DOI: 10.1111/j.1471-0528.2010.02771.
x
www.bjog.org
Tuberculosis in pregnancy
CN Mnyani, JA McIntyre
Anova Health Institute, Johannesburg, South Africa
Correspondence: Dr JA McIntyre, Anova Health Institute, 12 Sherborne Rd., Parktown, Johannesburg 2193, South Africa.
Email mcintyre@anovahealth.co.za
Accepted 17 September 2010. Published Online 18 November 2010.
Tuberculosis (TB) remains an important infection in women
globally. It is responsible for 700 000 deaths annually and is a
major contributor to maternal mortality. Mycobacterium
tuberculosis/HIV co-infection is common in areas of high HIV
prevalence, and may be associated with significant perinatal and
maternal morbidity. Improved diagnosis and treatment of TB in
pregnant women are important interventions for both maternal
Please cite this paper as: Mnyani C, McIntyre J. Tuberculosis in pregnancy. BJOG 2011;118:226–231.
Introduction
The World Health Organization (WHO) estimates that,
globally, there were approximately 13.7 million cases of
tuberculosis (TB) in 2008. TB incident cases have risen
from 6.6 million in 1990 to 9.4 million in 2008, with
3.6 million of the new infections in 2008 occurring in
women.1 TB is a leading cause of death in women,
accounting for about 700 000 deaths every year, and it is
also one of the leading nonobstetric causes of maternal
mortality, with an estimated one-third of deaths due to TB
occurring in women of child-bearing age, the majority in
resource-limited countries.2
Data from sub-Saharan Africa illustrate the significance
of Mycobacterium tuberculosis infection as a major cause of
maternal mortality, especially in the context of HIV co-
infection.3,4 Mycobacterium tuberculosis/HIV co-infection is
common, as areas of high TB incidence and prevalence are
also areas of high HIV incidence and prevalence. In an
audit of maternal mortality in Johannesburg, South Africa,
70% of deaths in women who were infected with HIV were
HIV-related, rather than from obstetric causes, and mainly
from TB and pneumonia.4 Although the greatest burden of
TB infection is in resource-limited countries, resource-rich
countries have seen a resurgence of TB over the past few
years, largely as a result of an increase in immigrant popu-
lations in these countries. A retrospective study in London
over a 5-year period—1997–2001—showed an increase in
226 ª 2010 The Authors Journal compilation ª RCOG 2010 BJOG An International Journal of Obstetrics and Gynaecology
Review article
and child health. Controlling TB in pregnancy in high-prevalence
areas requires a range of interventions, including active TB
screening in pregnant women, TB preventative therapy for
HIV-infected pregnant women, treatment of active TB and
linking mothers and children to TB care services.
Keywords AIDS, HIV, pregnancy, tuberculosis.
the number of pregnant women with TB.5 Another study
in 2008 estimated that the national incidence of TB in
pregnancy in the UK was 4.2 per 100 000 maternities, or
approximately 1 per 24 000 maternities.6 All pregnant
women with TB in both of these studies were of ethnic
minority origin, and a significant number had recently
immigrated into the UK. Although there has been a
reported decline in the incidence of TB in the USA, immi-
grant populations remain at a greater risk of TB infection
compared with individuals born in the USA—the risk is up
to 11 times higher.7
Epidemiology
In areas with stable or increasing TB transmission rates, the
highest incidence rate is in young adults,8 with more men
affected than women. In 2007, 1.65 million cases of smear-
positive TB notified were in men, compared with 0.9 mil-
lion in women.9 However, in resource-limited settings,
women of child-bearing age—especially in the 15–24-year
age group—are disproportionately affected by TB because
of the high HIV prevalence rates in this group.1 They bear
the brunt of M. tuberculosis/HIV co-infection in these set-
tings. HIV infection increases the risk of infection with TB:
results from a large cohort in South Africa showed that this
risk increased soon after HIV seroconversion and was sus-
tained for a few years thereafter.10 The extent of immuno-
suppression influences the risk of TB. Antiretroviral

therapy (ART) decreases the risk of TB, but HIV-infected
individuals on ART remain at some risk for TB infection,
albeit at a lower risk than individuals who are not on treat-
ment.11 Pregnancy on its own has not been found to be
associated with an increased risk of TB, but a general
increase in the incidence of TB will lead to an increase in
TB infection rates in pregnant women.12
Diagnosis
TB infection in pregnancy may present with diagnostic
challenges, mainly because of the often nonspecific nature
