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Can physiologic hyperlipidemia during pregnancy be the culprit for atherogenesis in utero?

Published:October 10, 2008DOI:https://doi.org/10.1016/j.ajog.2008.06.043
      To the Editors:
      We read the article by Liguori et al
      • Liguori A.
      • D'Armiento F.P.
      • Palagiano A.
      • Palinski W.
      • Napoli C.
      Maternal C-reactive protein and developmental programming of atherosclerosis.
      with great interest. However, there are some conflicting points that need to be clarified. The first thing that I want to mention is about the exclusion criteria that did not include gravids with polycystic ovary syndrome, diabetes, or gestational diabetes; patients with high body mass index or preterm labor; and smoking mothers.
      These disorders are well known to be associated with increased lipid levels and/or C-reactive protein (CRP) during pregnancy.
      • McGladdery S.H.
      • Frohlich J.J.
      Lipoprotein lipase and apoE polymorphisms: relationship to hypertriglyceridemia during pregnancy.
      To call something abnormal, the norm must have been defined. During pregnancy both CRP and maternal cholesterol levels (MCLs) increase as the gestational age advances.
      • Brizzi P.
      • Tonolo G.
      • Esposito F.
      • et al.
      Lipoprotein metabolism during normal pregnancy.
      • Hwang H.S.
      • Kwon J.Y.
      • Kim M.A.
      • Park Y.W.
      • Kim Y.H.
      Maternal serum highly sensitive C-reactive protein in normal pregnancy and pre-eclampsia.
      Serum CRP levels vary widely in healthy pregnant women; however, there is a slow increase of mean CRP during pregnancy (Table 1).
      • Hwang H.S.
      • Kwon J.Y.
      • Kim M.A.
      • Park Y.W.
      • Kim Y.H.
      Maternal serum highly sensitive C-reactive protein in normal pregnancy and pre-eclampsia.
      MCLs in healthy pregnant women are shown in Table 2 according to trimesters.
      • Brizzi P.
      • Tonolo G.
      • Esposito F.
      • et al.
      Lipoprotein metabolism during normal pregnancy.
      TABLE 1CRP levels among healthy pregnant women
      MeanRange
      5-9 wks0.760.16-13.61
      15-20 wks1.530.39-20.31
      24-30 wks2.080.50-9.45
      30-39 wks2.280.44-8.11
      Basaran. Can physiologic hyperlipidemia during pregnancy be the culprit for atherogenesis in utero? Am J Obstet Gynecol 2009.
      TABLE 2Maternal cholesterol levels in healthy pregnant women
      Mean (mg/dL)95% CI
      Nulliparous women177139.2-216.6
      First trimester177116-239.8
      Second trimester247.5162.4-332.6
      Third trimester286.2193.4-378.9
      CI, confidence interval.
      Basaran. Can physiologic hyperlipidemia during pregnancy be the culprit for atherogenesis in utero? Am J Obstet Gynecol 2009.
      When we compared the range of values for CRP and MCLs in the study of Liquori et al
      • Liguori A.
      • D'Armiento F.P.
      • Palagiano A.
      • Palinski W.
      • Napoli C.
      Maternal C-reactive protein and developmental programming of atherosclerosis.
      with values provided in the tables, they are still within the ranges of healthy pregnant women. And moreover, if we do not group the patients according to gestational age, patients in the second and third trimester will be falsely labeled as hypercholesterolemic.
      The placenta and fetal compartment is a substantially different environment from the mother, although there are exceptions for a variety of substances. The syncytiotrophoblastic layer of the placenta acts as a physical barrier between the maternal and fetal circulations. To supply the fetus with maternal cholesterol, the placenta must receive the vast majority of those nutrients in the form of lipoproteins. Cholesterol and lipids then cross the placenta by either diffusion or protein-mediated efflux.
      In their study, Marseille-Tremblay et al
      • Marseille-Tremblay C.
      • Ethier-Chiasson M.
      • Forest J.C.
      • et al.
      Impact of maternal circulating cholesterol and gestational diabetes mellitus on lipid metabolism in human term placenta.
      showed that mild hypercholesterolemia does not appear to affect the newborn lipid profile, possibly as a consequence of the modulation of lipid metabolism in the placenta. The maternal and fetal levels of cholesterol in the study by Marseille-Tremblay et al
      • Marseille-Tremblay C.
      • Ethier-Chiasson M.
      • Forest J.C.
      • et al.
      Impact of maternal circulating cholesterol and gestational diabetes mellitus on lipid metabolism in human term placenta.
      are shown in Table 3.
      • Marseille-Tremblay C.
      • Ethier-Chiasson M.
      • Forest J.C.
      • et al.
      Impact of maternal circulating cholesterol and gestational diabetes mellitus on lipid metabolism in human term placenta.
      TABLE 3Maternal and fetal cholesterol concentrations from the study of Marseille-Tremblay et al
      • Marseille-Tremblay C.
      • Ethier-Chiasson M.
      • Forest J.C.
      • et al.
      Impact of maternal circulating cholesterol and gestational diabetes mellitus on lipid metabolism in human term placenta.
      Maternal cholesterol level, mg/dL (95% CI)Newborn venous cord blood cholesterol level, mg/dL (95% CI)
      Low median cholesterol (n = 29)213.5 (203.5-223.5)67.3 (60.0-74.3)
      High median cholesterol (n = 30)299 (285.9-312.1)65.4 (59.2-71.2)
      Nongestational diabetes mellitus (n = 7)256 (221.2-290.8)70 (54.5-85.4)
      Gestational diabetes mellitus (n = 7)265.7 (219.2-312.1)69.6 (55.4-85.8)
      Basaran. Can physiologic hyperlipidemia during pregnancy be the culprit for atherogenesis in utero? Am J Obstet Gynecol 2009.
      When we take into account the data given here and the study of Liquori et al,
      • Liguori A.
      • D'Armiento F.P.
      • Palagiano A.
      • Palinski W.
      • Napoli C.
      Maternal C-reactive protein and developmental programming of atherosclerosis.
      the question that occurs is that without causing any alteration of cholesterol levels in the fetal compartment, how does increased MCL lead to increased atherogenesis? And could metabolic changes that are physiologically observed during pregnancy be classified as pathologic?
      In conclusion, the current study is lacking a cause-and-effect relationship, and statistically significant findings on the data sheets may not always translate into solid associations.

