Tuberculosis in Pregnancy: A Review

Abstract
Tuberculosis (TB) was declared a public health emergency by WH in
!""#$ The disease is a signi%icant contributor to maternal mortality and
is among the three leading causes o% death among women aged &#'(#
years in high burden areas$ The e)act incidence o% tuberculosis in
pregnancy* though not readily available* is e)pected to be as high as in
the general population$ +iagnosis o% tuberculosis in pregnancy may be
challenging* as the symptoms may initially be ascribed to the pregnancy*
and the normal weight gain in pregnancy may temporarily mas, the
associated weight loss$ bstetric complications o% TB include
spontaneous abortion* small %or date uterus* preterm labour* low birth
weight* and increased neonatal mortality$ -ongenital TB though rare* is
associated with high perinatal mortality$ Ri%ampicin* ./H and
0thambutol are the %irst line drugs while Pyra1inamide use in pregnancy
is gaining popularity$ .sonia1id preventive therapy is a WH innovation
aimed at reducing the in%ection in H.2 positive pregnant women$ Babies
born to this mother should be commenced on ./H prophyla)is %or si)
months* a%ter which they are vaccinated with B-3 i% they test negative$
4uccess%ul control o% TB demands improved living conditions* public
enlightenment* primary prevention o% H.25A.+4 and B-3 vaccination$
&$ .ntroduction
Tuberculosis (TB) is believed to be nearly as old as human history$
Traces o% it in 0gyptian mummies date bac, to about 6""" years ago*
when it was described as phthisis by Hippocrates 7&8$ .t was declared a
public health emergency in the A%rican Region in !""# 7&8 and has since
continued to be a ma9or cause o% disability and death$ About :$( million
new cases o% tuberculosis were diagnosed in !"": alone and &$6 million
people reportedly died %rom the disease in the same year* translating to
about (6"" deaths per day 7!8$
About one;third o% the world<s population (estimated to be about &$6#
billion) is in%ected with the tubercule bacillus 7=8$ As much as 6#> o%
individuals with TB are within the economically productive age group o%
&# to #( years$ This signi%icantly impairs socioeconomic development*
thereby perpetuating the poverty cycle 7(8$
Tuberculosis has been on the rise in tandem with H.25A.+4$ This is
because people with H.25A.+4* whose immune systems are wea,ened
have with a !"'=6 times the ris, o% developing a progressive disease
compared with H.2;negative individuals 7(8$
!$ ?icrobiology o% Tuberculosis
?ycobacterium tuberculosis* an aerobic* non;spore;%orming* nonmotile
bacillus* is one o% %ive members o% the ?ycobacterium tuberculosis
comple)* others being ?$ bovis* ?$ ulcerans* ?$ A%ricanum* and ?$
microti*though ?$ tuberculosis is the ma9or human pathogen$ .t belongs
to the %amily ?ycobacteriaceae$ ther?ycobacterium species that may
in%ect humans include ?ycobacterium leprae* ?$ avium* ?$
.ntracellulare*and ?$ scro%ulaceum$
=$ Pathophysiology
Tuberculosis a%%ects almost every organ in the body* but the usual site o%
the disease is the lungs* accounting %or more than @" percent o%
tuberculosis cases 7#8$ The pattern o% the in%ection in H.2 positive
patients may* however* be di%%erent* with increasing trends towards
e)trapulmonary spread 7A8$
Almost all tuberculosis in%ections are caused by inhalation o% in%ectious
particles aerosoli1ed by coughing* snee1ing* tal,ing* or manipulation o%
in%ected tissues$ ther modalities o% transmission may* however* include
ingestion o% unpasteurised mil, and direct implantation through s,in
abrasion or the con9unctiva$ Aerosoli1ed tuberculosis particles with si1es
ranging between & and # um are carried to the terminal air spaces o%
high;air%low areas* where multiplication o% the tubercle occurs$
Bollowing phagocytosis by pulmonary macrophages* a granulomatous
reaction may be initiated* in con9unction with the regional lymph nodes*
thereby %orming the 3honCs %ocus$ The bacilli remain in a state o%
dormancy within the 3honCs %ocus* %rom where they may later become
reactivated$
($ Tuberculosis in Pregnancy
