6/27/04njm

11/26/04 njm revise

**Here are 3 common questions about screening, diagnosis, and treatment
of tuberculosis during pregnancy and lactation.**

**\# 1**

**Q. Do we have an Indian health policy /recommendations on positive
skin tests in pregnancy for TB\--and treatment recommendations?**

A. Yes, we have brief policy in Chapter 13 of the IHS Manual. Here is an
expanded discussion.

The Indian Health policy on this is found in IHS Manual, Part 3
Professional Services, [Chapter 13:]{.underline} Maternal Child Health,
[Section 2.A]{.underline} [-]{.underline} [1.g]{.underline}

http://www.ihs.gov/PublicInfo/Publications/IHSManual/Part3/pt3chapt13/pt3chpt13.htm#2f2

\"[Tuberculin and coccidioidin skin testing may be indicated, depending
on the risk of the population served.\"]{.underline}

[Screening]{.underline}

In clinical practice, the majority of pregnant Native women are screened
with PPD early in pregnancy. This is appropriate because Native
Americans are a high risk group for TB, both for initial infection
leading to Latent TB Infection (LTBI) and for progression of untreated
LTBI to active, infectious TB disease.

For example, in Arizona the TB rate for Native Americans in 2001 was
19.7 / 100,000, or nearly 4 times the overall Arizona rate of 5.4 /
100,000.

In New Mexico, the approach for Mexican partners of Indian beneficiaries
is somewhat different. Most of the women from Mexico have received BCG,
hence many have (+) PPDs. In this one scenario the best plan was to wait
till postpartum to get a CXR and start INH, unless the woman was
symptomatic or was a household contact of a known case. If there is
particular issue in your locality, one should contact their local
municipal or state Department of Epidemiology.

So while the general recommendation is to screen high risk individuals,
annual screening tuberculin skin testing in asymptomatic individuals
includes many of the patients we serve.\*

Overall, the American Indian / Alaska Native population is at increased
risk and should be screened with a PPD early in pregnancy and be
prepared to treat if it a new positive result.

[Diagnosis]{.underline}

Pregnant women who have a positive tuberculin skin test or who have
negative skin-test results but who are recent contacts of persons with
infectious TB disease should have PA chest radiographs (with appropriate
shielding) as soon as feasible, even during the first trimester of
pregnancy. (See below).

If the chest film is suspicious for TB disease, sputum smear and culture
should be done immediately and appropriate management begun.

If the film is not suspicious for TB disease, treatment of LTBI (latent
TB infection) is begun (see below) with monitoring for INH hepatitis.

[Treatment]{.underline}

Treatment of LTBI, and especially active TB should start immediately
upon diagnosis, regardless of the trimester, or age of the patient.

Treatment of LTBI is with isoniazid (INH) 300 mg/day and pyridoxine 25
mg/day for 9 months. (See details below)

Treatment of active TB should include INH, rifampin (RIF), ethambutol
(EMB) and pyridoxine 25 mg/day for 9 months. (See details below)

\*

The list of at risk individuals is actually quite large (see below\*\*),
so that from a 'process' standpoint one could ask whether it is just
easier to continue universal testing, so that high risk patients don't
fall through the cracks, e.g., similar to GDM screening -- yes we could
perform selective screening if we wanted, but with all the exceptions we
would end up only excluding 10% of unnecessary screens.....so why bother
challenging your outpatient system which has enough challenges already?

\*\*Indications for annual screening tuberculin skin testing in
asymptomatic individuals include:

  ![](media/image1.wmf){width="6.25e-2in"
height="7.291666666666667e-2in"} HIV infection\
\
  ![](media/image1.wmf){width="6.25e-2in"
height="7.291666666666667e-2in"} Ongoing potential close contact with
cases of active tuberculosis (includes health care workers, prison
guards)\
\
  ![](media/image1.wmf){width="6.25e-2in"
height="7.291666666666667e-2in"} The presence of a medical condition
which increases the risk of active tuberculosis (eg, silicosis, diabetes
mellitus, anticipated or actual long-term therapy with glucocorticoids
or other immunosuppressive medications, hematologic or
reticuloendothelial malignancies, end-stage renal disease, alcoholism,
injection drug use, or conditions associated with rapid weight loss or
chronic malnutrition)\
\
  ![](media/image1.wmf){width="6.25e-2in"
height="7.291666666666667e-2in"} Member of a medically underserved, low
income population (does this describe you're AIAN population?)\
\
  ![](media/image1.wmf){width="6.25e-2in"
height="7.291666666666667e-2in"} Residence in a long term care facility
(eg correctional institutions, mental institutions, and nursing homes)

