Early Human Development 84 (2008) 795799

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Early Human Development

j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / e a r l h u m d e v

Perinatal tuberculosis
New challenges in the diagnosis and treatment of tuberculosis in infants and
the newborn
Elizabeth Whittaker a,, Beate Kampmann a,b,c,d,1
a
Academic Department of Paediatrics, Imperial College London, United Kingdom
b
Wellcome Centre for Clinical Tropical Medicine, Imperial College London, United Kingdom
c
Institute for Infectious Diseases and Molecular Medicine (IIDMM), University of Cape Town, South Africa
d
Centre for Respiratory Infections, Imperial College London, United Kingdom

a r t i c l e i n f o a b s t r a c t

Keywords: With increasing rates of tuberculosis (TB) infection and disease worldwide, the rate of perinatal TB is also
Perinatal affected. A high index of suspicion by health professionals, in both the developed and developing world, is
Tuberculosis
required to detect and manage tuberculosis in pregnancy and the early newborn period. Differences in
Neonatal
immune responses in the fetus and neonate add to the diagnostic difculties already recognised in young
children. Although specic guidelines for the treatment of this potentially devastating disease are lacking due
to paucity of experience, outcome is favourable, if the condition is recognised and treated according to
existing TB protocols. HIV co-infection, multi- and extensively-drug resistant (MDR/XDR) TB contribute to the
challenges. New diagnostic and vaccine developments hold future promise, but much work is needed to
completely understand the complex immune responses to tuberculosis and control this disease.
Crown Copyright 2008 Published by Elsevier Ireland Ltd. All rights reserved.

1. Background 2. Pregnancy and tuberculosis

Worldwide, tuberculosis has increased rapidly over the past three
decades, particularly in HIV endemic and impoverished areas in Africa
and Asia. This trend has been mirrored in the UK and other resource-
rich countries, mainly in the ethnic minority and immigrant commu-
nities. The classic age distribution of tuberculosis has also changed,
moving from a peak in over 50s to a median age of under 30 years [1].
The change in epidemiology has already resulted in an increase in the
proportion of women of child bearing age contracting tuberculosis
(40% increase in the US between 1985 and 1992, prevalence 143.3/
100,000 deliveries in London in 1998) [2,3] and subsequently is likely
to impact on the incidence of perinatal tuberculosis (TB). Co-infection
with HIV, drug resistant tuberculosis and infection control issues are
some of the newer challenges facing physicians caring for vulnerable
infants born to TB-infected mothers in both the developing and the
developed world.
Over time, opinions as to whether pregnancy and tuberculosis have
an impact on each other have varied. Hippocrates believed that
pregnancy was benecial and protected against tuberculosis. This view
persisted until the 19th century, when Grisolle reported that the
course of the disease was less favourable in pregnancy [4]. Such was
the estimated devastating effect of tuberculosis in pregnancy that until
recently abortion was recommended. In some parts of the world this
practice persists, especially in cases of multi- and extensively-drug
resistant (MDR/XDR) TB [5]. Recent studies support the view that TB,
and in particular extrapulmonary TB are associated with increased
antenatal hospitalisation, premature delivery, maternal mortality,
perinatal infant mortality and intra-uterine growth restriction com-
pared with healthy pregnant women (3, 6, 7). This is seen in both HIV
positive and negative cohorts and is more marked in incompletely
treated disease and women who are diagnosed later in pregnancy.

2.1. TB in the pregnant woman: diagnosis and management

The presentation of tuberculosis in pregnancy varies: some women

are symptom free, but a large number present with very non-specic
Corresponding author. Tel.: +44 20 7594 3717; fax: +44 20 7594 3894.
E-mail addresses: e.whittaker@imperial.ac.uk (E. Whittaker),
symptoms common in pregnancy like malaise and lethargy, or more
b.kampmann@imperial.ac.uk (B. Kampmann). typical severe symptoms of TB. Although pulmonary TB is the
1
Tel.: +44 20 7594 3915; fax: +44 20 7594 3894. commonest manifestation, extrapulmonary TB features more commonly