The wide array o% opinion o% ?edical practitioners on tuberculosis in
pregnancy simply re%lects the Public Health signi%icance o% the
condition$ .t is best described as a doubled;edged sword* one blade being
the e%%ect o% tuberculosis on pregnancy and the pattern o% growth o% the
newborn* while the other is the e%%ect o% pregnancy on the progression o%
tuberculosis$
Tuberculosis not only accounts %or a signi%icant proportion o% the global
burden o% disease* it is also a signi%icant contributor to maternal
mortality* with the disease being among the three leading causes o%
death among women aged &#'(# years 7!8$
The e)act incidence o% tuberculosis in pregnancy is not readily available
in many countries due to a lot o% con%ounding %actors$ .t is* however*
e)pected that the incidence o% tuberculosis among pregnant women
would be as high as in the general population* with possibly higher
incidence in developing countries$
0arlier study by 4chae%er reported a new case rate o% &@'!:5&""*""" in
pregnancy* which was similar to the &:'=:5&""*""" reported %or the city
o% /ew Dor, 768$ A recent Enited Fingdom study* however* Guoted an
incidence o% ($! per &""*""" maternities 7@8* which may be a re%lection
the current global %all in the incidence o% the disease 7!8$
#$ 0%%ects o% Pregnancy on Tuberculosis
Researchers %rom the days o% Hippocrates have e)pressed their worries
about the untoward e%%ects that pregnancy may have on pree)isting
tuberculosis$ Pulmonary cavities resulting %rom tuberculosis were
believed to collapse as a result o% the increased intra;abdominal pressure
associated with pregnancy$ This belie% was widely held till the beginning
o% the %ourteenth centuryH .ndeed* a 3erman physician recommended
that young women with TB should get married and become pregnant to
slow the progression o% the disease$ This was practiced in many areas till
the &:th century 7:8* while in the early !"th century* induced abortion
was recommended %or these women 7&"* &&8$ Researchers li,e Hedvall
7&!8 and 4chae%er 768* however* demonstrated no net bene%it or adverse
e%%ect o% pregnancy on the progression o% TB$ BreGuent* consecutive
pregnancies may* however* have a negative e%%ect* as they may promote
recrudescence or reactivation o% latent tuberculosis$
.t is* however* important to note that the diagnosis o% tuberculosis in
pregnancy may be more challenging* as the symptoms may initially be
ascribed to the pregnancy$ The weight loss associated with the disease
may also be temporarily mas,ed by the normal weight gain in
pregnancy$
A$ 0%%ects o% Tuberculosis on Pregnancy
The e%%ects o% TB on pregnancy may be in%luenced by many %actors*
including the severity o% the disease* how advanced the pregnancy has
gone at the time o% diagnosis* the presence o% e)trapulmonary spread*
and H.2 coin%ection and the treatment instituted$
The worst prognosis is recorded in women in whom a diagnosis o%
advanced disease is made in the puerperium as well as those with H.2
coin%ection$ Bailure to comply with treatment also worsens the prognosis
7&=8$
ther obstetric complications that have been reported in these women
include a higher rate o% spontaneous abortion* small %or date uterus* and
suboptimal weight gain in pregnancy 7&(* &#8$ thers include preterm
labour* low birth weight and increased neonatal mortality 7&=8$ Iate
diagnosis is an independent %actor* which may increase obstetric
morbidity about %our%olds* while the ris, o% preterm labour may be
increased nine%olds 7&#'&@8$
6$ Tuberculosis and the /ewborn
-ongenital tuberculosis is a rare complication o% in utero tuberculosis
in%ection 7&:8 while the ris, o% postnatal transmission is signi%icantly
higher 7!"8$ -ongenital tuberculosis may be as a result o%
haematogenous spread through the umbilical vein to the %oetal liver or
by ingestion and aspiration o% in%ected amniotic %luid 7!&8$ A primary
%ocus subseGuently develops in the liver* with involvement o% the peri;
portal lymph nodes$ The tubercle bacilli in%ect the lungs secondarily*
unli,e in adults where over @"> o% the primary in%ections occur in the
lungs 7#8$
