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Loss 10
Nilanchali Singh and Komal Rastogi
10.1 Introduction
The organisms responsible for recurrent pregnancy loss are bacterial, viral and para-
sitic as enumerated in Table 10.1.
10.3 Pathogenesis
Pathogens lead to the recruitment of macrophages and T cells into the endometrium
and secrete excessive amount of Th1 cytokines, which are detrimental to implanta-
tion and maintenance of successful pregnancy [3]. IL-1, IL-6 and TNF-alpha attract
neutrophils to the site of infection along with chemokine IL-8 [4]. Production of
toxins and cytokines induces uterine contractions and damage to feto-placental unit.
This mechanism is common to all pathogens. Bacteria in addition to this produce
proteins with an amino terminal N-formylated methionine, which activates comple-
ment fragments and receptors for chemokines [5].
Viral infections like CMV downregulate cytotrophoblast molecules (integrins
and MMP-9) which are responsible for placental invasion of uterine tissue and foe-
tal development [6]. Interaction between CMV and decidual NK cells may cause
NK cell activation and miscarriage [7]. The various mechanisms are summarized in
Fig. 10.1.
BACTERIA VIRUS
Abortion
Mycoplasma hominis were cultured at first visit from 48% of women with early
pregnancy loss as compared to 8.2% of control females (p < 0.0001).
However, the management is still uncertain. According to a meta-analysis by
Guise et al. [12], there is no benefit of routine bacterial vaginosis screening, but
there may be a benefit of treatment for bacterial vaginosis for preventing preterm
deliveries <37 weeks. A recent Cochrane review including 7847 women in 21 trials
also found decreased risk of late miscarriage when antibiotic treatment was admin-
istered [13]. CDC recommends either metronidazole 250 mg oral TDS for 7 days or
clindamycin 300 mg BD for 7 days [14].
Chlamydia is an obligate intracellular bacteria and is the most common sexually trans-
mitted bacterial disease worldwide. Chlamydia infection is mostly asymptomatic but
may result in acute urethral syndrome, cervicitis and pelvic inflammatory disease.
Diagnosis is made on PCR on vaginal swab samples, and treatment includes administra-
tion of antibiotics such as tetracycline and azithromycin. Various studies have reported
an association between Chlamydia trachomatis and recurrent pregnancy loss [16, 17].
Persisting chlamydial infection may lead to pregnancy loss by stimulating either foetal
inflammatory response or evoking maternal immunogenic reaction to chlamydial heat-
shock protein 60 antigen [18, 19]. According to a recent study, chlamydia was more
often detected by PCR in patients with previous abortion (11.8%) as compared to con-
trols (p = 0.029) [20], hence confirming its role in recurrent spontaneous miscarriages.
[25]. Another study conducted in China by Hong et al. reported a decrease in mis-
carriages after a screening programme to prevent mother to child transmission of
syphilis. Campylobacter jejuni may also be considered as a differential diagnosis of
recurrent miscarriages especially in women with diarrheal disease.
10.5.1 Cytomegalovirus
Parvovirus B19 has also been implicated as a cause of foetal loss. The virus infects
the erythroid precursors inhibiting erythropoiesis and causes non-immune hydrops.
An Egyptian study demonstrated a significantly higher rate of B19 IgM in women
with recurrent miscarriages as compared to controls and proposed it as a cause of
recurrent spontaneous abortions [29]. Another virus, the adeno-associated parvovi-
rus (AAV) belonging to Parvoviridae family, has also been reported to be associated
with recurrent miscarriages. HIV though not associated with recurrent abortions
may act as a predisposing factor for development of chronic infections leading to
adverse pregnancy outcomes.
