The new england journal of medicine
n engl j med 363;9 nejm.org august 26, 2010
Jantien Visser, M.D.
Danielle Cohen, M.D.
Kitty W.M. Bloemenkamp, M.D., Ph.D.
Leiden University Medical Center
Leiden, the Netherlands
No potential conflict of interest relevant to this letter was re-
The Authors Reply: We agree that both the An-
ticoagulants for Living Fetuses (ALIFE) study (Cur-
rent Controlled Trials number, ISRCTN58496168)
and the Scottish Pregnancy Intervention Study
(ISRCTNO6774126)1 have investigated a combina-
tion of low-molecular-weight heparin and aspirin,
and that a detrimental effect of aspirin cannot be
entirely ruled out. Therefore, studies of the effect
of low-molecular-weight heparin alone in women
with recurrent miscarriage would be interesting.
We disagree that a double-blind design is always
necessary. Rather, concealment of study-drug as-
signment is the quality item in randomized, con-
trolled trials that may lead to the most severely
biased effect estimates if it is inadequate.2 In the
ALIFE study, all randomly assigned women were
offered similar standards of care, thus avoiding
performance bias. The standard of care in the
ALIFE study involved a low threshold for visits and
ultrasonography in early pregnancy; these can be
considered a form of psychological support.
Currently, no consensus exists on the definition
of recurrent miscarriage. Guidelines published on
this topic and their respective definitions vary
with regard to the number of preceding miscar-
riages as well as the sequence of previous preg-
nancies. The American College of Obstetricians
and Gynecologists defines recurrent miscarriage
as two or more consecutive miscarriages, the Eu-
ropean Society of Human Reproduction and Em-
bryology defines it as three or more consecutive
miscarriages, and the Royal College of Obstetri-
cians and Gynaecologists defines it as three or
more miscarriages. This discrepancy is due to a
lack of evidence with regard to the role of risk
factors such as the number of preceding miscar-
riages. Maternal age has not been described in any
of the above-mentioned guidelines. The discrep-
ancy in definition has led to an ongoing discussion
regarding which couples should receive the diag-
nosis of recurrent miscarriage and when to start
the diagnostic workup.
The potential dilutive effects of recruiting
women with two miscarriages and advanced ma-
ternal age were fully taken into account when
our sample-size calculation was performed. This
consideration was mainly based on the study by
Brigham et al.,3 a large cohort study based on the
same patient group, including women with two
miscarriages and advanced maternal age.
We agree with Visser et al. that a meta-analysis
of data from individual patients could provide im-
portant information regarding a differential effect
of therapy in women with a history of two rather
than three miscarriages. In the ALIFE trial, the
exclusion of women with “only” two preceding
miscarriages or women 36 years of age or older
would have resulted in a missed opportunity.
Stef P. Kaandorp, M.D.
Mariëtte Goddijn, M.D., Ph.D.
Saskia Middeldorp, M.D., Ph.D.
Academic Medical Center
Amsterdam, the Netherlands
Since publication of their article, the authors report no fur-
ther potential conflict of interest.
Clark P, Walker ID, Langhorne P, et al. SPIN (Scottish Preg-
nancy Intervention) study: a multicenter, randomised controlled
trial of low-molecular-weight heparin and low-dose aspirin in
women with recurrent miscarriage. Blood 2010;115:4162-7.
Jüni P, Altman DG, Egger M. Systematic reviews in health
care: assessing the quality of controlled clinical trials. BMJ 2001;
Brigham SA, Conlon C, Farquharson RG. A longitudinal
study of pregnancy outcome following idiopathic recurrent mis-
carriage. Hum Reprod 1999;14:2868-71.
Cost Consciousness and Medical Education
to the editor: We commend Cooke’s efforts in
her Perspective article (April 8 issue)1 to increase
readers’ awareness of the near-universal ignorance
of actual costs associated with the delivery of
medical care.2-4 This lack of cost awareness affects
all other components of the price equation, ren-
dering us incapable of understanding the true
economic value of medical care. It also makes
us unable to engage efficiently in any potential
negotiation.5 As end consumers, we as physi-
cians must educate ourselves to know better —
prices will never drop (even if the true cost is
low) because of our lack of cost consciousness.
The asymmetry between physicians and adminis-
The New England Journal of Medicine
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