Hypertension in Pregnancy, 2014; 33(3): 311–321 ! Informa Healthcare USA, Inc. ISSN: 1064-1955 print / 1525-6065 online DOI: 10.3109/10641955.2013.877925
ORIGINAL ARTICLE
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Calcium level during the first trimester of pregnancy as a predictor of preeclampsia Aviezer Gabbay,1* Tamar Tzur,1* Adi Y. Weintraub,1 Ilana Shoham-Vardi,2 Ruslan Sergienko,2 and Eyal Sheiner1 1
Department of Obstetrics & Gynecology, Department of Epidemiology and Health Services Evaluation, Faculty of Health Sciences, Soroka University Medical Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel
2
Objective: To examine the association between calcium levels during the first trimester of pregnancy and preeclampsia. Methods: The study population included registered births (n = 5233) in a tertiary medical center between 2001 and 2011. A comparison was performed between women with and without hypocalcemia during the first trimester of pregnancy. A second analysis was performed after correcting calcium levels for albumin. Multiple logistic regression models were used to control for confounders. Receiver operating characteristic curve analysis graphs were used to describe the relationship between the true-positive rate (sensitivity) and the false-positive rate for different values of calcium during the first half of pregnancy in the prediction of preeclampsia. Results: Of 5233 deliveries, 841 (16%) had hypocalcemia and 4392 (84%) had a normal calcium level. No significant difference were found between the groups regarding mild preeclampsia [odds ratio (OR) = 1.216; 95% confidence interval (CI) 0.831–1.779; p = 0.312], severe preeclampsia (OR = 1.618; 95% CI 0.919–2.849; p = 0.092) and any hypertensive disorders (OR = 1.324; 95% CI 0.963–1.821; p = 0.083). Conclusions: Hypocalcemia during the first trimester of pregnancy is not a risk factor for preeclampsia. Keywords Calcium, Hypocalcemia, Preeclampsia, Hypertensive disorders.
BACKGROUND Preeclampsia complicates 2–8% of pregnancies and greatly contributes to maternal and perinatal morbidity and mortality worldwide (1). Unique to human pregnancy, preeclampsia is a multisystem disorder of unknown precise etiology. It is characterized by an abnormal vascular response to placentation and is associated with increased systemic vascular resistance, enhanced
*These authors contributed equally to this work. Correspondence: Tamar Tzur, MD, Department of Obstetrics & Gynecology, Faculty of Health Sciences, Soroka University Medical Center, Ben-Gurion University of the Negev, P.O. Box 151, Be’er-Sheva, Israel. Tel: +972-8-640-3902. Fax: +972-8-640-3102. E-mail: [email protected]
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platelet aggregation, activation of the coagulation system and endothelial cell dysfunction. The clinical findings of preeclampsia can manifest in a variety of ways. The disorder is heterogeneous; hence, pathogenesis and clinical findings can differ in women with varying risk factors (2). There is a constant search for markers that will enable identification during the early stage of pregnancy in women at risk to develop preeclampsia later on. A number of recognized markers were investigated for this purpose, among them, vascular endothelial growth factor (VEGF) and its soluble receptor (sFlt-1). However, these markers have low specificity and sensitivity and appeared to predict preeclampsia only a few weeks before the onset of clinical symptoms (3). Currently, women at risk are identified on the basis of epidemiological and clinical risk factors, but the diagnostic criteria of preeclampsia remain variable, with no precise biomarker. Treatment remains good prenatal care, timely diagnosis, proper management and judicious delivery (4). As a normal pregnancy progresses, there is a decrease in overall level of calcium in the maternal blood due to a dilutional drop in albumin concentration, and because of the high consumption of calcium by the fetus in the course of its development (5). The concentration of calcium in the serum must be maintained within a narrow range because of the critical role it plays in a wide array of cellular functions, especially those involved in neuromuscular activity, secretion and signal transduction (6). Calcium reduces smooth muscle contractility and vasoconstriction mainly by its effect on the parathyroid and intracellular calcium. It may also have an indirect effect on smooth muscle function by increasing magnesium levels (7). Research published during the 1980s found an inverse ratio between levels of calcium consumption and eclampsia among women from Guatemala (8). Subsequently, a number of researchers have investigated whether calcium supplementation affects the incidence and severity of preeclampsia. Extensive research conducted in 1997 disregarded any link between calcium supplementation and the incidence of preeclampsia (9). Likewise, a recent randomized, placebo-controlled trail did not show any benefit of calcium supplementation to Gambian women accustomed to a low calcium intake (10). On the other hand, a cochrane review that examined the same question did, indeed, conclude that calcium supplementation appears to approximately halve the risk of preeclampia (11). In addition, Villar et al. (12) found that calcium supplements did not prevent preeclampsia when taken by women with a low calcium intake, but did significantly decrease the risk of its more serious complications, including maternal and neonatal morbidity and mortality and decreased the rates of preterm delivery. Carroly et al. (13) showed calcium supplements to have an effect on uteroplacental blood flow by reducing resistance in the uterine and umbilical arteries. According to the published research, controversy exists regarding the role of calcium intake and maternal serum calcium concentration on the risk of preeclampsia. This study aimed to examine the association between low serum calcium levels during the first half of pregnancy and the development of preeclampsia and other pregnancy complications in the second half of the pregnancy.