0378-3782/$ see front matter. Crown Copyright 2008 Published by Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.earlhumdev.2008.09.005
796 E. Whittaker, B. Kampmann / Early Human Development 84 (2008) 795799

than in a non-pregnant population (510%) (1, 8). Of note is that the 3. Perinatal TB
tuberculin skin test (TST) is frequently found to be anergic, most likely
due to altered immunological responses to Mycobacterium tuberculosis 3.1. Prevention
in pregnant women [6].
A delay between onset of symptoms and diagnosis occurs Perinatal TB is extremely rare if the mother is effectively treated in
regularly, due to the non-specic nature of symptoms at presentation, pregnancy. According to WHO, a mother is no longer considered
reluctance to perform radiography and low index of suspicion, most infectious after treatment for 23 weeks [12]. If she is breastfeeding it
likely also related to limited resources in the settings where this is is recommended that 6 months isoniazid is given to the baby, or
more common [1,7]. alternatively 3 months isoniazid followed by a TST. If negative, BCG
Treatment response and time to clearance of bacilli from sputum vaccine should be administered and treatment stopped; if positive,
are equivalent to non-pregnant women, and prognosis, if treated treatment should continue for 6 months, followed by the BCG at the
early, can also be similar. end. If a diagnosis is made close to delivery, the baby and placenta
In the event of TB exposure, women with a positive TST, but should be carefully evaluated for evidence of perinatal TB infection
clinically well with a normal chest X-ray, should be given chemopro- and the infant treated empirically if there are any concerns or doubt.
phylaxis in accordance with national guidelines. Previous concerns All of these infants should be carefully followed for 2 years.
about the use of isoniazid in pregnancy for chemoprophylaxis are
unfounded, with an isoniazid-associated death rate of 0.001% [8]. 3.2. Denition and presentation of perinatal TB in the infant
If active tuberculous disease is found, anti-tuberculous treatment
(ATT) should be commenced. Some groups recommend delaying start Controversy has always surrounded the denition of congenital
of treatment to the second trimester if the mother is well, but all agree tuberculosis with criteria rst described by Beitzke in 1935 [13],
that the benet of treating the mother, preventing maternal morbidity followed by revised criteria by Cantwell in 2002 which stated: the
and mortality and avoiding perinatal transmission, outweigh the risk infant must have proved tuberculous lesions and at least one of a) lesions
of teratogenicity. A number of studies assessing rates of congenital in the rst week of life; b) a primary hepatic complex or caseating
malformations in infants exposed to ATT in utero have not demon- hepatic granulomata; c) tuberculous infection of the placenta or the
strated an appreciable difference [911]. A group in Peru have maternal genital tract; d) exclusion of the possibility of postnatal
followed up children after in utero exposure to second line agents transmission by a thorough investigation of contacts, including hospital
used for treatment of multidrug-resistant TB and performed a review staff [2]. Transmission is believed to be either in utero by haematogenous
of the literature showing that a low incidence of ototoxicity secondary spread through the umbilical vein or ingestion of infected amniotic uid;
to the aminoglycosides is the main concern [10]. Table 1 demonstrates intrapartum aspiration or ingestion of amniotic uid or direct contact
the safety prole of ATT in pregnancy, lactation and the newborn baby. with infected cervix/endometrium; or postpartum by inhalation or
ingestion from an infectious source [2].
Because of the difculties in ascertaining the exact time and
Table 1
circumstances of infection, more recently, perinatal tuberculosis is the
Anti-tuberculous drugs in pregnancy, lactation and in the newborn preferred description encompassing TB acquired in utero, intrapartum
or during the early newborn period and has replaced the term
Use of anti-tuberculosis drugs in pregnancy, lactation and in the newborn baby
congenital tuberculosis. Distinguishing between the time frames is not
Drug Pregnancy Lactation Newborn
crucial, as the presentation, diagnosis, management and prognosis are
Rifampicin Safe 0.5% of adult Safe 1020 mg/kg/day similar. Although unusual, (about 300 cases of perinatal TB have been
dose detected
Rifabutin Congenital defects in 0.5% of adult Use not established
described in the literature, in case reports, case series and reviews [2])
animal studies dose detected perinatal tuberculosis is believed to be increasing alongside a rise in TB
Rifapentine Rarely causes bleeding 0.5% of adult Use not established incidence. Prompt treatment is required for the survival of these
in mother if administered dose detected infants. Mortality is high, varying between 2 and 60% depending on
in last few weeks of
delay to presentation and other factors, such as prematurity and co-
