Clinical risk prediction for pre-eclampsia in nulliparous women: development of model in international prospective cohortBMJ 2011; 342 doi: https://doi.org/10.1136/bmj.d1875 (Published 07 April 2011) Cite this as: BMJ 2011;342:d1875
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We read with interest the article by North et al concerning an
international multicenter study of clinical risk prediction for
preeclampsia in healthy nulliparous women. The authors find a modest
ability to predict preeclampsia in nulliparous women using clinical
phenotype. They stress the prediction tool requires validation in other
populations and suggest it may be improved by adding biomarkers. Known
clinical risk factors for development of preeclampsia include chronic
hypertension, pregestational diabetes, multifetal gestation, and a
previous pregnancy complicated by preeclampsia. These women develop
preeclampsia at much higher rates, suggesting pre-existing vascular
dysfunction or increased trophoblast load contribute to risk of developing
preeclampsia. Although these risk factors identify a high risk population,
most are not applicable to nulliparous women and are associated with
preeclampsia in only 14% of nulliparas (1)
We have recently completed a multicenter RCT of antioxidant
supplementation to prevent preeclampsia in 10,154 nulliparous women (2)
that included a prospective observational study of clinical history and
biophysical and biochemical markers to predict preeclampsia. Previous
studies from this network have show systolic blood pressure at entry, pre-
pregnancy obesity, the number of previous abortions or miscarriages and
smoking history to be significantly associated with the development of
preeclampsia (3). In the current study mid-trimester insulin resistance
was associated with increased obesity and with the development of
preeclampsia (4). Hispanic and African American women, who develop
preeclampsia at an increased rate, had higher insulin resistance than
A question worth addressing is; Will the addition of biomarkers
substantially improve the predictive power of clinical risk assessment?
Many small cross-sectional studies and prospective studies involving women
of varying parity and risk levels have claimed that first trimester
markers of trophoblast invasion/placental function, pro- or anti-angiogenic markers, or second trimester Doppler ultrasound measurements
can be used to predict preeclampsia. Based on our experience and
observations, enthusiasm for very early biomarkers as independent
predictors is not warranted. It is not evident that these biomarkers have
sufficient sensitivity or specificity to be clinically useful for
predicting preeclampsia in healthy low risk nulliparous women when
employed either singly or in combination, especially in very early
pregnancy. One conclusion from this is that preeclampsia has several
underlying pathophysiologies that ultimately result in the clinical
syndrome. If this is the case, some biomarkers may predict only
particular subsets of preeclampsia. Alternatively, biomarkers selected
because of their appearance with established disease are likely
epiphenomena that do not reflect the root causes of preeclampsia and thus
are not relevant as predictors of subsequent clinical disease. It is also
likely that clinically useful markers may not be evident very early in
pregnancy as the unique features of preeclampsia may not yet exist We
therefore continue to struggle in clinical practice to predict
preeclampsia in healthy nulliparous women, the group that comprises the
majority of pregnancies in developed countries. We are hopeful that
clinical predictive rules, such as described by Dr. North and her
colleagues, combined with more clinically useful biomarkers developed
through increased understanding of the pathophysiology(ies) of
preeclampsia will assist in identification of risk in these women.
1. Myatt L, Miodovnik M. Prediction of preeclampsia. Semin Perinatol.
2. Roberts JM, Myatt L, Spong CY, Thom EA, Hauth JC, Leveno KJ, et al.
Vitamins C and E to prevent complications of pregnancy-associated
hypertension. N Engl J Med. 2010, 8;362(14):1282-91.
3. Sibai BM, Gordon T, Thom E, Caritis SN, Klebanoff M, McNellis D, et al.
Risk factors for preeclampsia in healthy nulliparous women: a prospective
multicenter study. The National Institute of Child Health and Human
Development Network of Maternal-Fetal Medicine Units. Am J Obstet Gynecol.
1995,172(2 Pt 1):642-8.
4. Hauth JC, Clifton RG, Roberts JM, Myatt L, Spong CY, Leveno KJ, et al.
Maternal insulin resistance and preeclampsia. Am J Obstet Gynecol.
Dept of Ob/Gyn,
University of Texas Health Science Center San Antonio,
James M Roberts
Magee-Womens Research Institute,
Competing interests: No competing interests
In relation to the study of North and colleagues (1) about risk clinical
factors for pre-eclampsia in nulliparous women, we agree that the proposed
model has a "modest" capacity for prediction. Once in a while, the
statistical methods used in research play us a mean trick and show results
on the contrary of common sense. That is when we consider cigarette
smoking and alcohol consumption as "protector" factors in association with
As strengthened by Professor Ricardo Gonzalez, tobacco and alcohol may
be considered to be drugs that are like wolves in sheep clothing with many negative implications for
people health, physics and psyche (2).
The harmful effects of tobacco use in pregnancy
are recognized (as much for mother as the fetus), in particular, placenta previa,
abruptio placentae, premature rupture of membranes, preterm birth,
intrauterine growth restriction and sudden infant death syndrome (3, 4).
Cigarette smoking is one of the most important and modifiable risk factors
associated with adverse perinatal outcomes.
Drinking alcohol during pregnancy may cause many health problems for
the mother and child: abruptio placentae and intrauterine growth
We recognize that risk prediction is very important to apply to
preventive and care actions for the main health problems affecting people, but we may
be careful when interpreting prediction models proposed by research.
Abel Quiala Rodriguez, MD
Angel Julio Romero Cabrera, MD, PhD.
1. North RA, McCowan LME, Dekker GA, Poston L, Chan EHY, Stewart AW
et al. Clinical risk prediction for pre-eclampsia in nulliparous women:
development of model in international prospective cohort. BMJ 2011;
2. Gonzalez R. Tobacco and alcohol. Drugs under lamb skin. Rev Cubana Med
Gen Integr 2007; 23(3): 20-6.
3. Andres RL. The association of cigarrette smoking with placenta previa
and abruptio placentae. Semin Perinatol 1996; 20(2): 154-9.
4. Andres RL, Day MC. Perinatal complications associated with maternal
tobacco use. Semin Neonatol 2000; 5(3): 231.41.
5. Du Toit MM, Smith M, Odendaal HJ. The role of prenatal alcohol exposure
in abruptio placentae. S Afr Med J 2010; 100(12): 832-5
Competing interests: No competing interests