perspective and doesn’t fulfil requirements for equity at
national or international levels.
Introducing user charges is likely to be inequitable as
well as adversely affecting adherence.18 19Many families
will already be living in poverty as a result of a reduction
in income or paying for AIDS care.Providing free access
to antiretroviral drugs based on rights and not ability to
pay,19as occurs in the Senegal national programme, will
be most equitable, will resolve dilemmas over the
treatment of migrants, and will also reduce migration to
obtain antiretroviral drugs.
The 3 by 5 initiative faces important challenges in
meeting the desperate need for antiretroviral drugs in
many developing countries,. Constructive dialogue
between stakeholders with different agendas, including
healthcare workers, public health managers, commu-
nity and faith based organisations, and people with
AIDS, will be crucial if the initiative is to succeed. The
carefully when setting up programmes and working
relationships, in order to capitalise on and not
undermine the existing social order. In an interview in
Bangkok, the executive director of UNAIDS noted that
“antiretroviral therapy is still a rare commodity, and it
will be for some time.The result of that is always higher
price,and also higher price in terms of power.Who has
access to it, and who comes first: it’s a terrible issue.”w20
Without addressing this and the other issues we have
raised, the 3 by 5 initiative may fall short of its goals.
ASF, IJH, and DSM have received support from Health and
Development Networks (www.hdnet.org) to report on interna-
tional AIDS events which have helped inform this article. The
views expressed do not necessarily represent the views of
organisations for which the authors work.We thank the external
reviewers for their helpful comments.
Contributors and sources:This article was written after discussion
between the authors at recent international AIDS conferences in
the light of keynote presentations by WHO/UNAIDS. The
authors have experience of working in AIDS programmes in Asia
wrote the first draft and is the guarantor. IJH, AD, and DSM all
revised and added to parts of the paper.
Competing interests: None declared.
1Mukherjee JS, Farmer PE, Niyizonkiza D, McCorkle L, Vanderwarker C,
Teixeira P, et al. Tackling HIV in resource poor countries. BMJ
2Word Health Organization. Treating 3 million by 2005: making it happen.
Geneva: WHO, 2003. www.who.int/3by5/en/ (accessed 15 Dec 03).
Osborne CM, van Praag E, Jackson H. Models of care for patients with
HIV/AIDS. AIDS 1997;11B:135-41.
Gayle H, Lange JM. Seizing the opportunity to capitalise on growing
access to HIV treatment to expand HIV prevention. Lancet 2004;364:6-8.
Harding R, Stewart K, Marconi K, O’Neill JF, Higginson IJ. Current HIV/
AIDS end-of-life care in sub-Saharan Africa: a survey of models, services,
challenges and priorities. BMC Public Health 2003;3:33.
Kumar S. India’s treatment programme for AIDS is premature. BMJ
Sharma DC. India unprepared for antiretroviral treatment plan. Lancet
Kitahata MM, Tegger MK, Wagner EH, Holmes KK. Comprehensive
health care for people infected with HIV in developing countries. BMJ
Parker R, Aggleton P. HIV and AIDS related stigma and discrimination: a
conceptual framework and implications for action. Soc Sci Med
10 Stanley LD. Transforming AIDS: the moral management of stigmatized
identity. Anthropol Med 1999;6:103-20.
11 Goffman E. Stigma: notes on the management of spoiled identity. Englewood
Cliffs, NJ: Prentice-Hall, 1963.
12 Holmes W. 3 by 5, but at what cost? Lancet 2004;363:1072-3.
13 World Health Organization.
resource-limited setting: treatment guidelines for a public health approach.
Geneva: WHO, 2003.
14 Gupta R, Irwin A, Raviglione MC, Kim JY. Scaling-up treatment for HIV/
AIDS: lessons learned from multidrug-resistant tuberculosis. Lancet
15 China Tuberculosis Control Collaboration. The effect of tuberculosis
control in China. Lancet 2004;364:417-22.
16 Stevens W, Kaye S, Corrah T. Antiretroviral therapy in Africa. BMJ
17 Lanièce I, Ciss M, Desclaux A, Diop K, Mbodj F, Ndiaye B, et al.
Adherence to HAART and its principal determinants in a cohort of Sen-
egalese adults. AIDS 2003;7(suppl 3): S103-8.