of the early symptoms of the infection, such as malaise and
fatigue, which may be attributed to pregnancy and not
raise the suspicion of TB infection.12–14 Despite this, the
presentation of TB in pregnant women is similar to that in
nonpregnant individuals, with pulmonary TB the most
common manifestation of the disease.14 The most impor-
tant step in making the diagnosis in pregnancy is the iden-
tification of the risk factors for TB infection and specific
enquiry about the symptoms which may be suggestive of
infection.12–14
Routine screening for TB in pregnancy is not standard
practice in many settings, and this is one of the factors
thought to delay the diagnosis and also contribute to
maternal mortality.4 In studies performed in Soweto, South
Africa, TB screening by the use of a limited number of
questions during routine antenatal care was found to be
feasible, and added very little time to the routine consulta-
tion.15,16 Recommendations have been made that routine
questioning for TB screening should be implemented in
settings of high HIV prevalence, as the rates of TB infection
in pregnant women are high in these settings.16–18
The usual diagnostic modalities—sputum microscopy for
acid-fast bacilli, culture of sputum and other specimens for
M. tuberculosis and chest radiography—remain the main-
stay of diagnosis. The tuberculin skin test is of value in the
diagnosis of latent TB infection, except in areas in which
there is a high prevalence and incidence of TB.14,19
Confirmation of M. tuberculosis infection remains a diffi-
cult issue, with outdated and inaccurate technology, espe-
cially in low-resource settings. Improved diagnostic
technology remains a priority area for development.20,21
Interferon-c release assays and the Quanti-FERON-TB Gold
In-Tube assay have been used for the diagnosis of latent
TB infection. They have increased the specificity and diag-
nostic accuracy, and are not affected by previous bacillus
Calmette–Guérin (BCG) vaccination or infection with non-
tuberculous mycobacteria.19 The Quanti-FERON-TB Gold
In-Tube assay is safe for use in pregnancy, but has not
been validated in pregnancy.
HIV infection modifies the expression of active TB
infection. Smear-negative TB is common in HIV-infected
ª 2010 The Authors Journal compilation ª RCOG 2010 BJOG An International Journal of Obstetrics and Gynaecology
Tuberculosis in pregnancy
individuals as they tend to produce fewer bacilli, and
microscopy alone should not be used to make the diagno-
sis.22 Chest radiography and sound clinical judgement are
essential aids in making a rapid diagnosis of smear-negative
TB; however, chest radiography may also be normal in up
to 14% of individuals with culture-confirmed TB.23 Extra-
pulmonary TB is not uncommon in pregnancy, and clini-
cians should have a high index of suspicion in individuals
with atypical symptoms.5,6,22
Infection control is important in controlling the spread
of TB, which is infectious only when it occurs in the lungs
or larynx, and is not usually spread by brief contact.24 Staff
and family members dealing with infected pregnant women
should be provided with information on transmission and
the need for screening.
Management of active TB
WHO recommends that the treatment of TB in pregnant
women should be the same as that in nonpregnant women;
the only exception being that streptomycin should be
avoided in pregnancy as it is ototoxic to the fetus.25 The
standard treatment is ethambutol, isoniazid, rifampicin and
pyrazinamide for 2 months—the intensive phase—followed
by 4 months of isoniazid and rifampicin—the continuation
phase. If pyrazinamide is not used in the first 2 months of
therapy, isoniazid and rifampicin are given for 7 months.
Directly observed therapy is recommended, especially if
compliance to treatment is a concern. The safety of the
first-line drugs for the management of active TB in preg-
nancy has been established, and therapy improves both
maternal and neonatal outcomes.12,26
The management of multidrug-resistant TB (MDR-TB)
in pregnancy is complex, and there are limited data on the
safety of second-line drugs in pregnancy. However, several
cases of successful treatment of MDR-TB in pregnancy,
with good maternal and neonatal outcomes, have been
reported.27–30 In a retrospective review of treatment and
pregnancy outcomes in a cohort of pregnant women
infected with MDR-TB in Peru, treatment outcomes were
comparable with those in nonpregnant women.30 Preg-
nancy outcomes in this cohort were also comparable with
those in the general population, and the suggestion is that
pregnant women diagnosed with MDR-TB should have an
option to continue with MDR-TB treatment during preg-
nancy, rather than terminating the pregnancy or discon-
tinuing treatment.
