Letters to editor

Calcium and linoleic acid supplements in the prevention of pre-eclampsia

Los suplementos de calcio y el ácido linoleico en la prevención de la preeclampsia

Leonelo E. Bautista

Department of Population Health Sciences, School of Medicine, University of Wisconsin at Madison, Madison, Wisconsin, United Estates

Corresponding author:
Department of Population Health Sciences, School of Medicine, University of Wisconsin at Madison, United States. 703 WARF 610 Walnut Street Madison, WI 53726.
E-mail: lebautista@wisc.edu

© 2016. Universidad del Valle. This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Dear Editor:

Alzate et al.¹, (http://www.ncbi.nlm.nih.gov/pmc/articles/ PMC4732504/) conducted a nested case-control study to (quote) “estimate the protective effect from calcium [supplement] alone [CC], compared to calcium plus conjugated linoleic acid [CC+CLA] in nulliparous women at risk of preeclampsia”. Based on a crude analysis of the data in Table 3,¹ they concluded that neither CC nor CC+CLA reduced the risk of preeclampsia in the whole sample, but that CC+CLA significantly decreased risk among women 13-18 years old. A quick look analysis of the data in this table shows this conclusion is mostly based on the fact that none of the cases in 13-18 year old women was treated with CC+CLA. Contrary to the authors’ interpretation, this does not point to a protective effect of CC+CLA, it simply indicates that the assumption of positivity has being violated and, consequently, that an effect for this age group cannot be estimated². In fact, the probability of getting no treated cases in this age-group was 28%, since only 15.5% of all women received CC+CLA. Also, accurate estimates of effect in women 34-45 years old were not possible, because there were only seven women who used CC+CLA in this age group. In spite of the limited sample size, the authors restricted their attention to the apparent protective effect of CC+CLA in 13-19 year old women, while ignoring apparent harmful effects in older women. I estimated age-specific rate ratios (RR) by fitting a saturated conditional complementary log-log³ to the data in Table 3 and found that CC+CLA was protective among women 13-19 (RR= 0.61, 95% CI: 0.41- 0.90), but harmful in women 19-34 (RR= 1.74, 95% CI: 1.21- 2.50) and 35-45 years old (RR= 4.98, 95% CI= 1.74-14.30). Of course, this approach is an improvement over a naive crude analysis, but does not solve the problem of violation and near violation of positivity described above. An overall age-adjusted RR was 1.02 (95% CI= 0.89-1.17; p= 0.756). Thus, this study provides no evidence of a beneficial effect of CC+CLA in preventing preeclampsia in any age group.

On the other hand, the authors neglected to explain why the total number of women is 2,703 in Table 3 and 1,441 in Figure 1 and Table 2¹. More important, it is surprising that they restricted their attention to the age-specific effects of CC+CLA, which were obviously unidentifiable, while ignoring the obvious age-related decrease in the effect of CC shown in Table 3: odds ratios of 1.3, 0.9, and 0.4 in 13-18, 19-34, and 35-45 years old, respectively. In fact, corresponding agespecific RR from a clog-log model with a treatment-by-age interaction (p= 0.069) were 1.44 (95% CI= 0.85-2.44), 0.92 (95% CI= 0.73-1.16), and 0.59 (95% CI= 0.34-1.01). This pattern could have resulted not from an effect of CC, but from CC being more frequently prescribed to younger women, who have a higher risk of preeclampsia. This selective use of treatment leads to confounding by indication, a wellrecognized limitation of observational studies of the effectiveness of therapeutic interventions⁴. Unfortunately, the authors made no attempt to address this type of bias, since they disregarded any clinical factor, such as blood pressure, that could increase the likelihood of both treatment with calcium supplements and risk of preeclampsia.

Moreover, the author’s claim that the beneficial effects of CC+CLA were greater than those of CC is not supported by the data. First, one treatment could not be better than the other because neither of them decreased the risk of preeclampsia. Second, no formal comparison of the two treatments was made. I tested this hypothesis by fitting a saturated clog-log model to the data (Table 3, n= 2,703) and found that none of the treatments decreased the risk of preeclampsia, and that CC (RR= 0.89) seemed more protective than CC+CLA (RR= 1.01), but not significantly so (p= 0.60). Of course, the authors’ findings as well as those from my analyses are likely biased, due to the lack of adjustment for confounding factors. Basically, these findings are of no use for clinical or policy decision making.

In spite of very large trials showing no clinical benefits^5,6, calcium supplements are still widely offered to women at high risk of preeclampsia in developing countries⁷. Maybe it is time to reevaluate their usefulness to prevent preeclampsia by looking again at the existing data. But this time with the clear purpose of avoiding confirmation bias⁸ and keeping in mind, as Feynman argued, that “the first principle [of science] is that you must not fool yourself—and [yet] you are the easiest person to fool”⁹.

Conflicts of interest:
I have no conflict of interest to declare.

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References

1. Alzate A, Herrera R, Pineda LM. Preeclampsia prevention: a case-control study nested in a cohort. Colomb Med (Cali). 2015; 46(4): 156-61.         [ Links ]

2. Petersen ML, Porter KE, Gruber S, Wang Y, van der Laan MJ. Diagnosing and responding to violations in the positivity assumption. Statist Meth Med Res. 2012; 21(1): 31-54.         [ Links ]

3. Martuzzi M, Elliott P. Estimating the incidence rate ratio in crosssectional studies using a simple alternative to logistic regression. Ann Epidemiol. 1998; 8(1): 52-5.         [ Links ]

4. Danaei G, Rodríguez LAG, Cantero OFN, Logan R, Hernán MA.Observational data for comparative effectiveness research: An emulationof randomised trials of statins and primary prevention of coronary heartdisease. Statist Meth Med Res. 2013; 22(1):70-96.         [ Links ]

5. Villar J, Abdel-Aleem H, Merialdi M, Mathai M, Ali MM, Zavaleta N, et al. World Health Organization randomized trial of calcium supplementation among low calcium intake pregnant women. Am J Obstet Gynecol. 2006; 194(3): 639-49.         [ Links ]

6. Levine RJ, Hauth JC, Curet LB, Sibai BM, Catalano PM, Morris CD, et al. Trial of calcium to prevent preeclampsia. New England J Med. 1997; 337(2): 69-77.         [ Links ]

7. Firoz T, Sanghvi H, Merialdi M, von Dadelszen P. Pre-eclampsia in low and middle income countries. Best Practice Res Clin Obstet Gynaecol. 2011; 25(4):537-48.         [ Links ]

8. Nickerson RS. Confirmation bias: A ubiquitous phenomenon in many guises. Rev Gen Psychol. 1998; 2(2): 175-220.         [ Links ]

9. Feynman RP. Some remarks on science, pseudoscience, and learning how to not fool yourself. Caltech’s 1974 commencement address. Available from: http://calteches.library.caltech.edu/51/2/CargoCult.htm. Accessed: 22 February 2016.         [ Links ]