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www.thelancet.com Vol 365 April 16, 2005 1367
2 Solimena M, Folli F, Denis-Sonini S, et al. Autoantibodies to glutamic acid
decarboxylase in a patient with stiff-man syndrome, epilepsy and type I
diabetes mellitus. N Engl J Med 1988; 318: 101220.
3 Folli F, Solimena M, Coell R, et al. Autoantibodies to a 128 kD synaptic
protein in stiff-man syndrome with breast cancer. N Engl J Med 1993; 328:
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4 Wessig C, Klein R, Schneider MF, Toyka KV, Naumann M, Sommer C.
Neuropathology and binding studies in anti-amphiphysin-associated stiff-
person syndrome. Neurology 2003; 61: 19598.
5 Yoshida Y, Kinuta M, Abe T, et al. The stimulatory action of amphiphysin
on dynamin function is dependent on lipid bilayer curvature. EMBO J 2004;
23: 348391.
6 Dinkel K, Meinck HM, Jury KM, Karges W, Richter W. Inhibition of gamma-
aminobutyric acid synthesis by glutamic acid decarboxylase
autoantibodies in stiff-man syndrome. Ann Neurol 1998; 44: 194201.
7 Lohmann T, Hawa M, Leslie RDG, Lane R, Picard J, Londei M. Immune
reactivity to glutamic acid decarboxylase 65 in stiff-man syndrome and
type 1 diabetes mellitus. Lancet 2000; 356: 3136.
8 Atkinson MA. The $64 000 question in diabetes continues . . .
Lancet 2000; 356: 46.
9 Dalakas MC, Li M, Fujii M, Jacobowitz DM. Stiff person syndrome:
quantication, specicity, and intrathecal synthesis of GAD
65
antibodies.
Neurology 2001; 57: 78084.
10 Brashear HR, Phillips LH. Autoantibodies to GABAergic neurons and
response to plasmapheresis in stiff-man syndrome. Neurology 1991; 41:
158892.
11 Koerner C, Wieland B, Richter W, Meinck H-M. Stiff-person syndromes:
motor cortex hyperexcitability correlates with anti-GAD autoimmunity.
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12 Burns TM, Jones HR, Phillips LH, Bugawan TL, Erlich HA, Lennon VA.
Clinically disparate stiff-person syndrome with GAD65 autoantibody in a
father and daughter. Neurology 2003; 61: 129193.
13 Burns TM, Jones HR, Phillips LH. Stiff person syndrome does not always
occur with maternal passive transfer of GAD65 antibodies. Neurology
2005; 64: 399400.
14 Pittock SJ, Kryzer TJ, Lennon VA. Paraneoplastic antibodies coexist and
predict cancer, not neurological syndrome. Ann Neurol 2004; 56: 71519.
15 Antoine JC, Absi L, Honnorat J, et al. Antiamphiphysin antibodies are
associated with various paraneoplastic neurological syndromes and
tumors. Arch Neurol 1999; 56: 17277.
16 Saiz A, Dalmau J, Husta Butler M, et al. Anti-amphiphysin I antibodies in
patients with paraneoplastic neurological disorders associated with small
cell lung cancer. J Neurol Neurosurg Psych 1999; 66: 21417.
17 Graus F, Delattre JY, Antoine JC, et al. Recommended diagnostic criteria
for paraneoplastic neurological syndromes. J Neurol Neurosurg Psych 2004;
75: 113540.
Pre-eclampsia remains one of the most complex
challenges for perinatal clinicians and researchers. As a
major cause of maternal and perinatal mortality and
morbidity worldwide, this condition lacks an effective
prevention strategy or curative treatment. Furthermore,
the efforts to develop screening tests have been
disappointing for potential use in clinical practice.
Agustin Conde-Agudelo and co-workers recently
published a systematic review of screening tests for pre-
eclampsia, derived from 87 studies in 211369 women.
1
On the basis of a comprehensive review of clinical,
biophysical, and biochemical tests, the authors conclude
that there is currently no clinically useful screening test
to predict the development of pre-eclampsia.
Why do we need an efcient screening tool for pre-
eclampsia? In general, risk screening is justied when a
test is able to dene a population that will benet from
an effective preventive treatment (primary prevention),
or when earlier diagnosis will lead to more timely
intervention that will decrease disease morbidity
(secondary prevention).