Hypocalcemia is not a predictor of preeclampsia
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METHODS A retrospective population-based study was conducted in order to examine whether low calcium level in the first trimester of pregnancy is associated with a high prevalence of obstetric complications and adverse perinatal outcomes, especially hypertensive disorders. The study was approved by the ethic committee of our institute. The study population included all registered births in our institute between 2001 and 2011. The data came from the computerized medical files of each birth, which included information about the course of pregnancy and delivery. Patients that had no available calcium test from the first trimester of pregnancy and patients with multiple gestations were excluded from the study. Each pregnant woman was placed in one of the following categories according to the results of her serum calcium test: Normal (8.8–10.6 mg/dl), low (58.8 mg/dl). The institutional computerized birth database was combined with the laboratory database. When multiple measurements of calcium per woman were available for the first trimester, the lowest value was extracted from the laboratory data. Preeclampsia was defined by a new onset of hypertension and proteinuria after 20 weeks of gestation in a previously normotensive woman and eclampsia defined as the development of grand mal seizures in a woman with gestational hypertension or preeclampsia. The hypertensive disorders were divided as follows: mild preeclampsia, severe preeclampsia and any hypertensive disorder (mild preeclampsia, severe preeclampsia and eclampsia). The control group comprised subjects with no hypertensive disorders. The distinction between mild and severe preeclampsia was made according to the recommendations of American College of Obstetricians and Gynecologists (14). The following demographic and clinical characteristics were collected and examined for each delivery: ethnicity (Jewish/Bedouin), maternal age, gestational age at delivery, gravidity, parity and recurrent pregnancy loss. The following obstetrical characteristics were collected and assessed: mild preeclampsia, severe preeclampsia, any hypertensive disorders, cesarean section, polyhydramnios, oligohydramnios, placental abruption, intra-uterine growth restriction (IUGR), preterm labor 537 weeks, preterm labor 534 weeks and postpartum hemorrhage. The following perinatal outcomes were assessed: fetal gender, small for gestational, Apgar 57 at 1 min, Apgar 57 at 5 min, birth weight 52500 g, birth weight 51500 g, macrosomia and perinatal mortality. Statistical analysis was performed using the SPSS (Chicago, IL). Statistical significance was calculated using Student 2 test for differences in qualitative variables, and Student t-test for differences in continuous variables. The statistical analysis was assessed once again for serum calcium levels corrected to albumin according to a widespread commonly used algorithm (6). Multivariate logistic regression models, with backward elimination, were constructed to demonstrate whether corrected low calcium levels are an independent risk factor for the development of mild or severe preeclampsia and for any hypertensive disorders. Odds ratios (ORs) and their 95% confidence intervals (CIs) were calculated. p Value 50.05 was considered statistically significant. Receiver operating characteristic (ROC) curve analysis was used to describe
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the relationship between the sensitivity (true-positive rate) and the falsepositive rate for the calcium level and the prediction of preeclampsia. It is noteworthy that a test with perfect discrimination has an ROC curve that passes through the upper left corner (100% sensitivity and 100% specificity). The area under the curve (AUC) was calculated to provide a summary of the diagnostic accuracy of the criterion. p Value50.05 was considered statistically significant.
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RESULTS The study population included 111,593 deliveries, of which 5249 (4.7%) had serum calcium levels measured during the first trimester of pregnancy. Of the final study group, 16% (841) had low serum calcium levels and 84% (4392) had normal levels. A comparison of the demographic and clinical characteristics between the two study groups is presented in Table 1. The mean maternal age of the entire study population was 28.46 ± 5.01 years with no significant difference between the hypocalcemic and normocalcemic groups (p = 0.309). Women with hypocalcemia during the first trimester were significantly more likely to be grandmultiparous Bedouin parturients. There was no significant difference between the groups for gestational age at delivery (p = 0.951). Table 2 presents a comparison of obstetric characteristics between the study groups. There was no significant difference between the study groups regarding mild preeclampsia (p = 0.312), severe preeclampsia (p = 0.092) and any hypertensive disorders (p = 0.083). There were significantly higher rates of placental abruption (OR = 2.049; 95% CI 1.100–3.816; p = 0.021) among women with hypocalcemia during the first trimester. Table 1. Demographic and clinical characteristics of patients with and without low serum calcium levels during the first half of pregnancy.
Ethnicity Jewish Bedouin Maternal age (years) Gestational age (wk ± SD) Gravidity 1 2–4 5 Parity 1 2–4 5 Smoking Obesity
Calcium 48.8 mg/dl (n = 841)
Calcium 8.8–10.6 mg/dl (n = 4392)
513 (61.0) 328 (39.0) 30.47 ± 5.824 38.56 ± 2.516
3227 (73.5) 1165 (26.5) 30.25 ± 5.535 38.56 ± 2.411
142 (16.9) 427 (50.8) 272 (32.3)
985 (22.4) 2395 (54.6) 1010 (23)
186 (22.1) 457 (54.3) 198 (23.5) 18 (2.1) 3 (0.4)
1272 (29) 2461 (56) 658 (15) 83 (1.9) 42 (1)
OR (95% CI)
p Value
0.564 (0.484–0.658)
50.001
0.309 0.951 50.001
50.001
1.135 (0.678–1.901) 0.37 (0.114–1.199)
0.629 0.084
Values are expressed as n (%), unless otherwise specified. PROM, pre-labor rupture of membranes; IUGR, intrauterine growth restriction; PPH, post-partum hemorrhage.
Hypocalcemia is not a predictor of preeclampsia Table 2. Obstetrical characteristics of patients with and without low serum calcium levels during the first half of pregnancy.
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Calcium 48.8 mg/dl (n = 841) Mild preeclampsia Severe preeclampsia Total hypertensive disorders Caesarean section Recurrent pregnancy loss Polyhydramnios Oligohydramnios Placental abruption PROM IUGR PPH Preterm labor 537 weeks Preterm labor 534 weeks
34 16 50 196 63 26 28 14 63 26 7 96 32
(4) (1.9) (5.9) (23.3) (7.4) (3.1) (3.3) (1.7) (7.5) (3.1) (0.8) (11.4) (3.8)
Calcium 8.8–10.6 mg/dl (n = 4392) 147 52 200 921 278 119 113 36 531 122 39 427 128
(3.3) (1.2) (4.6) (21) (6.3) (2.7) (2.6) (0.8) (12.1) (2.8) (0.9) (9.7) (2.9)
OR (95% CI) 1.216 1.618 1.324 1.145 1.177 1.145 1.303 2.049 0.588 1.116 0.937 1.196 1.317
(0.831–1.779) (0.919–2.849) (0.963–1.821) (0.96–1.364) (0.88–1.567) (0.744–1.763) (0.856–1.984) (1.100–3.816) (0.448–0.772) (0.726–1.715) (0.417–2.10) (0.946–1.512) (0.888–1.956)
p Value 0.312 0.092 0.083 0.13 0.261 0.536 0.215 0.021 50.001 0.615 0.874 0.134 0.169
Values are expressed as n (%), unless otherwise specified. PROM, pre-labor rupture of membranes; IUGR, intrauterine growth restriction; PPH, post-partum hemorrhage.