pregnancy
Isoniazid Safe, supplement with 0.752.3% of Safe 510 mg/kg/day infection with HIV [2,14]. Complications include a high rate of miliary
pyridoxine adult dose tuberculosis and meningitis, resulting in seizures, deafness and death.
detected
Pyrazinamide Limited data but 0.752.3% of Safe 2030 mg/kg/day 4. Tuberculosis in the neonateimmunological considerations
recommended adult dose
detected
Ethambutol Safe in human beings, Yes in minute Retrobulbar neuritis; The observation that young children, particularly under the age of
cleft palate, skull and amounts not recommended 2, are the most vulnerable to tuberculosis, opens a window to our
spine defects understanding of the immunopathogenesis of tuberculosis. The
Ethionamide Premature labour, Yes in minute Safe
neonatal period should also be considered as a particularly vulnerable
congenital amounts
abnormalities time for the following reasons: the fetal and neonatal immune system
Aminoglycosides Ototoxicity in fetus, 0.050.5% of Use with caution, not are subjected to multiple demands, such as protection against
renal damage adult dose absorbed orally infection, avoidance of potentially harmful pro-inammatory cytokine
detected responses that can induce alloimmune reactions between mother and
Amikacin Likely ototoxicity Yes, Poorly absorbed by GI
concentration tract
fetus and the transition from the sterile intra-uterine environment
not known to the antigen-exposed outside world. It is increasingly recognised
Kanamycin Ototoxicity, hearing 0.951.8 % of Poorly absorbed that CD4+CD25+ regulatory T-cells are abundant and potent at birth
loss 2.3% adult dose and inhibit Th1 cell immunity [15]. In the absence of acquired immune
Capreomycin Unknown, bronzing?? Not known Minimal GI absorption
responses and immunological memory, the rst line of defence lies
Streptomycin Ototoxicity, greatest 1st 0.9522.5% Safe
trimester, hearing loss with the innate immune response of the neonate. Flow cytometry has
in 811% children demonstrated reduced levels of MHC class II molecules between
Quinolones Bone developmental 0.050.5% of Use with caution, neonates and adults [16], which potentially contribute to impaired
abnormalities in adult dose shown to be safe for 5 activity of antigen-presenting cells (APC) and result in qualitative
animals detected 10 days
differences in monocytes. Blood derived DCs are functionally
 E. Whittaker, B. Kampmann / Early Human Development 84 (2008) 795799
immature at birth relative to adult DCs and continue to express a less
differentiated phenotype throughout early childhood [17]. It can be
postulated that the bias against Th1-cell polarizing cytokines makes
young infants more susceptible to tuberculosis, especially since the
perinatal infection might have occurred via haematogenous spread
rather than via primary lung infection.
Some studies also suggest that neonatal APCs lack the capacity to
deliver important Th1 polarizing signals to T-cells. Their capacity to
synthesise interleukin (IL)-12, a key APC-derived cytokine, matures
slowly during childhood [18] and neonatal, monocyte-derived DCs
have a specic defect in IL-12p35 expression [19]. IL-12 is critical for
the initial phases of Th1 polarization and also for maintaining the
efciency of the interferon (IFN)- transcription machinery in Th1
effector cells [19].
In cases of primary lung infection, the alveolar macrophage is the
rst line of defence in the innate immune response to TB and plays a
critical role in amplifying the response to infection. Studies in the
animal and human host have consistently demonstrated reduced
microbial killing [20,21] and diminished monocyte recruitment to the
site of infection in infants compared to adults [22].
Neonatal CD4 cells appear intrinsically decient in their capacity to
express Th1 effector function, partially attributed to hypermethylation
of the proximal promoter of the IFN- gene [23], resulting in a highly
restricted pattern of IFN- response to a variety of stimuli [24,25].
CD154 (CD40 ligand) expression is also signicantly reduced com-
pared with adult cells [26].
Impairment of innate pulmonary defences in the neonate and
infant may allow mycobacteria to overwhelm the effects of the innate
immune system prior to the initiation of an antigen-specic immune
responses. The nding of generally impaired cell-mediated immune
responses in the neonate and young children raise the question of
whether antigen-specic immune responses to mycobacteria are
equally affected.
Delayed type hypersensitivity to puried protein derivative may be
absent in up to 40% of HIV negative children presenting with extra-
pulmonary TB [27], compounding the difculties of diagnosis in young
children. However, studies measuring responses to neonatal vaccina-
tion with M. bovis BCG demonstrate potent Th1 responses, possibly
related to the potent APC-activating properties of BCG vaccine.
Much more needs to be learned from innate and antigen-specic
studies of immunity in the newborn, and further research in this area is
required, which will benet not just our understanding of tuberculosis