18 Loewenson R, McCoy D. Access to antiretroviral treatment in Africa. BMJ
19 Mukherjee J. Basing treatment on rights rather than ability to pay: 3 by 5.
up antiretroviraltherapy in
(Accepted 20 September 2004)
Natural killer cells, miscarriage, and infertility
Ashley Moffett, Lesley Regan, Peter Braude
Enthusiasm for new treatments aimed at natural killer cells in women with reproductive failure is
unfortunately not backed up by the science
Natural killer (NK) cells have an important role in the
early responses to viral infections and have also been
linked with failure of pregnancy. Recent reports in the
media and the internet have exposed women to a baf-
fling array of conflicting information about tests for
NK cells and “cures” for infertility and miscarriage.
These are based on the premise that malfunction of
NK cells causes these conditions. Increasingly, clinics
are offering blood tests to measure the number and
activity of circulating NK cells. As a result of these
investigations, many women are offered treatments
such as steroids, intravenous immunoglobulins, and
tumour necrosis factor ? blocking agents.The scientific
rationale for these tests and treatments, however, is not
supported by our current knowledge of the function of
uterine NK cells.
The 3 by 5 initiative aims to deliver antiretroviral drugs to three
million people with HIV infection in developing countries by 2005
To succeed, the initiative must develop a chronic disease model of
care through a strengthened public health infrastructure
Cooperation is needed with existing essential programmes to
manage scarce health staff
The influence of stigma requires monitoring
Access to treatment must be based on rights and not ability to pay
Education and debate
BMJ VOLUME 32927 NOVEMBER 2004bmj.com
Uterine natural killer cells
Natural killer cells (identified by the surface marker
CD56) are the dominant type of maternal immune cell
populating the uterine mucosa during formation of
the placenta.1These uterine NK cells are also present
in the endometrium of non-pregnant women, when
they are under the control of ovarian hormones,
cycling together with the glandular and stromal
compartments. After ovulation, uterine NK cells prolif-
erate vigorously so that by the late secretory phase they
account for at least 30% of the endometrial stroma.
Uterine NK cells persist in the early decidua and
accumulate in large numbers at the implantation site.
Here they are in close contact with the invading
placental trophoblast cells, which transform the spiral
arteries into high conductance vessels. This transfor-
mation is essential to ensure a normal blood supply to
the fetus and placenta throughout pregnancy. Of cen-
tral importance is that uterine NK cells are phenotypi-
cally and functionally different from NK cells in
peripheral blood and should be regarded as a separate
The presence of an apparently unique type of lym-
phocyte in the uterus at implantation and during early
placentation is intriguing. However, despite much
speculation, the function of uterine NK cells is
completely unknown. They may affect the cycling
endometrium by controlling vascular function through
secretion of angiogenic growth factors.In this way they
may be crucial in the decision to switch from endome-
trial breakdown (menstruation) to decidualisation in
pregnancy.2More attention has been directed at their
possible role in regulating the fetal supply line by
modulating the structural adaptation of the uterine
spiral arteries. This is achieved by invasion of the
maternal decidua and adjacent myometrium by
invasive fetal trophoblast cells. Trophoblast invasion is
defective in intrauterine growth restriction, pre-
eclampsia, and miscarriage.3How NK cells recognise
trophoblast and the outcome of this recognition are
under investigation. Recently, the NK cell receptors
that can bind to trophoblast MHC class I molecules
have been identified, and this has opened up new ways
to study the function of uterine NK cells.4 5
At present, despite their compelling name, there is
no evidence that uterine NK cells kill placental
trophoblast cells. Instead, they probably have an essen-
tial, beneficial effect on trophoblast by secreting
cytokines that alter the depth of placental invasion.
Natural killer cells acquired their name as a result of
the initial test used to identify them in vitro. Unlike T
lymphocytes, NK cells are able to spontaneously kill
cells in a non-MHC restricted manner.Regrettably,this
is a misleading name in reproduction, and the power-
ful image of maternal cells attacking the fetus is
emotive and easily exploited.
Testing of peripheral blood NK cells
Based on the assumed similarities between NK cells in
blood and uterine NK cells, it has become increasingly
common to examine peripheral blood NK cells in
women with infertility and recurrent miscarriage.
These tests are based on the speculation that women
with recurrent miscarriage and infertility have abnor-
malities in uterine NK cell function, and it has been
implied that these are discernible from analysis of NK
cells in blood.6 7This approach has several problems.
