are excreted in breast milk. Co-trimoxazole, in animal studies,
has caused the typical teratogenic effect of a folate antagonist and
its safety for pregnant women has not been demonstrated.
Furthermore, sulphonamide-containing products should not be
prescribed in the third trimester because of the risk of kernicterus. Although co-trimoxazole is found in breast milk, it prob-
ably represents negligible risk to the suckling infant.
By elimination, the antibiotic of choice in pregnancy is erythromycin, which should be given in a dose of 250 mg, four times
daily for 7 days39. Providing there has been compliance, an insensitive microbiological test of cure, for example, an enzyme
immunoassay, is almost certain to be negative and a sensitive
molecular technique, despite full compliance, may provide positive results for several weeks. Needless to say, neither is likely to
be cost-effective. Single 1g dose Azithromycin, a highly effective
azalide antibiotic against uncomplicated chlamydial infection in
the non-pregnant population was found to have comparable efficacy to Erythromycin and better tolerated by pregnant women in
one study of cervical chlamydia 40. However, Azithromycin is not
currently licensed for use in pregnancy.
Women pregnant, or otherwise, whose partners have chlamydial infections, should have a full screen for sexually transmitted
diseases and epidemiological treatment for C. trachomatis, using
the regimen indicated above, as is advised irrespective of the
results. Conversely, partners of women with chlamydial infections
should be investigated and treated appropriately.
If a diagnosis of chlamydial infection is made in the newborn,
both parents should be investigated and treated, irrespective of
the diagnosis. Doxycycline 100mg, taken twice daily for 7 days, is
preferred for mothers who are not breast feeding. The father
should be referred to a genitourinary physician for investigation
and treatment. Breast-feeding mothers should be treated with erythromycin as mentioned above.
Prevention of chlamydial infection in the
newborn
Prophylaxis may involve treatment of the mother, or of the
infant after birth, usually for conjunctivitis. Treatment of the
mother, in the manner mentioned previously, is preferred since it
prevents neonatal infection at all sites, as well as postpartum
endometritis. The use of antibiotic in the third trimester is more
than 90% effective in preventing neonatal infection and with less
than a 5% rate of side effects41. Logically, treatment would be
based on a late pregnancy screening programme (see above).
However, if screening were not possible in an area of high
chlamydial prevalence, an option would be to administer antibiotics to women in high risk categories, using the criteria outlined
above. In a population where the prevalence of chlamydial infection is low, the policy would not be to screen mothers but to
maintain vigilance and treat infection in the neonate when it
occurred.
The results of relatively recent studies have not confirmed the
efficacy of topical prophylaxis for conjunctivitis42. Moreover, it has
no effect on nasopharyngeal colonisation and does not prevent
pneumonia. Not surprisingly, oral rather than topical erythromycin is superior for the treatment and prevention of pneumonia43.
Treatment of the chlamydia-positive newborn
Once infection with C. trachomatis has been diagnosed, treatment of the newborn depends on the site affected. Conjunctivitis
is best treated with a combination of tetracyline eye ointment and
erythromycin systemically. Topical chloramphenicol is ineffective
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Chlamydial Infection In Pregnancy
and topical tetracycline alone inadequate.
Pharyngitis, pneumonia, vaginal and rectal infection are best
treated with erythromycin given systemically in a dose of 40
mg/kg per day for 14 days30.
psittaci in a sheep farmer’s wife. Brit J Med 1985; 290: 592-4
25. McKinlay AW, White N, Buxton D et al. Severe Chlamydia psittaci sepsis in pregnancy.
Quart J Med 1985; 57 : 222; 689-96
26. Herring AJ, Anderson IE, McClenaghan M et al. Restriction endonuclease analysis of DNA
from two isolates of Chlamydia psittaci obtained from human abortions. Brit Med J 1987;
References
1.