but other infections in this particularly vulnerable period of life.
4.1. Diagnosis of perinatal TB
The diagnosis of perinatal TB is difcult without doubta high
index of suspicion is required as TST is often negative (78% of the time
in two case series [2,28]) and symptoms are often non-specic. These
infants typically present at 24 weeks of age with fever, respiratory
distress, lethargy +/ hepatomegaly and tend to be commenced on
broad spectrum antibiotics for presumed sepsis. Unless there is a
suggestive history in the mother, TB is often not suspected until
deterioration/lack of response to antibiotics is noted. Diagnosis in the
infant is based on TST, which is often negative, CXR and other radiology
if symptoms suggest. Microbiological specimens such as gastric
aspirates, ascitic uid, lymph node biopsy, endotracheal aspirate,
bone marrow and cerebro-spinal uid should be obtained and stained
and cultured for AFB. Gastric aspirates in neonates have a higher
microbiological yield than in older infants (70%) and are well tolerated
[29]. The chest X-ray is nearly always abnormal, with 50% showing a
military TB pattern [30]. Newer modalities such as polymerase chain
reaction (PCR) and restriction fragment length polymorphisms can be
useful for diagnosis and identication of the index case. Ideally,
placental and maternal vaginal or endometrial samples should be
obtained, but this is frequently difcult given the later presentations.
797
Many mothers are only found to have TB following diagnosis in the
infant. As mentioned, the TST is typically unresponsive, but a repeat
after 3 months is frequently found to be positive [2]. Interferon
gamma release assays are an alternative immunological diagnostic
option for these infants, but there are some concerns about the
validity of these assays in newborns and infants, as depressed IFN-
production in response to antigenic stimuli has been described in this
age group [31]. However, positive responses to both the QFG-IT whole
blood and Elispot assays have been described in cases of perinatal TB
and in a contact tracing study [32,33]. Further investigations in this
area are required and a negative IGRA should not deter empirical anti-
tuberculosis treatment pending microbiological conrmation.
4.2. Treatment and outcome of the infant
Perinatal TB is usually fatal if untreated. Following appropriate
investigation, the infants should be empirically commenced on
treatment as per national guidelines. Since this is not a common
disease, no therapeutic trials have determined the optimal treatment
regimen and length. Complete recovery has been described following a
standard treatment course of 2 months of 4 drugs (isoniazid, rifampicin,
pyrazinamide and streptomycin), followed by 4 months of 2 drugs
(isoniazid and rifampicin) [34]. However other regimens for up to
18 months have been described and clinicians should seek expert advice.
Treatment length should be determined by clinical condition and
response to treatment. Infants should receive regular monthly review
following discharge until treatment is complete and follow up should
then continue for up to 2 years. These infants are often very unwell and
supportive therapy such as oxygen or respiratory support with
ventilation may be required. Steroids are recommended in cases of TB
meningitis or airway obstruction due to large lymphadenopathy. A case
series of 17 infants less than 6 months ventilated secondary to
respiratory failure caused by Mycobacterium tuberculosis revealed a
favourable outcome for all [35]. All infants were HIV seronegative,
median duration of stay in intensive care was 7 days (range 237 days),
steroids were used in all children with large airway obstruction (n = 10),
only one infant was TST positive and all responded to standard ATT. This
contrasts with previous reports of high mortality in infants with
tuberculosis. Improved outcome could be due to the fact that none of
these infants had TB meningitis or HIV, but with aggressive manage-
ment of TB in the very young, including intensive care, a good outcome
can be achieved.
4.3. MDR/XDR TB in mothers and infants
One of the greatest challenges facing physicians caring for patients
with tuberculosis is drug resistance. Rates of multidrug-resistant
(MDR) strains (resistant to both isoniazid and rifampicin) including
extensively drug resistant (XDR) strains (also resistant to uoroqui-
nolones and at least one second line injectable agent such as amikacin,
kanamycin and/or capreomycin) are rising in many parts of the world.
A case series of 7 infants born to mothers receiving treatment for
MDR-TB in pregnancy demonstrated good outcomes for both mother
and infant with no evidence of signicant late-presentation toxicity in
the infants [10,11]. All expecting mothers received treatment in the
rst or second trimester with smear and culture conversion in 6 of 7
patients. Each patient was managed with an aggressive individualised
treatment regimen during and after pregnancy with very close
monitoring. Use of chemoprophylaxis was not discussed in this