Although good outcomes have been reported in pregnant
women infected with MDR-TB, co-infection with HIV may be
associated with significant perinatal and maternal morbidity. In
a prospective study of pregnant women co-infected with MDR-
TB and HIV, conducted in KwaZulu Natal, South Africa,
multiple adverse maternal and neonatal outcomes were
227
 Mnyani, McIntyre
observed.31 The adverse outcomes included prematurity, intra-
uterine growth restriction, and maternal drug- and disease-
relatedcomplications.
Treatment of TB in pregnant women co-infected with
HIV presents several challenges. For those pregnant
women who have not yet started ART, there is the
question of timing of ART initiation and what regimen
to use, taking into account the potential for maternal
and fetal toxicities. Although TB treatment and ART
can be started concomitantly, the current recommenda-
tion is to start combination ART after starting TB treat-
ment, preferably within 8 weeks.25 With ART, TB may
be aggravated, and there is also the risk of immune
reconstitution syndrome, especially in the first 2 months
of treatment, and in individuals with significant immune
suppression.14 Delaying the initiation of ART decreases
the risk of overlapping drug toxicities and complica-
tions, especially immune reconstitution inflammatory
syndrome, but the delay needs to be balanced against
the risk of morbidity and mortality associated with not
starting ART.32 The administration of TB treatment and
ART is complicated by a high pill burden, potential
drug toxicities and drug interactions.14,33 Rifampicin
may reduce plasma concentrations of commonly used
antiretrovirals, especially non-nucleoside reverse trans-
criptase inhibitors (NNRTIs) and protease inhibitors.34,35
With NNRTIs, studies have found decreased plasma
levels of nevirapine in individuals on concomitant rifam-
picin-based TB treatment; levels of efavirenz at standard
doses appear to be largely unaffected, and hence it is
the preferred NNRTI.34,35 Efavirenz is contraindicated,
however, in the first trimester of pregnancy because of
concerns about teratogenicity. Rifampicin also causes a
marked reduction in the levels of protease inhibitors,
and there have been reports of hepatotoxicity in indi-
viduals initiated on rifampicin prior to the initiation of
a boosted protease inhibitor-based regimen.34,35 The rec-
ommendation is to monitor liver function. An alterna-
tive is to use rifabutin for the treatment of TB, as this
may decrease the risk of drug interactions with anti-
retroviral drugs.36 Management of M. tuberculosis/HIV
co-infection remains complex, and there are still a num-
ber of unresolved questions.28,37
Latent TB infection
Latent TB is common and HIV infection increases the risk
of reactivation, especially with significant immunosuppres-
sion.38 Latent TB is diagnosed using the tuberculin skin
test, and the recommended treatment is 9 months of
isoniazid monotherapy, which has been shown to be effec-
tive in pregnant women.39,40 Alternative treatment options
with varying efficacy and potential for complications are
228 ª 2010 The Authors Journal compilation ª RCOG 2010 BJOG An International Journal of Obstetrics and Gynaecology
available, but should be used by clinicians experienced in
the management of TB.36
There has been much debate regarding the management
of latent TB during pregnancy, with some recommenda-
tions that treatment should be deferred during pregnancy
and in the immediate postpartum period unless there is a
high risk of progression to active disease.41,42 The main
concern is the risk of hepatotoxicity associated with isonia-
zid use during pregnancy and in the immediate postpartum
period. This risk of isoniazid toxicity must be weighed
against the consequences of active TB developing during
pregnancy and in the postpartum period. For HIV-infected
pregnant women, the current recommendation remains
that they should receive isoniazid preventative therapy dur-
ing pregnancy, as the benefits of preventing active TB
infection far outweigh the risks of isoniazid-associated tox-
icity. Pregnant and breast-feeding women receiving isonia-
zid therapy should routinely receive pyridoxine as they are
at risk of isoniazid-associated peripheral neuropathy.25
Effect of TB on maternal and neonatal
outcomes
There are conflicting data on the effects of TB on maternal
and neonatal outcomes. Some studies have suggested that,
with timely and appropriate treatment, TB infection does
not have a negative effect on pregnancy outcomes, whereas
others have suggested that TB infection in pregnancy is
associated with adverse pregnancy outcomes. In a prospec-
tive study in India, there were no statistically significant
differences in pregnancy complications and pregnancy out-
comes in women diagnosed with and treated for TB in
pregnancy relative to matched controls who were pregnant
and had no TB.26 The only exception was in women who
started TB treatment late in pregnancy; neonatal mortality
and extreme prematurity were significantly higher in this
group. TB was diagnosed and treatment was initiated
between 13 and 24 weeks of gestation in the majority of
cases (64.7%). Treatment outcomes—sputum conversion,
disease stabilisation and rates of relapse—were similar to
those of matched controls who had TB and were not preg-
nant, but none of the pregnant women with TB in this
study were infected with HIV. In HIV-infected pregnant
women, the effect on TB appears to be related more to
HIV disease rather than to the pregnancy itself.