Firstly, as mentioned above, uterine NK cells are differ-
ent from those in peripheral blood. Examination of
peripheral blood NK cells will not tell us what is
happening in the uterus. This is akin to estimating the
number and activity of black cabs in Trafalgar Square
by analysing red mini-cabs circulating on the M25.
Secondly, the percentage of CD56+ NK cells in
peripheral blood in normal healthy individuals varies
from 5% to 29%.8Despite this, a finding of more than
12% NK cells in women with infertility or miscarriage
has been arbitrarily defined as abnormally raised and
used as an indication for treatment.9The percentage of
NK cells in blood can be affected by many factors
including sex, ethnicity, stress, and age, but there is no
indication that concentrations in the upper end of the
normal range are ever harmful.
Thirdly, NK activity is measured by a range of assays
and the results will vary in different laboratories. The
most commonly used in vitro assay is cytotoxicity,which
may not have much relevance to NK function in vivo.10
Certainly, in viral infection, NK cells function mainly by
producing cytokines. Furthermore, uterine NK cells
have much lower cytolytic activity than blood NK cells.
Thus, no clinically relevant information is gained from
studying either the percentage or cytotoxicity of blood
NK cells in women with pregnancy failure.
Uterine NK cells in pregnancy failure
Attempts have also been made to compare the
endometrium of women with recurrent miscarriage or
infertility with that in normal controls.11 12These stud-
ies are based on the doubtful premise that the
unknown roles of NK cells actually relate to the num-
bers present. Normally, numbers of uterine NK cells
change rapidly after ovulation, and quantification
must be carefully correlated with the surge in luteinis-
ing hormone. Furthermore, the density of NK cells
throughout the mucosa is not constant, so all samples
should be analysed at the same depth beneath the sur-
face epithelium. It is not surprising that the results are
conflicting. Regrettably, an anecdotal case of a woman
with “excessive natural killer cells” has been reported
on BBC Radio 4’s Woman’s Hour (22 Jan 2004) and
several national newspapers.13The so called excessive
Immunofluorescent light micrograph of human natural killer cells
Education and debate
School of Medicine,
London W2 1NY
professor of obstetrics
Guy’s, King’s and St
Thomas’ School of
professor of obstetrics
BMJ VOLUME 329 27 NOVEMBER 2004bmj.com
numbers and activity of NK cells,which are well within
the range for healthy women, are used as the reason
Treatments for miscarriage and
Infertile women and those with recurrent miscarriages
are being given treatments such as steroids, intra-
factor-? blocking drugs with the questionable aim of
suppressing NK cells. Recent high profile radio and
press reports have featured a UK trial of steroids in
recurrent miscarriage that has not been published but
claims a success rate of about 85% (Woman’s Hour, 29
How this study was controlled is
uncertain, but it is important to bear in mind the
placebo effect and the well documented success
achieved with such patients simply using care and
reassurance.15Neither steroids nor the other treat-
ments being offered to women with “raised” levels of
NK cells in blood are licensed for use in reproductive
medicine, and all these treatments are associated
with known risks to mother and fetus. The treatments
are offered despite recent guidelines from the Royal
Cochrane review, and a meta-analysis all concluding
thatthere is noevidence
beneficial.16–18The situation is reminiscent of the pub-
licity and controversy surrounding paternal leucocyte
immunisation as a treatment for recurrent miscarriage
in the 1980s. After much flurry and expense, this
treatment has now been banned by the US Food and
Understanding the function of uterine NK cells is
certainly a major challenge in human reproduction.
However, until more is known about their role in nor-
mal pregnancy, there is no evidence of any benefit in
offering NK cell testing to women with recurrent mis-
carriage or infertility. Of course, women with these dis-
tressing conditions will be disappointed. In the
technological medicine of today, patient expectations
and tumour necrosis
to showthey are
are high and a lack of a diagnosis and treatment is hard
to accept. The danger posed by internet sources, the
popular press, and radio highlighting idiosyncratic
personal practices of a few physicians should not be
underestimated. This unfortunate group of women are
particularly vulnerable to financial exploitation, and of
being exposed to powerful treatments that have, as yet,
no rational scientific basis.
Contributors and sources: AM is a leading international author-
ity on the role of uterine natural killer cells in reproduction, PB
is on the Human Fertilisation and Embryology Authority and is
a leading fertility expert, and LR is an expert on recurrent mis-
carriage and runs the largest miscarriage clinic in Europe. AM
provided the scientific basis and wrote the paper. LR and PB
provided clinical and ethical advice. AM is the guarantor.