2
For pre-eclampsia, primary
prevention with low-dose aspirin or calcium
supplementation is disappointing.
3
A possible reason for
this lack of effect is that the large trials that tested
interventions recruited low-risk to moderate-risk
women, or women judged at high-risk solely on the
basis of clinical risk factors. Given that pre-eclampsia is
likely to be a heterogeneous condition, potentially
involving several separate pathophysiological pathways,
it is not surprising that simple clinical indicators are
ineffective in identifying women who would benet
from a pathway-specic treatment.
Screening for pre-eclampsia: the quest for the Holy Grail?
S
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A few studies have used screening tests as inclusion
criteria in trials. For instance, a trial of prevention of pre-
eclampsia with antioxidant vitamins recruited women
with abnormal two-stage uterine-artery doppler
analysis.
4
This trial showed promising results and several
trials are underway to conrm this potential. In future
prevention trials, careful consideration must be given to
the choice of an appropriate screening strategy to select
women who are most likely to benet from the
proposed treatments, thus increasing the chance of
showing a reduction in the incidence of the disease.
Furthermore, trials can provide a unique opportunity to
stratify randomisation according to screening-test
results.
What are the pathophysiological bases for pre-
eclampsia screening? Whilst the causes of pre-eclampsia
remain elusive, it is accepted that abnormal early
placentation and reduced placental perfusion have a role
in the start of the condition. Coagulation activation,
oxidative stress, endothelial damage, and inammation
are all associated with pre-eclampsia.
5
In their review,
Conde-Agudelo and co-workers distinguish four
categories of dysfunction-related tests: placental
perfusion and vascular resistance (particularly on
doppler scan); the endocrinology of the fetoplacental
unit; tests for renal dysfunction; and tests for
endothelial dysfunction and oxidant stress. The
disappointingly low likelihood ratios obtained with
various individual tests might be partly explained by the
heterogeneous nature of the disease. Some types of
pre-eclampsia might be best detected by uterine artery
doppler while others will lead to abnormal serum levels
of placental peptides or markers of endothelial stress. It
would therefore be of interest to explore combinations
of tests of different categories.
What is the current evidence about screening tests for
pre-eclampsia? From Conde-Agudelo and co-workers
review,
1
it appears that several tests have acceptable
positive and negative likelihood ratios, in the range of
46. Although heterogeneous, results of doppler
screening of the uterine artery are encouraging. Doppler
should probably be part of any future prospective
evaluation, ideally during the rst trimester.
6
Similarly,
screening by serum levels of inhibin A provides higher
likelihood ratios than most other biochemical tests
alone.
1
Moreover, we have reported elevated levels of
inhibin A as early as 713 weeks gestation in women
who subsequently developed pre-eclampsia.
7
We agree
with Conde-Agudelo that, at present, there is no single
best screening test for pre-eclampsia. However, their
review provides an interesting overview of potential
candidates deserving further research.
What are the realistic expectations for pre-eclampsia
screening in the near future? Recent progress in
understanding of the disease process, combined with the
availability of powerful tools including proteomics and
metabolomics, will continue to provide promising new
markers. Consequently, the next important step in the
evaluation of screening tests for pre-eclampsia is to
assess the test properties of combinations of existing
tests.
8,9
For instance, combining doppler analysis of the
uterine artery, placental markers such as human chorionic
gonadotropin, inhibin A, pregnancy-associated plasma
protein A, and markers of endothelial or oxidative stress
could provide a comprehensive approach to the different
pathways of the disorder. If markers of a different nature
prove to be statistically independent in the prediction of
pre-eclampsia, their combination will improve the
screening strategy. An example of the successful
combination of screening tests of a different nature is
given by rst-trimester screening for Downs syndrome,
in which the addition of ultrasound to biochemical
markers has greatly improved the performance of
screening.
10
It is now time to start large prospective
studies evaluating multiple markers combining clinical,
biophysical, and biochemical tests for pre-eclampsia,
both in low-risk and high-risk populations.
Franois Audibert
Department of Obstetrics and Gynecology,
Hospital Sainte-Justine, Universit de Montreal, Montreal,
Qubec, Canada H3T 1C5
francois.audibert@umontreal.ca
I declare that I have no conict of interest.
1 Conde-Agudelo A, Villar J, Lindheimer M. World Health Organization
systematic review of screening tests for preeclampsia. Obstet Gynecol
2004; 104: 136791.