134 N. Singh and K. Rastogi
Table 10.2 Treatment options for infections associated with recurrent miscarriage
Bacterial Bacterial vaginosis Metronidazole
Clindamycin
Mycoplasma Tetracycline
Ureaplasma Azithromycin
Chlamydia
Listeria Ampicillin + Gentamycin
Brucella Doxycycline + Gentamycin
Virological Herpes simplex virus Valganciclovir
Cytomegalovirus Acyclovir
Parvovirus B-19 Intravenous
Immunoglobulin
Toxoplasma gondii can cause pregnancy loss during primary infection, but recurrent
infection is highly unlikely in subsequent pregnancies except in immunocompro-
mized host, where it may result in abortion, prematurity, growth restriction or still-
birth. Plasmodium falciparum infection causes stillbirth or miscarriage by proliferating
in intervillous space of the placenta. Screening for malaria in women with recurrent
abortions should be considered in endemic areas and in symptomatic patients.
10.8 R
ecommendations for Screening and Treatment of
Infections in RPL
Conclusion
In all patients with recurrent spontaneous abortions, personal risk of infections
should be assessed by history, physical and laboratory examination, and chronic
infections should be excluded. Immunological investigations including immuno-
globulin levels, T and B lymphocyte levels, and NK cytotoxic activity may also
be carried out as risk of developing placental and foetal infection depends upon
immune reactivity of pregnant women. Specific antibiotic or antiviral therapy
should be used for eradication of persistent bacterial and viral infections.
10 Microbiology of Recurrent Pregnancy Loss 135
Key Points
• Infections (bacterial, viral, protozoal) are associated only with sporadic
miscarriages and are rarely associated with recurrent pregnancy loss.
• Mechanism of abortion includes complement activation and production of
inflammatory cytokines.
• Routine testing for infectious agents and routine antibiotic treatment is not
recommended in recurrent pregnancy loss.
References
1. Kutteh WH. Recurrent pregnancy loss: an update. Curr Opin Obstet Gynecol. 1999;56:247–53.
2. Summers PR. Microbiology relevant to recurrent miscarriage. Clin Obstet Gynecol.
1994;37:722–9.
3. Bricker L, Farquharson RG. Types of pregnancy loss in recurrent miscarriage: implications for
research and clinical practice. Hum Reprod. 2002;17:1345–50.
4. Wegmann TG, Lin H, Guilbert L, Mosmann TR. Bidirectional cytokine interactions in the
maternal fetal relationship: is successful pregnancy a TH2 phenomenon? Immunol Today.
1993;14:353–6.
5. Sugiura-Ogasawara M, Nozawa K, Nakanishi T, Hattori Y, Ozaki Y. Complement as a predictor
of further miscarriage in couples with recurrent miscarriages. Hum Reprod. 2006;21:2711–4.
6. Yamamoto-Tabata T, McDonagh S, Chang H-T, Fisher S, Pereira L. Human cytomegalovirus
interleukin-10 downregulates matrix metalloproteinase activity and impairs endothelial cell
migration and placental cytotrophoblast invasiveness in vitro. J Virol. 2004;78:2831–40.
7. Tanaka K, Yamada H, Minami M, Kataoka S, Numazaki K, Minakami H, Tsutsumi
H. Screening for vaginal shedding of cytomegalovirus in healthy pregnant women using real-
time PCR: correlation of CMV in the vagina and adverse outcome of pregnancy. J Med Virol.
2006;78:757–9.
8. Viniker DA. Hypothesis on the role of sub-clinical bacteria of the endometrium (bacteria endo-
metrialis) in gynaecological and obstetric enigmas. Hum Reprod Update. 1999;5:373–85.
9. Ralph SG, Rutherford AJ, Wilson JD. Influence of bacterial vaginosis on conception and mis-
carriage in the first trimester: cohort study. BMJ. 1999;319:220–3.
10. Oakeshott P, Hay P, Hay S, Steinke F, Rink E, Keny S. Association between bacterial vaginosis
or chlamydial infection and miscarriage before 16 weeks gestation: prospective community
based cohort study. BMJ. 2002;325:1334–8.
11. Donders GG, Van Bulck B, Caudron J, Londers L, Vereecken A, Spitz B. Relationship of bac-
terial vaginosis and mycoplasma to the risk of spontaneous abortion. Am J Obstet Gynecol.
2000;183:431–7.