Competing interests: None declared.
1 Moffett-King A. Natural killer cells and pregnancy. Nat Rev Immuol
King A. Uterine leukocytes and decidualisation. Hum Reprod Update
Pijnenborg R, Vercruysse L, Hanssens M, Van Assche A. Incomplete tro-
phoblast invasion: the evidence. In: Critchley H, MacLean A, Poston L,
Walker J, eds. Pre-eclampsia. London: RCOG Press, 2003:15-26.
Parham P. NK cells and trophoblasts: partners in pregnancy. J Exp Med
Hiby SE, Walker JJ, O’Shaughnessy KM, Redman CWG, Carrington M,
Trowsdale J,et al.Combinations of maternal and paternal innate immune
genes influence the risk of pre-eclampsia. J Exp Med 2004;200:957-65.
Aoki K, Kajiura S, Matsumoto Y, Ogasawara M, Okada S, Yagami Y, et al.
Preconceptional natural-killer-cell activity as a predictor of miscarriage.
Ntrivalas EI, Kwak-Kim JY, Gilman-Sacchs A, Chung-Bang H, Ng SC,
Beaman KD,et al.Status of peripheral blood natural killer cells in women
with recurrent spontaneous abortions and infertility of unknown aetiol-
ogy. Hum Reprod 2001;16:855-61.
Bisset LR, Lung TL, Kaelin M, Ludwig E, Dubs RW. Reference values for
peripheral blood lymphocyte phenotypes applicable to the healthy adult
population in Switzerland. Eur J Haematol 2004;72:203-12.
Kwak JY,Kwak FM,Gilman-Sachs A,Beaman KD,Cho DD,Beer AE,et al.
Immunoglobulin G infusion treatment for women with recurrent
spontaneous abortions and elevated CD56+natural killer cells. Early Preg
10 Biron CA, Nguyen KB, Pien GC. Innate immune responses to LCMV
infections: natural killer cells and cytokines. Curr Top Microbiol Immunol
11 Shimada S, Kato EH, Morikawa M, Iqwabuchi K, Nishida R, Kishi R, et al.
No difference in natural killer or natural killer T-cell population, but
aberrant T-helper cell population in the endometrium of women with
repeated miscarriage. Hum Reprod 2004;19:1018-24.
12 Quenby S, Bates M, Doig T, Brewster J, Lewis-Jones DI, Johnson PM, et al.
Pre-implantation endometrial leukocytes in women with recurrent
miscarriage. Hum Reprod 1999;14:2386-91.
13 Quenby S, Farquharson R, Young M, Vince G. Successful pregnancy out-
come following 19 consecutive miscarriages: case report. Hum Reprod
14 Parenting: the simple £15 ‘cure’ for miscarriage. Sunday Times 2004
15 Clifford K, Rai R, Regan L Future pregnancy outcome in unexplained
recurrent first trimester miscarriage. Hum Reprod 1997;12:387-9.
16 RCOG Scientific Advisory Committee. Immunological testing and interven-
tions for reproductive failure. London: RCOG, 2003. (Opinion paper 5.)
17 Scott JR. Immunotherapy for recurrent miscarriage. Cochrane Database
Syst Rev 2003;(1):CD000112.
18 Daya S, Gunby J, Clark DA. Intravenous immunoglobulin therapy for
recurrent spontaneous abortion: a meta-analysis. Am J Reprod Immunol
19 Center for Biologics Evaluation and Research.Lymphocyte immune therapy.
www.fda.gov/cber/ltr/lit013002.htm (accessed 8 Sep 2003).
(Accepted 20 September 2004)
Natural killer (NK) cells are the main type of
lymphocyte in the uterine mucosa at implantation
and during early pregnancy
Uterine NK cells are different from those
circulating in peripheral blood
The function of uterine NK cells in pregnancy is
Tests to measure NK cells in peripheral blood
give no useful information on uterine NK cells
Use of powerful therapies to reduce levels of NK
cells in women with infertility or recurrent
miscarriage is unjustified and is associated with
known side effects to mother and fetus
Clarity and certainty are essential to surgeons in
training, at least until they discover that clarity is
not enough and certainty does not exist.
Le Vay D. The life of Hugh Owen Thomas.
Edinburgh: Livingstone, 1956
Alistair J Tindall, London
Education and debate
BMJ VOLUME 32927 NOVEMBER 2004bmj.com