If the above risk factors are absent, a single tuberculin skin test is
appropriate in the following patients:

  ![](media/image1.wmf){width="6.25e-2in"
height="7.291666666666667e-2in"} A single potential exposure to
tuberculosis (eg, diagnosis of tuberculosis in a family member) without
risk factors for repeated exposures in the future. If the patient is
being tested shortly after exposure, ie, before delayed hypersensitivity
might have developed, then a skin test should be repeated in
approximately 6 to 12 weeks.\
\
  ![](media/image1.wmf){width="6.25e-2in"
height="7.291666666666667e-2in"} Presence of an incidentally discovered
fibrotic lung lesion\
\
  ![](media/image1.wmf){width="6.25e-2in"
height="7.291666666666667e-2in"} Immigrants from countries with a high
prevalence of tuberculosis (eg, most countries in Latin America, Asia,
and Africa)

(this would also be non-Native partners of beneficiaries who get care at
your facility)

**#2**

**Q. Should INH therapy be withheld in women, or men, over 35 years
old?**

A. The decision about PPD testing and INH therapy of LTBI are no longer
based on age at all, but on risk.

That risk includes either the initial active infection, or progression
of LTBI to active TB disease. As elucidated in MMWR 2000; 49 (No. RR-6),
which is Reference no. 2 below, the benefit of treatment, outweighs the
risk of hepatotoxicity. As American Indians and Alaska Natives are at
increased risk, one should not withhold INH therapy based on age.

**\# 3**

**Q. Should breastfeeding be discouraged during antituberculosis
therapy?**

A. Breastfeeding should **not** be discouraged for women being treated
with the first-line antituberculosis agents.

The small concentrations of these drugs in breast milk do not produce
toxicity in the nursing newborn. Conversely, drugs in breast milk should
not be considered to serve as effective treatment for tuberculosis or
for latent tuberculosis infection in a nursing infant. Pyridoxine
supplementation (25 mg/day) is recommended for all women taking INH who
are either pregnant or breastfeeding. The amount of pyridoxine in
multivitamins is variable but generally less than the needed amount.

**[References:]{.underline}**

[\
]{.underline}#1

**Tuberculosis in pregnancy**

[John B Bass, Jr,
MD](http://www.uptodateonline.com/application/author.asp?ID=158725)

**UpToDate Software, 12.1, 2004**

<http://www.uptodateonline.com/application/topic.asp?file=tubercul/5058&type=A&selectedTitle=13~13>

Although there is no clear increase in the risk of tuberculosis
associated with pregnancy, there are several special considerations
which alter the standard recommendations for evaluation and therapy.
Women from populations at risk for tuberculosis, such as inner city
minority populations and people who have recently immigrated to this
country from an area of the world with a high prevalence of
tuberculosis, sometimes have their only contact with the health care
system during pregnancy
\[[1,2](http://www.uptodateonline.com/application/abstract.asp?TR=tubercul/5058&viewAbs=1~2&title=1,2)\].
Since screening for tuberculosis is recommended in all such individuals
regardless of pregnancy status, advantage should be taken of this
contact to screen for tuberculosis and, if appropriate, to provide HIV
counseling and screening as well
\[[3,4](http://www.uptodateonline.com/application/abstract.asp?TR=tubercul/5058&viewAbs=3~4&title=3,4)\].

**EVALUATION FOR TUBERCULOSIS IN PREGNANCY** --- Pregnancy does not
alter the response to the tuberculin skin test. ([See \"Tuberculin skin
testing and other tests for latent tuberculosis
infection\"](http://www.uptodateonline.com/application/topic.asp?file=tubercul/7414)).
Thus, all pregnant women from populations that are recommended to have
routine tuberculosis screening should have a skin test placed if they
have not had a previous test
\[[5,6](http://www.uptodateonline.com/application/abstract.asp?TR=tubercul/5058&viewAbs=5~6&title=5,6)\].
Positive skin test reactors who are asymptomatic and do not have
additional risk factors (eg, HIV infection) should have a chest
radiograph performed after the twelfth week of pregnancy to exclude
asymptomatic pulmonary tuberculosis.