Table 3. Comparison of neonatal outcomes between the groups. Calcium Calcium 48.8 mg/dl 8.8–10.6 mg/dl (n = 841) (n = 4392) Gender Male Female SGA Low Apgar 1 min (57) Low Apgar 5 min (57) Low birth weight 52500 g Very low birth weight 51500 g Macrosomia (weight 44000 g) Perinatal mortality
430 411 33 53 21 85 18 44 11
(51.1) (48.9) (3.9) (6.3) (2.5) (10.1) (2.1) (5.2) (1.3)
2159 2233 171 278 106 412 75 203 62
(49.2) (50.8) (3.9) (6.3) (2.4) (9.4) (1.7) (4.6) (1.4)
OR (95% CI)
p Value
1.082 (0.933–1.254)
0.295
1.008 1.005 1.035 1.085 1.259 1.138 0.925
0.967 0.976 0.885 0.510 0.384 0.445 0.814
(0.689–1.474) (0.734–1.347) (0.644–1.663) (0.848–1.388) (0.748–2.118) (0.814–1.592) (0.485–1.763)
Values are expressed as n (%), unless otherwise specified. SGA, small for gestational age.
No significant differences regarding neonatal outcomes were found between the study groups (Table 3). ROC curve analysis of the relationship between calcium level during the first trimester and mild and severe preeclampsia is shown in Figure 1. No significant association was noted between serum calcium levels during the first half of pregnancy, and the risk of mild (Figure 1A) or severe (Figure 1B) preeclampsia. AUC for serum calcium level was low and the graph was flat and far from the upper left corner for both mild preeclampsia (AUC = 0.466; SE = 0.022, 95% CI 0.424–0.508, p = 0.117) and severe preeclampsia (AUC = 0.492; SE = 0.038, 95% CI 0.418–0.566, p = 0.821).
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Figure 1. ROC curve analysis – relationship between uncorrected calcium level during the first trimester, and (A) mild preeclampsia; (B) severe preeclampsia.
A second analysis was performed after correcting calcium levels for albumin. There was no significant difference between the study groups regarding all obstetrical complications that were examined, including mild preeclampsia (p = 0.999), severe preeclampsia (p = 0.168) and any hypertensive disorders (p = 0.452) (Table 4). ROC analysis of the relationship between corrected serum calcium levels during the first trimester and mild and severe preeclampsia is shown in Figure 2. No significant association was noted between corrected serum calcium levels during the first trimester of pregnancy, and the risk of mild (Figure 2A) or severe (Figure 2B) preeclampsia. AUC for serum calcium level
Hypocalcemia is not a predictor of preeclampsia Table 4. Obstetrical characteristics of the study population, corrected to albumin.
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Calcium 48.8 mg/dl (n = 609) Mild preeclampsia Severe preeclampsia Total hypertensive disorders Cesarean section PPD Recurrent pregnancy loss Polyhydramnion Oligohydramnion Placental abruption PROM IUGR PPH Preterm labor 537 weeks Preterm labor 534 weeks
23 13 36 140 2 45 95 196 11 46 17 5 65 22
(3.8) (2.1) (5.9) (23.0) (0.3) (7.4) (15.6) (32.2) (1.8) (7.6) (2.8) (0.8) (10.7) (3.6)
Calcium 8.8–10.6 mg/dl (n = 2753) 104 38 142 592 19 198 408 912 26 312 84 24 300 94
(3.8) (1.4) (5.2) (21.5) (0.7) (7.2) (14.8) (33.1) (0.9) (11.3) (3.1) (0.9) (10.9) (3.4)
OR (95% CI) 1.00 1.55 1.15 1.08 0.47 1.02 1.06 0.95 1.93 0.63 0.91 1.88 0.97 1.06
(0.63–1.58) (0.82–2.94) (0.79–1.68) (0.88–1.34) (0.11–2.04) (0.73–1.44) (0.83–1.35) (0.79–1.15) (0.94–3.92) (0.46–0.88) (0.53–1.54) (0.35–2.47) (0.73–1.29) (0.66–1.70)
p Value 0.999 0.168 0.452 0.422 0.305 0.865 0.626 0.654 0.065 0.006 0.734 0.902 0.872 0.809
Values are expressed as n (%), unless otherwise specified. PROM, pre-labor rupture of membranes; IUGR, intrauterine growth restriction; PPD, post-partum death; PPH, post-partum hemorrhage.
was low and the graph was flat and far from the upper left corner for both mild preeclampsia (AUC = 0.483; SE = 0.026, 95% CI 0.432–0.534, p = 0.519) and severe preeclampsia (AUC = 0.516; SE = 0.044, 95% CI 0.429–0.603, p = 0.697). Multiple logistic regression models were used to control for the confounders such as maternal age, ethnicity (Jewish or Bedouin), gravidity, diabetes mellitus, obesity and chronic hypertension. No significant difference was found between the groups regarding mild preeclampsia (OR = 0.9; 95% CI 0.56–1.44; p = 0.663), severe preeclampsia (OR = 0.6; 95% CI 0.32–1.21; p = 0.162) and any hypertensive disorders (OR = 0.8; 95% CI 0.54–1.17; p = 0.238).
DISCUSSION In this study we evaluated the level of corrected calcium during the first trimester of pregnancy as a marker for the development of preeclampsia in the later course of pregnancy. Thereby, we were hoping to find a marker that is generally available and can easily be used in everyday practice for the prediction of preeclampsia. The main finding of our study is that there was no significant correlation between serum calcium levels during the first trimester of pregnancy and mild preeclampsia, severe preeclampsia or any hypertensive disorders. This lack of correlation was demonstrated in both single-variable processing (corrected and uncorrected to albumin) and multivariable analysis. In addition, ROC curve analysis showed that calcium levels in maternal serum during the first trimester of pregnancy cannot predict the development of mild or severe preeclampsia during the second half of pregnancy.