      References

        • Liguori A.
        • D'Armiento F.P.
        • Palagiano A.
        • Palinski W.
        • Napoli C.
        Maternal C-reactive protein and developmental programming of atherosclerosis.
        Am J Obstet Gynecol. 2008; 198: e281-e285
        • McGladdery S.H.
        • Frohlich J.J.
        Lipoprotein lipase and apoE polymorphisms: relationship to hypertriglyceridemia during pregnancy.
        J Lipid Res. 2001; 42: 1905-1912
        • Brizzi P.
        • Tonolo G.
        • Esposito F.
        • et al.
        Lipoprotein metabolism during normal pregnancy.
        Am J Obstet Gynecol. 1999; 181: 430-434
        • Hwang H.S.
        • Kwon J.Y.
        • Kim M.A.
        • Park Y.W.
        • Kim Y.H.
        Maternal serum highly sensitive C-reactive protein in normal pregnancy and pre-eclampsia.
        Int J Gynaecol Obstet. 2007; 98: 105-109
        • Marseille-Tremblay C.
        • Ethier-Chiasson M.
        • Forest J.C.
        • et al.
        Impact of maternal circulating cholesterol and gestational diabetes mellitus on lipid metabolism in human term placenta.
        Mol Reprod Dev. 2008; 75: 1054-1062

      Linked Article

      • Maternal C-reactive protein and developmental programming of atherosclerosis
        American Journal of Obstetrics & GynecologyVol. 198Issue 3
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          Maternal hypercholesterolemia during pregnancy enhances the susceptibility to atherosclerosis in their offspring by oxidation-dependent mechanisms. The present study investigated whether maternal C-reactive protein (CRP) level, which is an indicator of inflammation and cardiovascular risk, or smoking, which enhances oxidative stress, predict the in utero programming of atherosclerosis.
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        American Journal of Obstetrics & GynecologyVol. 200Issue 1
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          In his comment on our paper,1 Dr Basaran raises the question why we did not exclude some conditions associated with increased C-reactive protein (CRP) and the need to define hypercholesterolemia and elevated CRP in dependency of the trimester. An impairment of CRP levels is not described in the paper2 quoted by Dr Basaran.
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