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Microbiology of Recurrent Pregnancy

Loss 10
Nilanchali Singh and Komal Rastogi

10.1 Introduction

Clinically recognized pregnancy loss occurs in 15–20% of pregnancies [1].


Infections are considered to cause recurrent pregnancy loss in 4% of cases [2].
Recurrent pregnancy loss is defined as the occurrence of two or more clinical preg-
nancy losses before 20 weeks from last menstrual period.
Ureaplasma urealyticum, Mycoplasma hominis, Listeria monocytogenes, chla-
mydia, Toxoplasma gondii, cytomegalovirus, rubella and herpes virus have been
frequently identified in serum and cervical and vaginal cultures of women with
sporadic miscarriages. All microorganisms can cause acute infection and occasional
abortion, but only those causing chronic maternal disease are responsible for recur-
rent abortions. The role of infections in recurrent pregnancy loss is not clear due to
lack of prospective studies. In this chapter we will discuss the infectious causes of
recurrent pregnancy loss, their pathogenesis, diagnosis and therapeutic
management.

10.2 Organisms Associated with Recurrent Pregnancy Loss

The organisms responsible for recurrent pregnancy loss are bacterial, viral and para-
sitic as enumerated in Table 10.1.

N. Singh (*) • K. Rastogi


Obstetrics and Gynecology, Maulana Azad Medical College and Lok Nayak Hospital,
Delhi, India
e-mail: nilanchalisingh@gmail.com

© Springer Nature Singapore Pte Ltd. 2018 129


S. Mehta, B. Gupta (eds.), Recurrent Pregnancy Loss,
https://doi.org/10.1007/978-981-10-7338-0_10
130 N. Singh and K. Rastogi

Table 10.1  Pathogens in recurrent abortions


Bacteria Viruses Parasites Spirochetes
Bacterial vaginosis Cytomegalovirus Toxoplasma gondii Treponema
pallidum
Listeria Herpes simplex Plasmodium
monocytogenes falciparum
Ureaplasma Rubella
urealyticum
Mycoplasma Human immunodeficiency
hominis virus
Chlamydia
trachomatis

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.

10.4 Bacterial Infections

10.4.1 Bacterial Vaginosis

Bacterial vaginosis is characterized by an overgrowth of predominantly anaerobic


bacteria along with a reduction or absence of lactobacilli within the vagina [8].
Bacterial vaginosis may be asymptomatic or may result in a vaginal discharge,
which is grey in colour and has a ‘fishy’ odour. The diagnosis is made on the pres-
ence of ‘clue cells’ on microscopic examination of vaginal swab sample. According
to various studies, bacterial vaginosis has been predominantly associated with late
miscarriages [9, 10]. However, according to a study by Donders et  al. [11], an
increased risk of miscarriage during early pregnancy was found amongst women
with bacterial vaginosis. Gardnerella vaginalis, Ureaplasma urealyticum or
10  Microbiology of Recurrent Pregnancy Loss 131

BACTERIA VIRUS

Production of F-Met-Leu-Phe peptide and Recruitment of T cells and


activation of complement fragments macrophages into
and chemokine receptor the endometrium

Secretion of Th1 cytokines


(IL-1, IL-6, IL-8, TNF-a)

Attract neutrophils to the site of infection

Excessive maternal immune response

Abortion

Fig. 10.1  Mechanism for induction of abortion by microorganisms

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].

10.4.2 Mycoplasma hominis and Ureaplasma urealyticum

The genital mycoplasmas, M. hominis and U. urealyticum, have been associated


with increased risk of recurrent pregnancy loss, preterm labour and preterm prema-
ture rupture of membranes. According to a study, endometrial colonization by these
organisms was more frequent in patients with recurrent pregnancy loss (27.6%) as
compared to controls (9.7%) (p < 0.05) [15]. Antibiotic treatment for women colo-
nized with mycoplasmas has been seen to prevent recurrent spontaneous
miscarriages.
132 N. Singh and K. Rastogi

10.4.3 Chlamydia trachomatis

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.