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Figure 2. ROC curve analysis – relationship between corrected calcium level during the first trimester and (A) mild preeclampsia; (B) severe preeclampsia.
Higher levels of calcium cause reduced secretion of the parathyroid hormone into the blood as well as reduced levels of intracellular calcium in smooth muscles in blood vessels and the uterus. This process causes a reduction in the resistance of blood vessels and, thus, a reduction in blood pressure. It also reduces uterine contractility and consequently, the risk of preterm labor (15). This study did not find an association between low calcium levels and increased preeclamptic morbidity and therefore does not support these suggested pathophysiological explanations. The major report that found an association between administering calcium supplements and preeclamptic morbidity is a meta-analysis summarizing 13 studies (11), six of which reported an association, whereas in the other seven no association was found.
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Hypocalcemia is not a predictor of preeclampsia
The meta-analysis included a total of 15,730 subjects, and found that the OR for preeclampsia following the use of calcium supplements is 0.45 (95% CI 0.31–0.65). The meta-analysis was limited by different definitions of the exposure. In contrast, this study is a cohort study that accurately sampled exposure according to laboratory data. In addition, while the previously mentioned study of the association between consumption of calcium supplements and rates of preeclampsia (11) examined exposure during the second and even third trimesters of pregnancy, in our study serum calcium levels during the first half of pregnancy were assessed and no significant association was found between them and rates of preeclampsia. It could be assumed that taking calcium supplements would increase blood calcium levels. Therefore, the findings of the present study concur with previous research (9,10), which found no significant correlation between consumption of calcium supplements and reduced incidence of preeclampsia. On the other hand, Villar et al. (12) suggested that the prevalence of preeclampsia can be significantly reduced by administering calcium supplements, especially among women whose diet contains little calcium. Moreover, they (12) found that preeclampsia was less severe in women who consumed oral calcium supplements. Yet, their study did not examine calcium levels as predictors of preeclampsia. The single-variable model showed that Bedouin Arab women are at greater risk of hypocalcemia. This could be at least partly explained by the fact that their traditional manner of dress reduces their exposure to sunlight, leading to a lower level of activated vitamin D (16), and thus to a lowered level of serum calcium. Nevertheless, a low calcium level does not necessarily indicate a low vitamin D level and vice versa, and in our study we did not control for vitamin D levels (a known risk factor for preeclampsia) (17). The univariate analysis showed significantly higher rates of placental abruption (OR = 2.049; 95% CI 1.100–3.816; p = 0.021) among women with hypocalcemia during the first trimester. The association between hypocalcemia and placental abruption was not described before and further investigation is needed. There is a common pathophysiology pathway to preeclampsia and placental abruption. They are both a consequence of inadequate placentation, but the clinical expression is different (18). However, after correcting calcium levels for albumin, there was no significant difference between the study groups (p = 0.065). The advantages of this study are the use of two combined and reliable databases that made it possible to obtain laboratory data regarding levels of calcium during the first half of pregnancy. This comprehensive database provided access to detailed information regarding the pregnancies studied. However, our study has several inherent weaknesses, mostly due to its retrospective design, such as the potential for missing data. Nevertheless, data were reported by an obstetrician directly after delivery and skilled medical secretaries routinely reviewed the information prior to entering it into the database, thereby minimizing recall bias. Coding was done after assessing the medical prenatal care records together with the routine hospital documents. Despite all of the above, as well as the fact that women who lacked prenatal care were excluded from the study, there is a likelihood of indication bias in the current study, due to differences in severe preeclampsia morbidity
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between women who were tested for calcium and albumin levels during the first half of pregnancy and women who were not tested. In conclusion, this retrospective cohort study reveals that low serum calcium concentration during the first half of pregnancy is not a risk factor for preeclampsia. Therefore, a blood test for calcium serum levels cannot be a predictor of preeclampsia later in pregnancy.
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DECLARATION OF INTEREST The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this paper.
REFERENCES 1. Duley L. The global impact of pre-eclampsia and eclampsia. Semin Perinatol 2009; 33:130–7. 2. Sibai B, Dekker G, Kupferminc M. Pre-eclampsia. Lancet 2005;365:785–99. 3. Duckitt K, Harrington D. Risk factors for pre-eclampsia at antenatal booking: systematic review of controlled studies. BMJ 2005;330:565. 4. Thangaratinam S, Langenveld J, Mol BW, Khan KS. Prediction and primary prevention of pre-eclampsia. Best Pract Res Clin Obstet Gynaecol 2011;25:419–33. 5. Cunningham FG, Leveno KJ, Bloom SL, et al. Williams obstetrics. 23rd ed. New York: McGraw-Hill Professional Publishing; 2010. 6. Longo DL, Fauci AS, Kasper DL, et al. Harrison’s principles of internal medicine. 18th ed. New York: McGraw-Hill Medical; 2012. 7. Repke J, Villar J, Bergel E, Belizan JM. The effect of iron absorption in patients receiving calcium supplementation. 9th Annual Meeting of the Society of Perinatal Obstetricians; 1989; New Orleans, Louisiana, USA. 512 p. 8. Belizan JM, Villar J. The relationship between calcium intake and edema, proteinuria, and hypertension-gestosis: an hypothesis. Am J Clin Nutr 1980;33: 2202–10. 9. Levine RJ, Hauth JC, Curet LB, et al. Trial of calcium to prevent preeclampsia. N Engl J Med 1997;337:69–77. 10. Goldberg GR, Jarjou LM, Cole TJ, Prentice A. Randomized, placebo-controlled, calcium supplementation trial in pregnant Gambian women accustomed to a low calcium intake: effects on maternal blood pressure and infant growth. Am J Clin Nutr 2013;98:972–82. ´ N, Duley L. Calcium supplementation during 11. Hofmeyr GJ, Lawrie TA, Atallah A pregnancy for preventing hypertensive disorders and related problems. Cochrane Database Syst Rev 2010;(8):CD001059. 12. Villar J, Abdel-Aleem H, Merialdi M, et al. World Health Organization randomized trial of calcium supplementation among low calcium intake pregnant women. Obstet Gynecol 2006;194:639–49. 13. Carroli G, Merialdi M, Wojdyla D, et al. Effects of calcium supplementation on uteroplacental and fetoplacental blood flow in low-calcium-intake mothers: a randomized controlled trial. Am J Obstet Gynecol 2010;202:45.e1–9. 14. ACOG, Committee on Obstetric Practice. Practice bulletin# 33: diagnosis and management of preeclampsia and eclampsia. Obstet Gynecol 2002;99:159–67. 15. Villar J, Belizan JM, Repke J. The effect of calcium supplementation on the incidence of hypertensive disorders of pregnancy and prematurity. 7th World Congress of Hypertension in Pregnancy; 1990; Perugia, Italy. 54 p. 16. Narchi H, El Jamil M, Kulaylat N. Symptomatic rickets in adolescence. Arch Dis Child 2001;84:501–3.