295: 1239
Hammersclag MR, Anderka M, Semine DZ et al. Prospective study of maternal and infantile
infection with C. trachomatis . Pediatrics 1979; 64: 142-8
2.
Hardy PH, Hardy JB, Neil EE et al. Prevalence of six sexually transmitted disease agents
among pregnant inner city adolescents and pregnancy outcome. Lancet 1984; ii: 337-7
3.
Schachter J, Grossman M, Sweet RL et al. Prospective study of perinatal transmission of
Chlamydia trachomatis. J Amer Med Assoc 1986; 255: 3374-7
4.
Sweet RL, Gibbs RS, editors. Chlamydial Infections. Infectious Diseases of the female genital
tract, 2nd edn. Baltimore 1990, Williams & Wilkins, pp 45-74
5.
Ridgway GL, Mumtaz G, Stephens RA et al. Therapeutic abortion and chlamydial infection.
Wood PL, Hobson D, Rees E. Genital infection with Chlamydia trachomatis in women
attending an antenatal clinic. Brit J Obstet Gynaecol 1984; 91: 1171-76
7.
Preece PM, Ader A, Thompson RG et al. Chlamydia trachomatis infection in late pregnancy:
a prospective study. Paed Perinatol Epidemiol 1989; 3: 268-77
8.
Blackwell A, Thomas PD, Wareham K et al. Health gains from screening for infection of the
lower genital tract in women attending for TOP. Lancet 1993; 342: 206-10
9.
Chlamydia psittaci of sheep origin: a histological and ultrastructural study. J Clin Pathol
1985; 38: 707-11
28. Hobson D, Morgan - Capner P. Chlamydial antibodes in farmers in North West England.
Epidemiol Infect 1988; 101: 397-404
29. Sweet RL, Gibbs RS, editors. Chlamydial infections. Infectious diseases of the female genital
tract. Baltimore 1985, Williams & Wilkins, pp 103-26
30. Schachter J. Oculogenital chlamydia. Hare MJ, editor. Genital tract infection in Women.
London 1998, Churchill Livingstone, pp 216-27
31. Harrison HR, Taussig LM, Fulginiti VA. Chlamydia trachomatis and chronic respiratory
Brit Med J 1983; 286: 1478-79
6.
27. Wong SY, Gray ES, Buxton D et al. Acute placentitis and spontaneous abortion caused by
Fish ANJ, Fairweather DVI, Oriel JD et al. Chlamydia trachomatis infection in gynaecology
clinic population: identification of high risk groups and the value of contact tracing. Eur J
disease in childhood. Pediat Infect Dis 1982; 1: 29-33
32. Schaefer C, Harrison HR, Boyce WR et al. Illnesses in infants born to women with
Chlamydia trachomatis infection. A prospective study. Amer J Dis Child 1985; 139: 127-133
33. Weiss SG, Newcomb RW, Beem MO. Pulmonary assessment of children after chlamydial
pneumonia of infancy. J Pediat 1986; 108: 659-64
34. Taylor-Robinson D, THomas BJ. Laboratory techniques for the diagnosis of chlamydial
infections. Genitourin Med 1991; 67: 256-66
35. Thomas BJ, Osborn MF, Munday PE et al. A 2-year quantitative assessment of Chlamydia
trachomatis in a sexually transmitted diseases clinic population by the Micro Trak direct