In contrast with the findings of the above study, a retro-
spective review in Taiwan found that women who were
diagnosed with TB in pregnancy had an increased risk of
adverse pregnancy outcomes compared with unaffected
mothers.43 There was a significantly higher percentage of
low-birth-weight and small-for-gestational-age infants in
pregnant women diagnosed with TB, but no significant
difference in preterm birth between the two groups.

Despite the conflicting reports, timely diagnosis and treat-
ment of TB in pregnancy are important; TB is still a cause
of significant maternal morbidity and mortality, especially
in the context of HIV co-infection.3,4,44,45
Paediatric transmission
In TB-endemic areas, cases of perinatal TB will be more
common. In a survey performed in the Western Cape,
South Africa, an area with a high prevalence and incidence
of TB, infants born to HIV-infected mothers had a high risk
of TB exposure, and this exposure may contribute to the
high rates of TB infection in this group of infants.46 A pro-
spective study performed in the same area, the Western
Cape, showed that the incidence of TB was much higher in
HIV-infected infants: 24.2-fold higher rates for any form of
TB.47 The mean age at diagnosis was 6 months and,
although pulmonary disease was the most common mani-
festation of TB, extrapulmonary and disseminated TB were
not uncommon.47 Both pulmonary and extrapulmonary dis-
ease were found in 30.2%, extrapulmonary TB only in 5.3,
and 20% had disseminated TB. TB/HIV co-infection in the
neonatal period has been shown to carry a poor prognosis,
with rapidly progressive HIV infection and early death.48
Mother-to-child transmission of TB may occur in utero
through haematogenous spread through the umbilical
vein and aspiration or swallowing of infected amniotic
fluid, and in the intrapartum period through contact
with infected amniotic fluid or genital secretions. Post-
partum infection may occur through aerosol spread, or
through infected breast milk from an active tuberculous
lesion in the breast. Although transmission through breast-
feeding is negligible, an infant of a mother with active TB
may still be infected, through aerosol spread, even if
formula fed.12 Hence, if the mother has newly diagnosed,
untreated, active TB, she should be separated from her
infant to prevent exposure, regardless of the mode of infant
feeding.19 The diagnosis of TB in the newborn may be chal-
lenging; clinical suspicion is important as early symptoms
are often nonspecific and may be indistinguishable from
those of other congenital infections.14,49–51 With congenital
TB, symptoms are usually seen in the second and third
weeks of the infant’s life, and a definitive diagnosis rests on
the culture of M. tuberculosis from tissues or fluids.49
Abnormal findings on chest radiograph are common, with
nearly one-half having a miliary pattern. If active disease is
diagnosed, full treatment must be given. If there is no
evidence of active disease, isoniazid prophylaxis is given.
Conclusion
Improved diagnosis and treatment of TB in pregnant
women are important interventions for both maternal and
ª 2010 The Authors Journal compilation ª RCOG 2010 BJOG An International Journal of Obstetrics and Gynaecology
Tuberculosis in pregnancy
child health.52 They are also key strategies towards meeting
the Millennium Development Goal target to halt the spread
of TB, and to begin to reverse the worldwide TB incidence
by 2015, and, in turn, contribute to the reduction in child
and maternal mortality covered by Millennium Develop-
ment Goals 4 and 5. Reversing the adverse effects of TB in
pregnancy, particularly in settings in which HIV and
M. tuberculosis co-infection is common, will require a range
of interventions, including the screening of all pregnant
women for TB, preventative therapy for HIV-infected preg-
nant women after the exclusion of active TB, treatment of
active TB and forging stronger links to local TB services for
longer term care.14,17,53 WHO’s ‘3 I’s Policy’ is central to
this: intensified TB case finding, infection control and
isoniazid preventative therapy for the prevention of HIV-
associated TB.54
Disclosure of interest
The authors have no competing interests to declare.
Contribution to authorship
CNM and JAMcI contributed to the design and writing of
the paper.
Details of ethics approval
Not applicable for this review.
Funding
CM and JMcI are supported in part by the US President’s
Emergency Plan for AIDS Relief (PEPFAR) through the
United States Agency for International Development
(USAID) under the terms of award no. 674-A-00-08-
00009-00. The opinions expressed herein are those of the
authors and do not necessarily reflect the views of
USAID. j
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