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17. Tabesh M, Salehi-Abargouei A, Tabesh M, Esmaillzadeh A. Maternal vitamin D status and risk of pre-eclampsia: a systematic review and meta-analysis. J Clin Endocrinol Metab 2013;98:3165–73. 18. Ananth CV, Oyelese Y, Prasad V, et al. Evidence of placental abruption as a chronic process: associations with vaginal bleeding early in pregnancy and placental lesions. Eur J Obstet Gynecol Reprod Biol 2006;128:15–21.
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ORIGINAL ARTICLE
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Calcium level during the first trimester of pregnancy as a predictor of preeclampsia Aviezer Gabbay,1* Tamar Tzur,1* Adi Y. Weintraub,1 Ilana Shoham-Vardi,2 Ruslan Sergienko,2 and Eyal Sheiner1 1
Department of Obstetrics & Gynecology, Department of Epidemiology and Health Services Evaluation, Faculty of Health Sciences, Soroka University Medical Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel
2
Objective: To examine the association between calcium levels during the first trimester of pregnancy and preeclampsia. Methods: The study population included registered births (n = 5233) in a tertiary medical center between 2001 and 2011. A comparison was performed between women with and without hypocalcemia during the first trimester of pregnancy. A second analysis was performed after correcting calcium levels for albumin. Multiple logistic regression models were used to control for confounders. Receiver operating characteristic curve analysis graphs were used to describe the relationship between the true-positive rate (sensitivity) and the false-positive rate for different values of calcium during the first half of pregnancy in the prediction of preeclampsia. Results: Of 5233 deliveries, 841 (16%) had hypocalcemia and 4392 (84%) had a normal calcium level. No significant difference were found between the groups regarding mild preeclampsia [odds ratio (OR) = 1.216; 95% confidence interval (CI) 0.831–1.779; p = 0.312], severe preeclampsia (OR = 1.618; 95% CI 0.919–2.849; p = 0.092) and any hypertensive disorders (OR = 1.324; 95% CI 0.963–1.821; p = 0.083). Conclusions: Hypocalcemia during the first trimester of pregnancy is not a risk factor for preeclampsia. Keywords Calcium, Hypocalcemia, Preeclampsia, Hypertensive disorders.
BACKGROUND Preeclampsia complicates 2–8% of pregnancies and greatly contributes to maternal and perinatal morbidity and mortality worldwide (1). Unique to human pregnancy, preeclampsia is a multisystem disorder of unknown precise etiology. It is characterized by an abnormal vascular response to placentation and is associated with increased systemic vascular resistance, enhanced
*These authors contributed equally to this work. Correspondence: Tamar Tzur, MD, Department of Obstetrics & Gynecology, Faculty of Health Sciences, Soroka University Medical Center, Ben-Gurion University of the Negev, P.O. Box 151, Be’er-Sheva, Israel. Tel: +972-8-640-3902. Fax: +972-8-640-3102. E-mail: [email protected]
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platelet aggregation, activation of the coagulation system and endothelial cell dysfunction. The clinical findings of preeclampsia can manifest in a variety of ways. The disorder is heterogeneous; hence, pathogenesis and clinical findings can differ in women with varying risk factors (2). There is a constant search for markers that will enable identification during the early stage of pregnancy in women at risk to develop preeclampsia later on. A number of recognized markers were investigated for this purpose, among them, vascular endothelial growth factor (VEGF) and its soluble receptor (sFlt-1). However, these markers have low specificity and sensitivity and appeared to predict preeclampsia only a few weeks before the onset of clinical symptoms (3). Currently, women at risk are identified on the basis of epidemiological and clinical risk factors, but the diagnostic criteria of preeclampsia remain variable, with no precise biomarker. Treatment remains good prenatal care, timely diagnosis, proper management and judicious delivery (4). As a normal pregnancy progresses, there is a decrease in overall level of calcium in the maternal blood due to a dilutional drop in albumin concentration, and because of the high consumption of calcium by the fetus in the course of its development (5). The concentration of calcium in the serum must be maintained within a narrow range because of the critical role it plays in a wide array of cellular functions, especially those involved in neuromuscular activity, secretion and signal transduction (6). Calcium reduces smooth muscle contractility and vasoconstriction mainly by its effect on the parathyroid and intracellular calcium. It may also have an indirect effect on smooth muscle function by increasing magnesium levels (7). Research published during the 1980s found an inverse ratio between levels of calcium consumption and eclampsia among women from Guatemala (8). Subsequently, a number of researchers have investigated whether calcium supplementation affects the incidence and severity of preeclampsia. Extensive research conducted in 1997 disregarded any link between calcium supplementation and the incidence of preeclampsia (9). Likewise, a recent randomized, placebo-controlled trail did not show any benefit of calcium supplementation to Gambian women accustomed to a low calcium intake (10). On the other hand, a cochrane review that examined the same question did, indeed, conclude that calcium supplementation appears to approximately halve the risk of preeclampia (11). In addition, Villar et al. (12) found that calcium supplements did not prevent preeclampsia when taken by women with a low calcium intake, but did significantly decrease the risk of its more serious complications, including maternal and neonatal morbidity and mortality and decreased the rates of preterm delivery. Carroly et al. (13) showed calcium supplements to have an effect on uteroplacental blood flow by reducing resistance in the uterine and umbilical arteries. According to the published research, controversy exists regarding the role of calcium intake and maternal serum calcium concentration on the risk of preeclampsia. This study aimed to examine the association between low serum calcium levels during the first half of pregnancy and the development of preeclampsia and other pregnancy complications in the second half of the pregnancy.