12. Guise JM, Mahon SM, Aickin M, Helfand M, Peipert JF, Westhoff C. Screening for bacterial
vaginosis in pregnancy. Am J Prev Med. 2001;20(Suppl 3):62–72.
13. Brocklehurst P, Gordon A, Heatley E, Milan S. Antibiotics for treating bacterial vaginosis
in pregnancy. Cochrane Database Syst Rev. 2013;(1):CD000262. doi: 10.1002/14651858.
CD000262.pub4.
14. Centres for Disease Control and Prevention. Sexually transmitted diseases treatment guide-
lines 2002. MMWR Morb Mortal Wkly Rep. 2002;51:1–80.
15. Narssens A, Foulon W, Cammu H, Goossens A, Lauwers S. Epidemiology and pathogenesis
of ureaplasma urealyticum in spontaneous abortion and early preterm labour. Acta Obstet
Gynecol Scand. 1987;66:513–6.
16. McGregor JA, French CNN. Chlamydia trachomatis infection during pregnancy. Am J Obstet
Gynecol. 1991;164:1782–4.
17. Centres for Disease Control and Prevention. Sexually transmitted disease surveillance 2007,
Chlamydia Prevalence Monitoring Project Annual Report, Atlanta; 2007.
136 N. Singh and K. Rastogi
18. Stirrat GM. Recurrent pregnancy loss. II. Clinical associations, causes, and management.
Lancet. 1990;336:728–33.
19. Witkin S. Immune pathogenesis of asymptomatic Chlamydia trachomatis in the female genital
tract. Infect Dis Obstet Gyneol. 1995;3:169–74.
20. Wilkowska-Trojniel M, Zdrodowska-Stefanow B, Ostaszewska-Puchalaska I, Redzko S,
Przepiesc J, Zdrodowski M. The influence of Chlamydia trachomatis infection on spontaneous
abortions. Adv Med Sci. 2009;54:86–90.
21. Romana C, Salleras L, Sage M. Latent listeriosis may cause habitual abortion, intrauterine
deaths, fetal malformations. When diagnosed and treated adequately normal children will be
born. Acta Microbiol Hung. 1989;36:171–2.
22. Jamshidi M, Jahromi AS, Davoodian P, Amirian M, Zangeneh M, Jadcareh F. Seropositivity
for listeria monocytogenes in women with spontaneous abortion: a case control study in Iran.
Taiwan J Obstet Gynecol. 2009;48:46–8.
23. Manganiello PD, Yearke RR. A 10-year prospective study of women with a history of recur-
rent fetal losses fails to identify Listeria monocytogenes in female genital tract. Fertil Steril.
1991;56:781–2.
24. Kochar DK, Gupta A, Gupta BK, Kalla A, Nayak KC. Hospital based case series of 175 cases
serologically confirmed brucellosis. J Assoc Physicians India. 2007;55:271–5.
25. Myer L, Abdool Karim SS, Lombard C, Wilkinson D. Treatment of maternal syphilis in rural
South Africa: effect of multiple doses of benzathine penicillin on pregnancy loss. Trop Med Int
Health. 2004;9:1216–21.
26. Van Lijnschoten G, Stals F, Evers JCH, Bruggeman CA, Havenith MH, Geraedts JPM. The
presence of cytomegalovirus antigens in karyotyped abortions. Am J Reprod Immunol.
1994;32:211–20.
27. Radcliffe JJ, Hart CA, Francis WJ, Johnson PM. Immunity to cytomegalovirus in women
with unexplained recurrent spontaneous abortion. Am J Reprod Immunol Microbiol.
1986;12:103–5.
28. Kapranos NC, Kotronias DC. Detection of herpes simplex virus in first trimester pregnancy
loss using molecular techniques. In Vivo. 2009;23:839–42.
29. el-Sayed Zaki M, Goda H. Relevance of parvovirus B19, herpes simplex virus 2, and cytomeg-
alovirus virologic markers in maternal serum for diagnosis of unexplained recurrent abortions.
Arch Pathol Lab Med. 2007;131:956–60.