The diagnosis of tuberculosis may be delayed during pregnancy because of
the background frequency of malaise and fatigue
\[[6](http://www.uptodateonline.com/application/abstract.asp?TR=tubercul/5058&viewAbs=6&title=6)\].
Women with symptoms suggestive of pulmonary tuberculosis should have an
appropriately shielded chest radiograph performed regardless of the
stage of pregnancy, even if the tuberculin skin test is negative. In
addition, women with a positive tuberculin skin test and other risk
factors, such as HIV infection, should have a chest radiograph performed
regardless of the stage of pregnancy. If the chest radiograph is
suggestive of tuberculosis in any of the above categories of patients,
sputum examination for mycobacteria should be performed.

**PREVENTIVE THERAPY** --- Although
[isoniazid](http://www.uptodateonline.com/application/topic.asp?file=drug_a_k/135645&drug=true)
(INH) crosses the placenta, there is no increased toxicity to the fetus.
However, there may be some increase in hepatic toxicity in women,
particularly women from minority populations
\[[7](http://www.uptodateonline.com/application/abstract.asp?TR=tubercul/5058&viewAbs=7&title=7)\].
As a result, INH preventive therapy is usually postponed until delivery,
unless other risk factors (eg, HIV infection or recent skin test
conversion with known tuberculosis contact) are present
\[[8](http://www.uptodateonline.com/application/abstract.asp?TR=tubercul/5058&viewAbs=8&title=8)\].
([See \"Clinical use of
isoniazid\"](http://www.uptodateonline.com/application/topic.asp?file=antibiot/6049)
and [see \"Isoniazid
hepatotoxicity\"](http://www.uptodateonline.com/application/topic.asp?file=antibiot/4951)).

Preventive therapy with INH 300 mg/day plus
[pyridoxine](http://www.uptodateonline.com/application/topic.asp?file=drug_l_z/217142&drug=true)
for a duration of 9 months should be started during pregnancy if the
previous risk factors are present
\[[9](http://www.uptodateonline.com/application/abstract.asp?TR=tubercul/5058&viewAbs=9&title=9)\],
and should be started after delivery if they are absent. Although INH is
present in breast milk, the concentrations are low, and breast feeding
is not contraindicated
\[[10](http://www.uptodateonline.com/application/abstract.asp?TR=tubercul/5058&viewAbs=10&title=10)\].
Because of the possible increase in hepatic toxicity in women,
particularly minorities, careful screening with monthly questioning for
symptoms plus hepatic enzyme measurements is recommended. ([See
\"Treatment of latent tuberculosis infection in HIV-negative
patients\"](http://www.uptodateonline.com/application/topic.asp?file=tubercul/5950)).

**THERAPY OF ACTIVE TUBERCULOSIS** --- The benefits of treating active
tuberculosis in pregnancy dramatically outweigh any potential drug
toxicity
\[[8,11](http://www.uptodateonline.com/application/abstract.asp?TR=tubercul/5058&viewAbs=8~11&title=8,11)\].
Pregnancy does not significantly affect the response to antituberculous
medications, and tuberculosis is not a medical indication for abortion.

However, standard regimens for treating tuberculosis should be slightly
modified in pregnant women. ([See \"General principles of the treatment
of
tuberculosis\"](http://www.uptodateonline.com/application/topic.asp?file=tubercul/5321)).

  ![](media/image2.png){width="6.25e-2in"
height="7.152777777777777e-2in"} [Streptomycin](http://www.uptodateonline.com/application/topic.asp?file=drug_l_z/7257&drug=true)
should not be used because of possible ototoxicity in the fetus.\
\
  ![](media/image2.png){width="6.25e-2in"
height="7.152777777777777e-2in"} [Pyrazinamide](http://www.uptodateonline.com/application/topic.asp?file=drug_l_z/216402&drug=true)
is generally not recommended because of a lack of data on the risk for
teratogenicity. However, the benefits of a pyrazinamide-containing
regimen are thought to outweigh risks to the fetus among HIV-positive
women with active tuberculosis
\[[12](http://www.uptodateonline.com/application/abstract.asp?TR=tubercul/5058&viewAbs=12&title=12)\].