Obstet Gynaecol 1989; 31: 67-74
10. Moller BR, Ahrons S, Laurin J et al. Pelvic infection after elective abortion associated with
Chlamydia trachomatis. Obstet Gynecol 1982; 59:210-13
11. Giertz G, Kallings I, Nordenvall M et al. A prospective study of Chlamydia trachomatis
infection following legal abortion. Acta Obstet Gynaecol Scand 1987; 66: 107-9
12. Frommel GT, Rothenberg R, Wang S-P et al. Chlamydial infection of mothers and their
infants. J Pediat 1979; 95: 28-32
smear immunoflourecence test. Int J STD & AIDS 1990; 1: 264-7
36. Lefebvre J, Laperriere H, Rouseau H et al. Comparison of three techniques for detection of
Chlamydia trachomatis in endocervical specimens from asymptomatic women. J Clin
Microbiol 1988;26: 726-31
37. Estany A, Todd M, Varquez M et al. Early detection of genital clamydial infection in women:
an economic evaluation. Sex Transm Dis 1989; 16: 21-7
13. Schachter J, Holt J, Goodner E et al. Prospective study of chlamydial infection in neonates.
Lancet 1979; ii: 377-80
38. Brunham RC, Holmes KK, Embree JE. Sexually transmitted diseases in pregnancy. Holmes
KK, Mårdh P-A, Sparling PE et al. editors. Sexually transmitted diseases, New York 1990,
14. Mårdh P-A, Helin I, Bobeck S et al. Colonisation of pregnant and puerperal women and
neonates with Chlamydia trachomatis. Brit J Vener Dis 1980; 56: 96-100
15. Martin DH, Koutsky L, Eschenbach DA et al. Prematurity and perinatal mortality in
pregnancies complicated by maternal Chlamydia trachomatis infections. J Amer Med Assoc
1982; 247: 1585-8
McGraw-Hill, pp 771-801
39. Stamm WE, Holmes KK. Chlamydia trachomatis infections of the adult. Holmes KK, Mårdh
P-A, Sparling PF el al, editors. Sexually Transmitted Diseases, New York 1990, McGraw Hill,
pp 181-94
40. Bush R. M, Rosa C. Azithromycin and Erythromycin in the treatment of cervical chlamydial
16. Harrison HR, Boyce WT, Haffner WH et al. The prevalence of genital Chlamydia trachomatis
and mycoplasmal infections during pregnancy in an American Indian population. Sex Transm
Dis 1983; 10: 184-6
infection during pregnancy. Obstet Gynaecol 1994; 84: 61-3
41. Schachter J, Sweet RL, Grossman M et al. Experience with the routine use of erythromycin
for chlamydial infections in pregnancy. New Engl J Med 1986; 314: 276-9
17. Sherman KY, Daling JR, Steryachis A et al. Sexually transmitted diseases and tubal
pregnancy. Sex Transm Dis 1990; 17: 115-21
42. Hammerschlag MR, Cummings C, Roblin PM et al. Efficacy of neonatal occular prophylaxis
for the prevention of chlamydial and gonococcal conjunctivitis. New Engl J Med 1989; 320:
18. Gates WJC, Wasserheit JN. Genital chlamydia infections: epidemiology and reproductive
sequelae. Amer J Obstet Gynecol 1991;164: 1771-81
19. Hoyme UB, Kiviat N, Eschenbach DA. Microbiology and treatment of late post partum
769-72
43. Patamasucon P, Rettig PJ, Faust KL et al. Oral versus topical erythromycin therapies for
chlamydial conjunctivitis. Amer J Dis Child 1982; 136: 817-21
endometritis. Obstet Gynecol 1986; 68: 226-32
20. Ong, G, Thomas BJ, Mansfield AO et al. Detection and widespread distribution of Chlamydia
pneumoniae in the vascular system and its possible implications. J Clin Pathol 1996; 49: 102-6
21. Giroud P, Roger F, Dumes N. Certains avortements chez la femme peuvent etre dus a des
agents situés a coté du groupe de la psittacose. Comptes Rendus Hebdomadaire des Séances
de L’Académie des Sciences 1956; 242:697-9
22. Roberts W, Grist NE, Giroud P, Human abortion associated with infection by ovine abortion
agent. Brit Med J 1967; 222: 37
23. Beer RJS, Bradford WP, Hart RJC. Pregnancy complicated by psittacosis acquired from sheep.
Brit Med J 1982; 284: 1156-7
24. Johnson FWA, Matheson BA, Williams H et al. Abortion due to infection with Chlamydia
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