-ongenital tuberculosis may be di%%icult to distinguish %rom other
neonatal or congenital in%ections %rom which similar symptoms may
arise in the second to the third wee, o% li%e$ These symptoms include
hepato;splenomegaly* respiratory distress* %ever* and lymphadenopathy$
Radiographic abnormalities may also be present but these generally
appear later 7&=8$ The diagnosis o% neonatal tuberculosis may* however*
be %acilitated by employing a set o% diagnostic criteria developed by
-antwell et al$ 7!!8* including the demonstration o% primary hepatic
comple)5caseating granuloma on percutaneous liver biopsy at birth*
tuberculous in%ection o% the placenta* or maternal genital tract
tuberculosis* and the demonstration o% lesions during the %irst wee, o%
li%e$ The possibility o% postnatal transmission must be e)cluded by a
thorough investigation o% all contacts* including hospital sta%%s and
attendants$
As much as hal% o% the neonates delivered with congenital tuberculosis
may eventually die* especially in the absence o% treatment 76* !='!A8$
@$ +iagnosis o% Tuberculosis in Pregnancy
To diagnose this condition* history o% e)posure to individuals with
chronic cough or recent visit to areas endemic with tuberculosis should
be obtained$ History o% symptoms* which is li,ely to be the same as in
nonpregnant women* is also essential$ -aution must* however* be
e)ercised* as these symptoms may be nonspeci%ic in pregnancy 7!6* !@8$
These symptoms include night sweat* evening pyre)ia* haemoptysis*
progressive weight loss* and chronic cough o% over = wee,s duration$
There may also be a history o% ine%%ective attempts at antibiotics therapy
7!6* !:8$
.n pregnant women with suggestive symptoms and signs o% TB* a
tuberculin s,in test should be carried out$ This has since been accepted
to be sa%e in pregnancy 7!&* ="8$ The debate* however* is about the
sensitivity o% tuberculin test during pregnancy$ 0arlier reports suggested
diminished tuberculin sensitivity in pregnancy 7=&8* while recent studies
revealed no signi%icant di%%erences in the pregnant and nonpregnant
populations 7!6* =!'=#8$
The two types o% tuberculin s,in tests are discussed below$
@$&$ Tine Test
This test utilises an instrument with multiple needles that are dipped in a
puri%ied %orm o% the TB bacteria called old tuberculin (T)$ The s,in is
pric,ed with these needles and the reaction is analysed (@'6! hours
later$ .t is* however* no longer popular e)cept in large population
screening$
@$!$ ?antou) Test
A single;needle intradermal in9ection o% "$& mI o% puri%ied protein
derivative (# Tuberculin units) is administered* and the s,in reaction is
analysed (@'6! hours later* based on the largest diameter o% the
indurations developed$ .t is a more accurate and reproducible test than
the Tines test$
Balse;positive results may be obtained in individuals who had previously
been vaccinated with the B-3 vaccine* those with previously treated
tuberculosis* as well as in people with in%ection %rom other
?ycobacterium species$ Balse negatives on the other hand are
commonly due to a compromised immune system and technical errors
7=A8$
A chest radiograph with abdominal lead shield may be done a%ter the
tuberculin s,in testing* though pregnant women are more li,ely to
e)perience a delay in obtaining a chest J;ray due to concerns about %etal
health 7!68$
?icroscopic e)amination o% sputum or other specimen %or Acid;%ast
bacilli (ABB) remains the cornerstone o% laboratory diagnosis o% TB in
pregnancy$ Three samples o% sputum should be submitted %or smear*
culture* and drug;susceptibility testing$ 4taining %or ABB is also done*
using the Kiehl;/eelsen* %luorescent* Auramine;Rhodamine* and the
Finyoun techniGues 7=68$ Iight;emitting diode (I0+) %luorescent
microscopy has recently been introduced to improve diagnosis 7=68$
According to the WH<s !"": report on global TB control* the
percentage o% new cases o% smear;positive TB detected ranged between
#A and A@>$ The staining techniGues may* there%ore* not su%%icient %or
the diagnosis o% TB* as smear;negative cases will be missed 7=68$