Hypocalcemia is not a predictor of preeclampsia
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METHODS A retrospective population-based study was conducted in order to examine whether low calcium level in the first trimester of pregnancy is associated with a high prevalence of obstetric complications and adverse perinatal outcomes, especially hypertensive disorders. The study was approved by the ethic committee of our institute. The study population included all registered births in our institute between 2001 and 2011. The data came from the computerized medical files of each birth, which included information about the course of pregnancy and delivery. Patients that had no available calcium test from the first trimester of pregnancy and patients with multiple gestations were excluded from the study. Each pregnant woman was placed in one of the following categories according to the results of her serum calcium test: Normal (8.8–10.6 mg/dl), low (58.8 mg/dl). The institutional computerized birth database was combined with the laboratory database. When multiple measurements of calcium per woman were available for the first trimester, the lowest value was extracted from the laboratory data. Preeclampsia was defined by a new onset of hypertension and proteinuria after 20 weeks of gestation in a previously normotensive woman and eclampsia defined as the development of grand mal seizures in a woman with gestational hypertension or preeclampsia. The hypertensive disorders were divided as follows: mild preeclampsia, severe preeclampsia and any hypertensive disorder (mild preeclampsia, severe preeclampsia and eclampsia). The control group comprised subjects with no hypertensive disorders. The distinction between mild and severe preeclampsia was made according to the recommendations of American College of Obstetricians and Gynecologists (14). The following demographic and clinical characteristics were collected and examined for each delivery: ethnicity (Jewish/Bedouin), maternal age, gestational age at delivery, gravidity, parity and recurrent pregnancy loss. The following obstetrical characteristics were collected and assessed: mild preeclampsia, severe preeclampsia, any hypertensive disorders, cesarean section, polyhydramnios, oligohydramnios, placental abruption, intra-uterine growth restriction (IUGR), preterm labor 537 weeks, preterm labor 534 weeks and postpartum hemorrhage. The following perinatal outcomes were assessed: fetal gender, small for gestational, Apgar 57 at 1 min, Apgar 57 at 5 min, birth weight 52500 g, birth weight 51500 g, macrosomia and perinatal mortality. Statistical analysis was performed using the SPSS (Chicago, IL). Statistical significance was calculated using Student 2 test for differences in qualitative variables, and Student t-test for differences in continuous variables. The statistical analysis was assessed once again for serum calcium levels corrected to albumin according to a widespread commonly used algorithm (6). Multivariate logistic regression models, with backward elimination, were constructed to demonstrate whether corrected low calcium levels are an independent risk factor for the development of mild or severe preeclampsia and for any hypertensive disorders. Odds ratios (ORs) and their 95% confidence intervals (CIs) were calculated. p Value 50.05 was considered statistically significant. Receiver operating characteristic (ROC) curve analysis was used to describe
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the relationship between the sensitivity (true-positive rate) and the falsepositive rate for the calcium level and the prediction of preeclampsia. It is noteworthy that a test with perfect discrimination has an ROC curve that passes through the upper left corner (100% sensitivity and 100% specificity). The area under the curve (AUC) was calculated to provide a summary of the diagnostic accuracy of the criterion. p Value50.05 was considered statistically significant.
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RESULTS The study population included 111,593 deliveries, of which 5249 (4.7%) had serum calcium levels measured during the first trimester of pregnancy. Of the final study group, 16% (841) had low serum calcium levels and 84% (4392) had normal levels. A comparison of the demographic and clinical characteristics between the two study groups is presented in Table 1. The mean maternal age of the entire study population was 28.46 ± 5.01 years with no significant difference between the hypocalcemic and normocalcemic groups (p = 0.309). Women with hypocalcemia during the first trimester were significantly more likely to be grandmultiparous Bedouin parturients. There was no significant difference between the groups for gestational age at delivery (p = 0.951). Table 2 presents a comparison of obstetric characteristics between the study groups. There was no significant difference between the study groups regarding mild preeclampsia (p = 0.312), severe preeclampsia (p = 0.092) and any hypertensive disorders (p = 0.083). There were significantly higher rates of placental abruption (OR = 2.049; 95% CI 1.100–3.816; p = 0.021) among women with hypocalcemia during the first trimester. Table 1. Demographic and clinical characteristics of patients with and without low serum calcium levels during the first half of pregnancy.
Ethnicity Jewish Bedouin Maternal age (years) Gestational age (wk ± SD) Gravidity 1 2–4 5 Parity 1 2–4 5 Smoking Obesity
Calcium 48.8 mg/dl (n = 841)
Calcium 8.8–10.6 mg/dl (n = 4392)
513 (61.0) 328 (39.0) 30.47 ± 5.824 38.56 ± 2.516
3227 (73.5) 1165 (26.5) 30.25 ± 5.535 38.56 ± 2.411
142 (16.9) 427 (50.8) 272 (32.3)
985 (22.4) 2395 (54.6) 1010 (23)
186 (22.1) 457 (54.3) 198 (23.5) 18 (2.1) 3 (0.4)
1272 (29) 2461 (56) 658 (15) 83 (1.9) 42 (1)
OR (95% CI)
p Value
0.564 (0.484–0.658)
50.001
0.309 0.951 50.001
50.001
1.135 (0.678–1.901) 0.37 (0.114–1.199)
0.629 0.084
Values are expressed as n (%), unless otherwise specified. PROM, pre-labor rupture of membranes; IUGR, intrauterine growth restriction; PPH, post-partum hemorrhage.