Pregnant women who are not likely to be infected with drug-resistant
organisms should be treated with a combination of INH,
[rifampin](http://www.uptodateonline.com/application/topic.asp?file=drug_l_z/222515&drug=true),
and
[ethambutol](http://www.uptodateonline.com/application/topic.asp?file=drug_a_k/97469&drug=true)
for nine months.
[Pyrazinamide](http://www.uptodateonline.com/application/topic.asp?file=drug_l_z/216402&drug=true)
should be included if there is reasonable likelihood of a drug-resistant
organism.
[Pyridoxine](http://www.uptodateonline.com/application/topic.asp?file=drug_l_z/217142&drug=true)
is generally recommended to decrease the incidence of INH neurotoxicity.

Standard therapy of tuberculosis is covered in more detail elsewhere.
([See \"General principles of the treatment of
tuberculosis\"](http://www.uptodateonline.com/application/topic.asp?file=tubercul/5321)
and [see \"Diagnosis and treatment of drug-resistant
tuberculosis\"](http://www.uptodateonline.com/application/topic.asp?file=tubercul/9394)).

**CONSIDERATIONS FOR THE FETUS AND INFANT** --- Congenital
transplacental transmission of tuberculosis is rare and occurs almost
exclusively when the placenta is actively infected (although placental
involvement does not automatically lead to congenital tuberculosis)
\[[6](http://www.uptodateonline.com/application/abstract.asp?TR=tubercul/5058&viewAbs=6&title=6)\].
Thus, tuberculosis that is confined to the thorax or limited to
lymphadenitis poses little risk to the fetus, while adverse fetal
outcomes are more frequent with extrapulmonary disease. As an example,
one study which compared pregnancy outcomes in 21 pregnant women with
extrapulmonary tuberculosis (excluding lymphadenitis) versus 132 healthy
controls found significantly higher frequencies of low birthweight
infants (33 versus 11 percent) and infants with Apgar scores \<7 (19
versus 3 percent) among mothers with extrapulmonary tuberculosis
\[[13](http://www.uptodateonline.com/application/abstract.asp?TR=tubercul/5058&viewAbs=13&title=13)\].

Transmission of infection from the mother to the infant can occur after
delivery; thus the mother should be carefully evaluated for potential
infectiousness at the time of delivery
\[[14](http://www.uptodateonline.com/application/abstract.asp?TR=tubercul/5058&viewAbs=14&title=14)\].
A case series of four HIV-negative pregnant patients with
multidrug-resistant tuberculosis describes the difficult management
issues raised
\[[15](http://www.uptodateonline.com/application/abstract.asp?TR=tubercul/5058&viewAbs=15&title=15)\].
Treatment was individualized and postponed until after delivery in two
patients; one patient elected to have a therapeutic abortion. The three
babies were all born healthy and without evidence of tuberculosis,
although one mother with highly refractory cavitary tuberculosis, who
was treated after delivery with
[ethambutol](http://www.uptodateonline.com/application/topic.asp?file=drug_a_k/97469&drug=true),
[cycloserine](http://www.uptodateonline.com/application/topic.asp?file=drug_a_k/68507&drug=true),
para-aminosalicylic acid,
[capreomycin](http://www.uptodateonline.com/application/topic.asp?file=drug_a_k/41266&drug=true),
[ofloxacin](http://www.uptodateonline.com/application/topic.asp?file=drug_l_z/185240&drug=true),
and
[clofazimine](http://www.uptodateonline.com/application/topic.asp?file=drug_a_k/61447&drug=true),
was separated from her baby for two years; the neonate also received BCG
vaccination.