2 Dekker G, Sibai B. Primary, secondary, and tertiary prevention of
pre-eclampsia. Lancet 2001; 357: 20915.
3 Sibai BM. Prevention of preeclampsia: a big disappointment.
Am J Obstet Gynecol 1998; 179: 127578.
4 Chappell LC, Seed PT, Briley AL, et al. Effect of antioxidants on the
occurrence of pre-eclampsia in women at increased risk: a randomised
trial. Lancet 1999; 354: 81016.
5 Roberts JM, Cooper DW. Pathogenesis and genetics of pre-eclampsia.
Lancet 2001; 357: 5356.
6 Harrington K, Carpenter RG, Goldfrad C, Campbell S. Transvaginal Doppler
ultrasound of the uteroplacental circulation in the early prediction of pre-
eclampsia and intrauterine growth retardation. Br J Obstet Gynaecol 1997;
104: 67481.
1368 www.thelancet.com Vol 365 April 16, 2005
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Comment
www.thelancet.com Vol 365 April 16, 2005 1369
When a child presents to a medical provider with
suspicious bruising, one of the rst tasks is to nd out
whether the bruises are the result of abuse or merely a
side-effect of normal childhood activity. If an injury is
found to be a result of abuse, the next question will
invariably be a request about the age of the bruise.
These are the most frequent questions posed to
physicians evaluating maltreated children. How these
questions are answered can determine if a child is
removed from their home or if a parent or caregiver is
criminally prosecuted. The weight of the response
should be balanced by the knowledge of the science:
bruises are one of the most common manifestations of
child abuse. Bruises in active mobile children are very
common.
Recently, Sabine Maguire and colleagues summarised
the current literature about patterns of bruising and
ageing of bruises. In their rst article,
1
a review of the
literature on bruising in infants and children in general,
they describe their methods. When 6984 papers
spanning 53 years were reviewed, they found 23 papers
met their criteria for full analysis by 15 reviewers. Seven
papers addressed bruising in non-abused children while
two more discussed both abused and non-abused
children. No differences were noted between children
of various socioeconomic groups. Increased bruising
was noted as age and development advances, during
summer months, and with increased family size. Also,
lack of bruising in children not yet independently
mobile was noted. There was a strong correlation in
areas of bruising in non-abused children: forward, bony
prominences. Abusive bruises had a typical pattern and
distribution as bruises were seen on soft parts of the
body. Fourteen papers covered bruising in abused
children alone and two more discussed both abused
and non-abused children. The head was the most
common site for bruises in abused children.
The conclusions are clinically intuitive, but provide a
more empiric literature-based review that provides an
essential framework for any clinician attempting to
determine the cause of bruising. Jenny cautions that
the aging of bruises is an inexact process and that
soft tissue injury is extremely uncommon in younger
children and the distribution of bruises in abused and
non-abused children differed by development and
age.
2
Jenny and colleagues also noted that in infants,
bruising might be an ominous indicator of more
serious maltreatment, namely abusive head injury.
Indeed, when apparently minor bruising was
overlooked in a non-mobile infant, serious and even
fatal injury could follow.
3
Maguire and colleagues have done a comprehensive
review of the medical literature for evidence-based
medicine about bruising. Their ndings on patterns of
Bruising in children
7 Salomon LJ, Benattar C, Audibert F, et al. Severe preeclampsia is associated
with high inhibin A levels and normal leptin levels at 7 to 13 weeks into
pregnancy. Am J Obstet Gynecol 2003; 189: 151722.
8 Florio P, Reis FM, Pezzani I, Luisi S, Severi FM, Petraglia F. The addition of
activin A and inhibin A measurement to uterine artery Doppler
velocimetry to improve the early prediction of pre-eclampsia.
Ultrasound Obstet Gynecol 2003; 21: 16569.
9 Audibert F, Benchimol Y, Benattar C, Champagne C, Frydman R. Prediction
of preeclampsia or intrauterine growth restriction by second trimester
serum screening and uterine Doppler velocimetry. Fetal Diagn Ther 2005;
20: 4853.
10 Audibert F, Dommergues M, Benattar C, Taieb J, Thalabard JC, Frydman R.
Screening for Down syndrome using rst-trimester ultrasound and
second-trimester maternal serum markers in a low-risk population: a
prospective longitudinal study. Ultrasound Obstet Gynecol 2001; 18:
2631.