Hypocalcemia is not a predictor of preeclampsia Table 2. Obstetrical characteristics of patients with and without low serum calcium levels during the first half of pregnancy.
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Calcium 48.8 mg/dl (n = 841) Mild preeclampsia Severe preeclampsia Total hypertensive disorders Caesarean section Recurrent pregnancy loss Polyhydramnios Oligohydramnios Placental abruption PROM IUGR PPH Preterm labor 537 weeks Preterm labor 534 weeks
34 16 50 196 63 26 28 14 63 26 7 96 32
(4) (1.9) (5.9) (23.3) (7.4) (3.1) (3.3) (1.7) (7.5) (3.1) (0.8) (11.4) (3.8)
Calcium 8.8–10.6 mg/dl (n = 4392) 147 52 200 921 278 119 113 36 531 122 39 427 128
(3.3) (1.2) (4.6) (21) (6.3) (2.7) (2.6) (0.8) (12.1) (2.8) (0.9) (9.7) (2.9)
OR (95% CI) 1.216 1.618 1.324 1.145 1.177 1.145 1.303 2.049 0.588 1.116 0.937 1.196 1.317
(0.831–1.779) (0.919–2.849) (0.963–1.821) (0.96–1.364) (0.88–1.567) (0.744–1.763) (0.856–1.984) (1.100–3.816) (0.448–0.772) (0.726–1.715) (0.417–2.10) (0.946–1.512) (0.888–1.956)
p Value 0.312 0.092 0.083 0.13 0.261 0.536 0.215 0.021 50.001 0.615 0.874 0.134 0.169
Values are expressed as n (%), unless otherwise specified. PROM, pre-labor rupture of membranes; IUGR, intrauterine growth restriction; PPH, post-partum hemorrhage.
Table 3. Comparison of neonatal outcomes between the groups. Calcium Calcium 48.8 mg/dl 8.8–10.6 mg/dl (n = 841) (n = 4392) Gender Male Female SGA Low Apgar 1 min (57) Low Apgar 5 min (57) Low birth weight 52500 g Very low birth weight 51500 g Macrosomia (weight 44000 g) Perinatal mortality
430 411 33 53 21 85 18 44 11
(51.1) (48.9) (3.9) (6.3) (2.5) (10.1) (2.1) (5.2) (1.3)
2159 2233 171 278 106 412 75 203 62
(49.2) (50.8) (3.9) (6.3) (2.4) (9.4) (1.7) (4.6) (1.4)
OR (95% CI)
p Value
1.082 (0.933–1.254)
0.295
1.008 1.005 1.035 1.085 1.259 1.138 0.925
0.967 0.976 0.885 0.510 0.384 0.445 0.814
(0.689–1.474) (0.734–1.347) (0.644–1.663) (0.848–1.388) (0.748–2.118) (0.814–1.592) (0.485–1.763)
Values are expressed as n (%), unless otherwise specified. SGA, small for gestational age.
No significant differences regarding neonatal outcomes were found between the study groups (Table 3). ROC curve analysis of the relationship between calcium level during the first trimester and mild and severe preeclampsia is shown in Figure 1. No significant association was noted between serum calcium levels during the first half of pregnancy, and the risk of mild (Figure 1A) or severe (Figure 1B) preeclampsia. AUC for serum calcium level was low and the graph was flat and far from the upper left corner for both mild preeclampsia (AUC = 0.466; SE = 0.022, 95% CI 0.424–0.508, p = 0.117) and severe preeclampsia (AUC = 0.492; SE = 0.038, 95% CI 0.418–0.566, p = 0.821).
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Figure 1. ROC curve analysis – relationship between uncorrected calcium level during the first trimester, and (A) mild preeclampsia; (B) severe preeclampsia.
A second analysis was performed after correcting calcium levels for albumin. There was no significant difference between the study groups regarding all obstetrical complications that were examined, including mild preeclampsia (p = 0.999), severe preeclampsia (p = 0.168) and any hypertensive disorders (p = 0.452) (Table 4). ROC analysis of the relationship between corrected serum calcium levels during the first trimester and mild and severe preeclampsia is shown in Figure 2. No significant association was noted between corrected serum calcium levels during the first trimester of pregnancy, and the risk of mild (Figure 2A) or severe (Figure 2B) preeclampsia. AUC for serum calcium level
Hypocalcemia is not a predictor of preeclampsia Table 4. Obstetrical characteristics of the study population, corrected to albumin.
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Calcium 48.8 mg/dl (n = 609) Mild preeclampsia Severe preeclampsia Total hypertensive disorders Cesarean section PPD Recurrent pregnancy loss Polyhydramnion Oligohydramnion Placental abruption PROM IUGR PPH Preterm labor 537 weeks Preterm labor 534 weeks
23 13 36 140 2 45 95 196 11 46 17 5 65 22
(3.8) (2.1) (5.9) (23.0) (0.3) (7.4) (15.6) (32.2) (1.8) (7.6) (2.8) (0.8) (10.7) (3.6)
Calcium 8.8–10.6 mg/dl (n = 2753) 104 38 142 592 19 198 408 912 26 312 84 24 300 94
(3.8) (1.4) (5.2) (21.5) (0.7) (7.2) (14.8) (33.1) (0.9) (11.3) (3.1) (0.9) (10.9) (3.4)
OR (95% CI) 1.00 1.55 1.15 1.08 0.47 1.02 1.06 0.95 1.93 0.63 0.91 1.88 0.97 1.06
(0.63–1.58) (0.82–2.94) (0.79–1.68) (0.88–1.34) (0.11–2.04) (0.73–1.44) (0.83–1.35) (0.79–1.15) (0.94–3.92) (0.46–0.88) (0.53–1.54) (0.35–2.47) (0.73–1.29) (0.66–1.70)
p Value 0.999 0.168 0.452 0.422 0.305 0.865 0.626 0.654 0.065 0.006 0.734 0.902 0.872 0.809
Values are expressed as n (%), unless otherwise specified. PROM, pre-labor rupture of membranes; IUGR, intrauterine growth restriction; PPD, post-partum death; PPH, post-partum hemorrhage.
was low and the graph was flat and far from the upper left corner for both mild preeclampsia (AUC = 0.483; SE = 0.026, 95% CI 0.432–0.534, p = 0.519) and severe preeclampsia (AUC = 0.516; SE = 0.044, 95% CI 0.429–0.603, p = 0.697). Multiple logistic regression models were used to control for the confounders such as maternal age, ethnicity (Jewish or Bedouin), gravidity, diabetes mellitus, obesity and chronic hypertension. No significant difference was found between the groups regarding mild preeclampsia (OR = 0.9; 95% CI 0.56–1.44; p = 0.663), severe preeclampsia (OR = 0.6; 95% CI 0.32–1.21; p = 0.162) and any hypertensive disorders (OR = 0.8; 95% CI 0.54–1.17; p = 0.238).