# #2

# Targeted Tuberculin Testing and Treatment of Latent Tuberculosis Infection, MMWR 2000; 49 (No. RR-6) 

<http://www.cdc.gov/mmwr/preview/mmwrhtml/rr4906a1.htm>

***Chest Radiographs***

A chest radiograph is indicated for all persons being considered for
treatment of LTBI to exclude active pulmonary TB. Children younger than
5 yr of age should have both posterior\--anterior and lateral
radiographs. All other persons should receive posterior\--anterior
radiographs; additional radiographs should be performed at the
physician\'s discretion. Because of the risk for progressive and/or
congenital TB, pregnant women who have a positive tuberculin skin test
or who have negative skin-test results but who are recent contacts of
persons with infectious TB disease should have chest radiographs (with
appropriate shielding) as soon as feasible, even during the first
trimester of pregnancy.

**Pregnancy and lactation.** Pregnancy has minimal influence on the
pathogenesis of TB or the likelihood of LTBI progressing to disease
(*133, 134*). Although one study demonstrated a decrease in lymphocyte
reactivity to tuberculin during pregnancy (*135*), other studies have
not demonstrated an effect of pregnancy on cutaneous delayed
hypersensitivity to tuberculin (*136, 137*). The current classification
scheme for interpreting the Mantoux tuberculin skin test is likely valid
in pregnancy, although it has not been verified in this group of women.
There is no evidence that the tuberculin skin test has adverse effects
on the pregnant mother or fetus (*138*).

Pregnant women should be targeted for tuberculin skin testing only if
they have a specific risk factor for LTBI or for progression of LTBI to
disease. Although the need for treatment of active TB during pregnancy
is unquestioned, the treatment of LTBI in pregnant women is more
controversial. Some experts prefer to delay treatment until after
delivery because pregnancy itself does not increase the risk of
progression to disease, and two studies suggest that women in pregnancy
and the early postpartum period may be vulnerable to isoniazid
hepatotoxicity (*91, 92*). However, because conditions that promote
hematogenous spread of organisms to the placenta (e.g., recent infection
and HIV infection) or progression of LTBI to disease can endanger both
the mother and baby (*139*), many experts agree that pregnant women with
these conditions and LTBI should be treated during pregnancy and have
careful clinical and laboratory monitoring for hepatitis. The possible
risk for isoniazid hepatotoxicity must be weighed against the risk for
developing active TB and the consequences to both the mother and her
child should active disease develop.

Extensive use of isoniazid during pregnancy has indicated that although
it readily crosses the placental barrier, the drug is not teratogenic
even when given during the first 4 mo of gestation (*140*). Regarding
rifampin, one study revealed that 3% of 446 fetuses exposed *in utero*
to rifampin had abnormalities (i.e., limb reductions, central nervous
system abnormalities, and hypoprothrombinemia) compared with 2% for
ethambutol and 1% for both isoniazid and controls (*138*). Hemorrhagic
disease of the newborn has been described following the use of rifampin
in the mother (*141*). However, extensive experience with the use of
rifampin to treat TB in pregnant women suggests it is safe in most
circumstances. Although pyrazinamide has been used to treat TB in
pregnant women, no published data exist concerning the effects of the
drug on the fetus. Thus, although pyrazinamide may be considered after
the first trimester in women with HIV infection (*142*), it should
otherwise be avoided.

The preferred regimen for treatment of LTBI in pregnant women is
isoniazid, administered either daily or twice weekly. Although rifampin
is probably safe, no efficacy data support its use. For women at high
risk for progression of LTBI to disease, especially those who are
infected with HIV or who have been infected recently, initiation of
therapy should not be delayed on the basis of pregnancy alone, even
during the first trimester. For these women, careful clinical and/or
laboratory monitoring for hepatitis should be undertaken. Pregnant women
taking isoniazid should receive pyridoxine supplementation.

Toxic effects of antituberculosis drugs delivered in breast milk have
not been reported. One study concluded that a breastfeeding infant would
develop serum levels of no more than 20% of the usual therapeutic levels
of isoniazid for infants and \<11% of other antituberculosis drugs
(*143*). Breastfeeding is not contraindicated when the mother is being
treated for LTBI. However, infants whose breastfeeding mothers are
taking isoniazid should receive supplemental pyridoxine. The amount of
isoniazid provided by breast milk is inadequate for treatment of the
infant.