:$ -ulture
The traditional culture on Iowenstein;Lensen<s medium may ta,e ('A
wee,s to obtain a result$ This may* however* still be use%ul in cases o%
diagnostic doubts and management o% suspected drug;resistant
tuberculosis 7=@8$ /ewer diagnostic tools are now available to %acilitate
diagnosis* including the liGuid Bactec culture medium* which has been
endorsed by WH$ ther culture media that could be used include the
modi%ied Iowenstein<s medium* Petragnani medium* Trudeau
-ommittee medium* Pei1er<s medium* +ubos ?iddlebroo, media*
Tarshis blood agar* ?iddlebroo,<s 6;H=* ?iddlebroo,<s 6;H:* and
?iddlebroo,<s 6H;&" media 7=@8$ IiGuidisation and decontamination
with /;Acetytl;I;-ysteine in &> 4odium Hydro)ide solution be%ore
inoculation may enhance sensitivity 7=@8$
?$ tuberculosis produces niacin and heat;sensitive catalase and it lac,s
pigment$ .t may* there%ore* be di%%erentiated %rom other mycobacterium
species using these %eatures$ thers include reduction o% nitrates and its
isonia1ide sensitivity* which may* however* not be reliable in cases o%
./H resistance$
?olecular Iine Probe Assay (IPA) as well as the use o% polymerase
chain reaction (P-R) are presently %acilitating the speci%ic identi%ication
o% the tubercle bacilli 7=68$
&"$ Treatment o% Tuberculosis
MEntreated tuberculosis represents a %ar greater ha1ard to a pregnant
woman and her %etus than does treatment o% the diseaseN 7=:8$
The management o% tuberculosis in pregnancy is a multidisciplinary
approach* with the team comprising the obstetrician* communicable
disease specialty personnel* neonatologists* counselling unit* and public
health o%%icials$
Treatment is achieved through the use o% +irectly bserved Therapy*
4hort -ourse (+T4)$ This therapy entails the use o% combination
therapy %or at least A months* depending on the combination o%
antituberculous agents that are available$ This combination includes
isonia1ide and ri%ampicin compulsorily* supported by ethambutol and
pyra1inamide 7("'((8$
Bor patients with drug;susceptible TB and good drug adherence* these
regimens will cure around :"> o% TB cases$ Treatment is done on out;
patient basis* unless otherwise indicated 7=68$
The use o% these %irst;line antituberculous drugs in pregnancy are
considered sa%e %or the mother and the baby by The British Thoracic
4ociety* .nternational Enion Against Tuberculosis and Iung +isease*
and the World Health rganisation 7&A* (#8$
&"$&$ .sonia1ide
./H is sa%e during pregnancy even in the %irst trimester* though it can
cross the placenta 7&&8$ The women must* however* be %ollowed up
because o% the possibility o% ./H;induced hepatoto)icity$ Pyrido)ine
supplementation is recommended %or all pregnant women ta,ing ./H at
a dose o% #" mg daily 7=:* (A8$
&"$!$ Ri%ampicin
This is also believed to be sa%e in pregnancy* though in an un,nown
proportion o% cases* there may be an increased ris, o% haemorrhagic
disorders in the newborn (some authorities prescribe supplemental
vitamin F (&" mg5day) %or the last %our to eight wee,s o% pregnancy$)
while some other researchers reported the possibility o% limb de%ormity
but none o% these are in e)cess o% what is obtained in the normal
population$
&"$=$ 0thambutol
The retrobulbar neuritis that may complicate the use o% this drug in
adults generated the %ear that it may inter%ere with ophthalmological
development when used in pregnancy but this has not been demonstrated
when the standard dose is used$ This was also con%irmed in e)perimental
studies on some abortuses 7(68$
&"$($ Pyra1inamide
The use o% pyra1inamide in pregnancy was avoided by many physicians
%or a long time due to unavailability o% adeGuate data on its
teratogenicity$ Presently* many international organi1ations now
recommend its use* including the .nternational Enion Against
Tuberculosis And Iung diseases (.EATI+)* British Thoracic 4ociety*
American Thoracic 4ociety* the World Health rganisation as well as
the Revised /ational Tuberculosis -ontrol Programme o% .ndia$ There
are no reports o% signi%icant adverse events %rom the use o% this drug in