DISCUSSION In this study we evaluated the level of corrected calcium during the first trimester of pregnancy as a marker for the development of preeclampsia in the later course of pregnancy. Thereby, we were hoping to find a marker that is generally available and can easily be used in everyday practice for the prediction of preeclampsia. The main finding of our study is that there was no significant correlation between serum calcium levels during the first trimester of pregnancy and mild preeclampsia, severe preeclampsia or any hypertensive disorders. This lack of correlation was demonstrated in both single-variable processing (corrected and uncorrected to albumin) and multivariable analysis. In addition, ROC curve analysis showed that calcium levels in maternal serum during the first trimester of pregnancy cannot predict the development of mild or severe preeclampsia during the second half of pregnancy.
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Figure 2. ROC curve analysis – relationship between corrected calcium level during the first trimester and (A) mild preeclampsia; (B) severe preeclampsia.
Higher levels of calcium cause reduced secretion of the parathyroid hormone into the blood as well as reduced levels of intracellular calcium in smooth muscles in blood vessels and the uterus. This process causes a reduction in the resistance of blood vessels and, thus, a reduction in blood pressure. It also reduces uterine contractility and consequently, the risk of preterm labor (15). This study did not find an association between low calcium levels and increased preeclamptic morbidity and therefore does not support these suggested pathophysiological explanations. The major report that found an association between administering calcium supplements and preeclamptic morbidity is a meta-analysis summarizing 13 studies (11), six of which reported an association, whereas in the other seven no association was found.
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Hypocalcemia is not a predictor of preeclampsia
The meta-analysis included a total of 15,730 subjects, and found that the OR for preeclampsia following the use of calcium supplements is 0.45 (95% CI 0.31–0.65). The meta-analysis was limited by different definitions of the exposure. In contrast, this study is a cohort study that accurately sampled exposure according to laboratory data. In addition, while the previously mentioned study of the association between consumption of calcium supplements and rates of preeclampsia (11) examined exposure during the second and even third trimesters of pregnancy, in our study serum calcium levels during the first half of pregnancy were assessed and no significant association was found between them and rates of preeclampsia. It could be assumed that taking calcium supplements would increase blood calcium levels. Therefore, the findings of the present study concur with previous research (9,10), which found no significant correlation between consumption of calcium supplements and reduced incidence of preeclampsia. On the other hand, Villar et al. (12) suggested that the prevalence of preeclampsia can be significantly reduced by administering calcium supplements, especially among women whose diet contains little calcium. Moreover, they (12) found that preeclampsia was less severe in women who consumed oral calcium supplements. Yet, their study did not examine calcium levels as predictors of preeclampsia. The single-variable model showed that Bedouin Arab women are at greater risk of hypocalcemia. This could be at least partly explained by the fact that their traditional manner of dress reduces their exposure to sunlight, leading to a lower level of activated vitamin D (16), and thus to a lowered level of serum calcium. Nevertheless, a low calcium level does not necessarily indicate a low vitamin D level and vice versa, and in our study we did not control for vitamin D levels (a known risk factor for preeclampsia) (17). The univariate analysis showed significantly higher rates of placental abruption (OR = 2.049; 95% CI 1.100–3.816; p = 0.021) among women with hypocalcemia during the first trimester. The association between hypocalcemia and placental abruption was not described before and further investigation is needed. There is a common pathophysiology pathway to preeclampsia and placental abruption. They are both a consequence of inadequate placentation, but the clinical expression is different (18). However, after correcting calcium levels for albumin, there was no significant difference between the study groups (p = 0.065). The advantages of this study are the use of two combined and reliable databases that made it possible to obtain laboratory data regarding levels of calcium during the first half of pregnancy. This comprehensive database provided access to detailed information regarding the pregnancies studied. However, our study has several inherent weaknesses, mostly due to its retrospective design, such as the potential for missing data. Nevertheless, data were reported by an obstetrician directly after delivery and skilled medical secretaries routinely reviewed the information prior to entering it into the database, thereby minimizing recall bias. Coding was done after assessing the medical prenatal care records together with the routine hospital documents. Despite all of the above, as well as the fact that women who lacked prenatal care were excluded from the study, there is a likelihood of indication bias in the current study, due to differences in severe preeclampsia morbidity
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between women who were tested for calcium and albumin levels during the first half of pregnancy and women who were not tested. In conclusion, this retrospective cohort study reveals that low serum calcium concentration during the first half of pregnancy is not a risk factor for preeclampsia. Therefore, a blood test for calcium serum levels cannot be a predictor of preeclampsia later in pregnancy.
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DECLARATION OF INTEREST The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this paper.
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Hypocalcemia is not a predictor of preeclampsia
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17. Tabesh M, Salehi-Abargouei A, Tabesh M, Esmaillzadeh A. Maternal vitamin D status and risk of pre-eclampsia: a systematic review and meta-analysis. J Clin Endocrinol Metab 2013;98:3165–73. 18. Ananth CV, Oyelese Y, Prasad V, et al. Evidence of placental abruption as a chronic process: associations with vaginal bleeding early in pregnancy and placental lesions. Eur J Obstet Gynecol Reprod Biol 2006;128:15–21.
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