\# 3

# Treatment of Tuberculosis, American Thoracic Society, CDC, and Infectious Diseases Society of America, MMWR 2003; 52 (No. RR-11)

<http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5211a1.htm>

***Pregnancy and breastfeeding***

Because of the risk of tuberculosis to the fetus, treatment of
tuberculosis in pregnant women should be initiated whenever the
probability of maternal disease is moderate to high. The initial
treatment regimen should consist of INH, RIF, and EMB. Although all of
these drugs cross the placenta, they do not appear to have teratogenic
effects. Streptomycin is the only antituberculosis drug documented to
have harmful effects on the human fetus (congenital deafness) and should
not be used. Although detailed teratogenicity data are not available,
PZA can probably be used safely during pregnancy and is recommended by
the World Health Organization (WHO) and the International Union against
Tuberculosis and Lung Disease (IUATLD). If PZA is not included in the
initial treatment regimen, the minimum duration of therapy is 9 months.

Breastfeeding should not be discouraged for women being treated with the
first-line antituberculosis agents because the small concentrations of
these drugs in breast milk do not produce toxicity in the nursing
newborn. Conversely, drugs in breast milk should not be considered to
serve as effective treatment for tuberculosis or for latent tuberculosis
infection in a nursing infant. Pyridoxine supplementation (25 mg/day) is
recommended for all women taking INH who are either pregnant or
breastfeeding. The amount of pyridoxine in multivitamins is variable but
generally less than the needed amount.

**Use in pregnancy.** INH is considered safe in pregnancy, but the risk
of hepatitis may be increased in the peripartum period (*9,23*).
Pyridoxine supplementation (25 mg/day) is recommended if INH is
administered during pregnancy (*18*). It should be noted that
multivitamin preparations have variable amounts of pyridoxine but
generally less than 25 mg/day and, thus, do not provide adequate
supplementation.

**Use in pregnancy.** RIF is considered safe in pregnancy (*38*).

**Use in pregnancy.** There are insufficient data to recommend the use
of rifabutin in pregnant women; thus, the drug should be used with
caution in pregnancy.

**Use in pregnancy.** There is not sufficient information to recommend
the use of rifapentine for pregnant women.

**Use in pregnancy.** There is little information about the safety of
PZA in pregnancy. However, when there are sound reasons to utilize a
6-month course of treatment, the benefits of PZA may outweigh the
possible (but unquantified) risk. The WHO and the IUATLD recommend this
drug for use in pregnant women with tuberculosis (see Section 10:
Treatment of Tuberculosis in Low-Income Countries: Recommendations of
the WHO and the IUATLD).

**Use in pregnancy.** EMB is considered safe for use in pregnancy
(*70\--72*)*.*

**Use in pregnancy.** Rifamate® may be used in daily treatment of
pregnant women. Rifater® should not be used because it contains PZA.

**Use in pregnancy.** Cycloserine crosses the placenta. There are
limited data on safety in pregnancy; thus, it should be used in pregnant
women only when there are no suitable alternatives (*77*).

**Use in pregnancy.** Ethionamide crosses the placenta and is
teratogenic in laboratory animals. It should not be used in pregnancy.

**Use in pregnancy. Streptomycin** is contraindicated in pregnancy
because of the risk of fetal hearing loss (77,97,98).

**Use in pregnancy.** Both amikacin and kanamycin are contraindicated in
pregnant women because of risk of fetal nephrotoxicity and congenital
hearing loss (77).

**Use in pregnancy.** Capreomycin should be avoided in pregnancy because
of risk of fetal nephrotoxicity and congenital hearing loss (*77*).

**Use in pregnancy.** No studies have been done in humans; however, PAS
has been used safely in pregnancy. The drug should be used only if there
are no alternatives (see below) for a pregnant woman who has
multidrug-resistant tuberculosis.

**Use in pregnancy.** The Levofloxacin class of drugs should be avoided
in pregnancy because of teratogenic effects (*119,134*).

#4

**CDC Questions and Answers About TB**

Latent TB Infection

<http://www.cdc.gov/nchstp/tb/faqs/qa_latenttbinf.htm#Infection3>

#5

Salpeter SR, Sanders GD, Salpeter EE, Owens DK. Monitored isoniazid
prophylaxis for low-risk tuberculin reactors older than 35 years of age:
a risk-benefit and cost-effectiveness analysis. Ann Intern Med 1997 Dec
15;127(12):1051-61.\
<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9412307>