the treatment o% TB in pregnant women despite its use as part o% the
standard regimen in many countries 7(@8$
.ts use is particularly indicated in women with tuberculous meningitis in
pregnancy* H.2 coin%ection* and suspected ./H resistance 7(:'#!8$
Breast%ed in%ants o% mothers on antituberculous therapy should*
however* be monitored %or 9aundice* which may suggest drug;induced
hepatitis* as well as 9oint pains resulting %rom drug;induced
hyperuricaemia$
&"$#$ 4treptomycin
The drug has been proven to be potentially teratogenic throughout
pregnancy$ .t causes %etal mal%ormations and eighth;nerve paralysis*
with de%icits ranging %rom mild hearing loss to bilateral dea%ness$ ?any
centres are against the use o% this drug in pregnancy 7(:* #=* #(8$
&&$ ?ultidrug;Resistant Tuberculosis in Pregnancy (?+R;TB)
Pregnant women with ?+R;TB have a less %avourable prognosis 7##8$
They may sometimes reGuire treatment with second;line drugs*
including cycloserine* o%lo)acin* ami,acin* ,anamycin* capreomycin*
and ethionamide$ The sa%ety o% these drugs is un%ortunately not well;
established in pregnancy 7(:8$
Para;amino salicylic acid had been used as combination therapy with
./H in pregnancy in the past without any signi%icant teratogenic side
e%%ects* though maternal gastrointestinal side e%%ects may be pronounced$
0thionamide is associated with growth retardation* central nervous
system and s,eletal abnormalities in animal studies involving rats and
rabbits 7#A* #68$ Human studies also demonstrated increased central
nervous system de%ects %ollowing its use in early pregnancy 7#@8$ .ts use
is* there%ore* not recommended in pregnancy$
Therapeutic abortion has been proposed as an option o% management %or
these women 7#:8* as ?+R;TB poses more ris, to the woman and the
society at large$ Another option is to delay initiating treatment to the
second trimester where possible 7&"8$ .ndividualised Treatment Regimen
(.TR) using various combinations o% the !nd line antituberculous agents
based on their susceptibility pro%ile had* however* been tried in some
pregnant women with no adverse obstetric outcome 7A"8$
The outloo, %or those patients is e)pected to improve as e)perience and
,nowledge in the management o% the condition increases$
&!$ Treatment o% TB in Iactating Women
Breast%eeding is simply the cheapest and healthiest way to %eed a baby$
The %inal decision on breast%eed must* there%ore* be ta,en with necessary
input %rom the neonatologists* obstetricians* and pharmacologists$ The
American Academy o% Pediatrics recommends that women with
tuberculosis who have been treated appropriately %or two wee,s or more
and who are not considered contagious may breast%eed 7A&8* while the
R/T-P recommends breast;%eeding o% neonates regardless o% the
mother<s TB status 7A!8$
Antituberculous drugs are e)creted into breast mil,* though the dose is
less compared with the therapeutic dose %or in%ants$ Breast%ed in%ants
may receive as much as !"> o% the therapeutic dose o% ./H %or in%ants*
while other antituberculous drugs are less e)creted$ /o to)icity has been
reported %rom this small concentration in breast mil, 7(:8$ -aution must*
however* be e)ercised as the breast mil, dose may contribute to the
development o% abnormally high plasma levels in newborns who are on
antituberculous medications$ To minimise this possibility* the mother
may ta,e her medications immediately a%ter a %eed and substitute a bottle
%or the ne)t %eed$ 4he may then return to her usual pattern o% %eeding
7(:* A=8$
Pyrido)ine de%iciency may cause sei1ures in the newborn$ 4upplemental
pyrido)ine should* there%ore* be administered to in%ants on ./H or
whose mother is ta,ing the drug$
Breast%eeding may be discouraged in women who are yet to commence
treatment at the time o% delivery and those who are still actively
e)creting the bacillus while coughing$ .t may also be discouraged as part
o% a prevention o% mother to child transmission in H.2 coin%ection and
women with tuberculosis o% the lacti%erous ducts or glands$
.n the absence o% evidence o% congenital tuberculosis* isonia1ide (&"