paper, however in other reports, chemoprophylaxis was only given to
the infant if the mother remained smear or culture positive at delivery
[36]. In 2 cases, ethambutol and pyrazinamide were used for 3 months
as chemoprophylaxis [33]. Klaus-Dieter et al. recommended screening
the newborn infant for infection (TST/gastric washings/CXR) and
recommended BCG, careful observation and repeat TST at 3 months if
there was no evidence of infection in association with smear-negative
798 E. Whittaker, B. Kampmann / Early Human Development 84 (2008) 795799
maternal disease. WHO guidelines currently recommend the avoid-
ance of chemoprophylaxis in the case of exposure to MDR-TB and
observation for 2 years provided they are clinically well.
5. Infection control on the NICU
In the context of late diagnosis of perinatal tuberculosis, a number
of publications have discussed the risk of exposures to other neonates
in the setting of the neonatal intensive care unit. Laartz et al. reviewed
literature concerning congenital tuberculosis with particular attention
to infection control, following a case in their unit [37]. Summarising 6
different publications with around 2814 infants exposed to perinatally
infected infants, infected staff and infected parents in NICU and
nursery settings, only 2 infants developed active tuberculosis. They
concluded that aggressive follow up with a TST and isoniazid
prophylaxis for those at risk was warranted. All infants at high risk
were evaluated clinically and with radiography. Due to previously
described anergy to the TST, the TST was repeated at 3 months. The
use of an oscillatory ventilator with no expiratory lter was described
as posing a theoretical risk of aerosolized respiratory secretions, but
no secondary cases were found. Despite the low transmission rate in
the NICU, careful consideration of air handling and use of isolation
rooms where available are advised.
6. Neonatal TB and HIVspecial considerations
As mentioned above, the increasing rate of tuberculosis globally is
driven by the HIV pandemic. The relationship between HIV and TB has
been well described in the literature and a number of groups have
investigated the effect of HIV co-infection on incidence and outcome of
perinatal TB. Adhikari et al. described the investigation of 77 neonates
with suspected TB in KwaZulu Natal, South Africa [38]. 11 infants had
culture conrmed perinatal TB, of whom 6 were born to mothers with
HIV/TB co-infection (55%, compared with a local antenatal prevalence
rate of HIV infection of 23%). These neonates presented similarly to those
described in the literature without HIV exposure and although there
were no signicant differences between the HIV exposed and un-
exposed groups, there was a trend towards more severe disease in the
mothers and infants, in particular a greater incidence of prematurity and
IUGRwhich is known to be associated with HIV disease. Three of the 6
infants born to HIV seropositive mothers were HIV infected, reecting a
higher transmission rate than the 34% normally found in KwaZulu Natal.
A further prospective case series of 107 pregnant women with TB, found
a HIV infection rate of 77% and a mother to infant transmission rate for
TB of 16%, with similar disease patterns in both mothers and infants to
HIV uninfected controls. The VTRTB (vertical transfer of Mycobacterium
tuberculosis) was not inuenced by CD4 count or perinatal maternal viral
load. The only risk factor of signicance was untreated tuberculosis or
default from treatment (p = 0.04) [39]. HIV transmission rate was 11%.
Less than half of the mothers who transmitted TB to their neonates were
sputum smear or culture positive, highlighting the signicant problem
of smear-negative transmission of TB previously reported. In this study,
it was noted that some mothers transmitted TB despite long durations of
ATT, emphasising the importance of investigation and comprehensive
observation of these exposed infants for up to 2 years. It is essential that a
high index of suspicion for perinatal TB is adopted by health care
workers in areas where TB and/or HIV are prevalent, or in mothers
recently immigrating from TB/HIV endemic areas [40,41]. Latent TB was
found in 49% of 400 pregnant women in a study in Johannesburg.
Although there is no evidence that there is an increased reactivation rate
in pregnancy, given how deadly TB in pregnancy can be for both mother
and infant, active screening and isoniazid preventative treatment of
latent TB should be considered in areas of high TB endemicity.
In summary, perinatal TB is a potentially devastating disease, but
with a high index of suspicion and aggressive management can have a
good outcome. Neonatalogists and paediatricians need to be aware of TB
and potentially HIV-co-infection in women of childbearing age
presenting to our healthcare services, particularly from TB/HIV endemic
countries. The care for the infant with perinatal TB starts with careful
screening and treatment of pregnant women with TB to prevent this
condition from occurring in the rst place.
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