10.4.4 Listeria monocytogenes

Listeria monocytogenes enters through gastrointestinal tract leading to bacteremia and


transplacental spread to the foetus. Ascending infection through introduction of Listeria
into the vagina and cervix also may occur. Listeria may interfere with immune toler-
ance to foetus in pregnancy resulting in pregnancy loss. Listeria causes intrauterine
infection in third trimester and leads to preterm labour, neonatal infection or stillbirth.
Romana et al. proposed that latent listeriosis may cause recurrent pregnancy loss
[21]. Another Iranian study demonstrated high seroprevalence of Listeria monocy-
togenes in patients with previous spontaneous abortion as compared to controls
[22]. However, Manganiello and Yearke [23] in their study on patients with two or
more foetal losses demonstrated that Listeria monocytogenes contributes to foetal
loss but not on recurrent basis as none of the patients with recurrent pregnancy loss
were found to harbour Listeria in their genital tract and concluded that routine cul-
turing for Listeria monocytogenes and therapy in patients with recurrent pregnancy
loss is not needed.

10.4.5 Other Bacterial Infections

Acute brucellosis caused by Brucella melitensis has been considered as a cause of


recurrent miscarriages in humans. It is transmitted via consumption of unpasteur-
ized dairy products. However, acute brucellosis rarely causes miscarriage as human
placenta does not contain erythritol, which is a substrate for brucella adhesion and
spread to foetus [24]. Another organism Borrelia duttonii causing relapsing fever is
also believed to be a common cause of abortion in sub-Saharan Africa. Klebsiella
pneumoniae has also been reported as a cause of abortions due to seminal contami-
nation by the organism. Syphilis caused by Treponema pallidum has also been
implicated as a cause of recurrent spontaneous abortions. It is transmitted sexually
or by coming in contact with blood of an infected person. Diagnosis is made using
PCR.  A study conducted in South Africa demonstrated a reduction in perinatal
death and a reduced risk of pregnancy loss by treatment with benzathine penicillin
10  Microbiology of Recurrent Pregnancy Loss 133

[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 Viral Infections

10.5.1 Cytomegalovirus

Cytomegalovirus (CMV) is a member of Herpesviridae family. Infection with CMV


is very common with seropositivity rates ranging from 40% in developed countries
to 100% in developing countries. Symptomatic disease occurs mostly in immuno-
compromized hosts or when immunocompetent host is critically ill. Congenital
CMV may occur due to primary infection during pregnancy or due to reactivation
of previously acquired CMV. During pregnancy CMV reaches placenta from cervix
or by viremia causing tissue damage, vascular insufficiency and foetal infection.
Abortion can occur as a result of placental detachment and foetal death.
According to a study, CMV antigen pp65 was detected in decidua of 35% of
patients with spontaneous abortions [26]. Another study demonstrated a higher per-
centage of vaginal CMV DNA detection in women with miscarriages as compared
to controls [7]. Radcliffe et al. [27] proposed that patients with unexplained recur-
rent abortions have an immune difficulty in responding to CMV and such patients
should be considered for immunotherapy.

10.5.2 Herpes Simplex Virus

HSV causes subclinical intrauterine endometrial infection leading to transplacental


embryo infection and spontaneous abortion. Kapranos reported on the role of HSV
in early pregnancy loss and its detection by nested PCR, which allowed appropriate
antiviral therapy and successful future pregnancy [28].
Other herpes viruses, Epstein–Barr virus, varicella-zoster virus and human her-
pesvirus-­6 have been associated with occasional abortions.

10.5.3 Other Viral Infections

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

10.6 Protozoan Infections

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.

10.7 Treatment for Patients with Recurrent Miscarriages

Although routine screening of infections is not recommended in women with RPL,


therapeutic options can be considered in case the infection is persistent as summa-
rized in Table 10.2.

10.8 R
 ecommendations for Screening and Treatment of 
Infections in RPL

According to the American Society of Reproductive Medicine, due to lack of con-


vincing data and prospective studies linking infectious agents and recurrent miscar-
riages, testing for these infectious agents and routine antibiotic treatment is not
recommended. RCOG also does not recommend TORCH screening in patients with
recurrent pregnancy loss.

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.

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