mg5,g5day) should be commenced at birth and continued %or si) months$
-linical or radiological %eatures o% active tuberculosis and a positive
tuberculin s,in test are indications %or a %ull course o% anti;tuberculous
treatment$ The tuberculin s,in test and chest J;rays are done at A wee,s*
&! wee,s* and A months$ The baby is vaccinated with B-3 at A months
i% these tests are negative$ The baby is* however* changed to multiple
drug therapy i% any o% these tests turn positive during the period o%
monitoring$
&=$ H.2 and TB -oin%ection in Pregnancy
H.2 and TB are ine)tricably lin,ed$ Their e%%ect is even more deadly in
pregnancy* when they may contribute signi%icantly to maternal
morbidity and mortality$ ver #"> o% the maternal mortality occurring
in mothers with TB in pregnancy is due to coin%ection with H.2 7A(8$
?oreover* treatment is complicated by the challenges o% adherence*
polypharmacy and the overlapping side e%%ect pro%iles o%
antituberculosis and antiretroviral drugs 7A#'A68$
The ,ey concern is about the interactions between the ri%amycins and
antituberculous drugs$ The suboptimal outcomes o% therapeutic trials
without a ri%amycin has made the use o% the drug mandatory* even in the
%ace o% drug interactions 7A@* A:8$
The spectrum o% antiretroviral drugs available %or use in pregnancy is
limited$ 0%aviren1 is contraindicated be%ore the thirteenth wee, o%
gestation* while the ris, o% to)icity %rom the use o% didanosine and
stavudine is signi%icantly increased in pregnancy$ Ri%ampicin may cause
a reduction in the serum concentration o% e%aviren1* though* increasing
the dose o% e%aviren1 does not result in any signi%icant outcome 76"8$
/evirapine* which is an alternative to the use o% e%aviren1* also e)hibits
some drug interaction with ri%ampicin$ Ri%ampicin may lead to the
reduction o% serum concentration o% nevirapine by as much as #">$ To
circumvent this problem* ri%abutin* another ri%amycin that is as e%%ective
as ri%ampicin in the treatment o% tuberculosis may be used* as the drug
has less e%%ect on the -DP=A system that metaboli1es nevirapine 76&8$
3enerally* there is a dearth o% studies and data on how pregnancy may
a%%ect the a%orementioned interactions$ -aution is* there%ore* o% great
importance when managing pregnant women with this cruel duo$
&($ Prevention o% Tuberculosis
The B-3 vaccine has been incorporated into the /ational immuni1ation
policy o% many countries* especially the high burden countries* thereby
con%erring active immunity %rom childhood$ /onimmune women
travelling to tuberculosis endemic countries should also be vaccinated$ .t
must* however* be noted that the vaccine is contraindicated in pregnancy
76!8$
The prevention* however* goes beyond this as it is essentially a disease
o% poverty$ .mproved living condition is* there%ore* encouraged with
good ventilation* while overcrowding should be avoided$ .mprovement
in nutritional status is another important aspect o% the prevention$
Pregnant women living with H.2 are at higher ris, %or TB* which can
adversely in%luence maternal and perinatal outcomes 76=8$ As much as
&$& million people were diagnosed with the co;in%ection in !"": alone
7!8$ Primary prevention o% H.25A.+4 is* there%ore* another ma9or step in
the prevention o% tuberculosis in pregnancy$ 4creening o% all pregnant
women living with H.2 %or active tuberculosis is recommended even in
the absence o% overt clinical signs o% the disease$
.sonia1id preventive therapy (.PT) is another innovation o% the World
Health rganisation that is aimed at reducing the in%ection in H.2
positive pregnant women based on evidence and e)perience and it has
been concluded that pregnancy should not be a contraindication to
receiving .PT$ However* patientCs individualisation and rational clinical
9udgement is reGuired %or decisions such as the best time to provide .PT
to pregnant women 76=8$
?ost importantly* governments commitments are highly encouraged so
that the World Health rganisation and all other international bodies
involved in %ighting tuberculosis may succeed in chasing this monster
out o% all communities$