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Published:August 29, 2008DOI:https://doi.org/10.1016/j.ajog.2008.06.044
      In his comment on our paper,
      • Liguori A.
      • D'Armiento F.P.
      • Palagiano A.
      • Palinski W.
      • Napoli C.
      Maternal C-reactive protein and developmental programming of atherosclerosis.
      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 paper
      • McGladdery S.H.
      • Frohlich J.J.
      Lipoprotein lipase and apoE polymorphisms: Relationship to hypertriglyceridemia during pregnancy.
      quoted by Dr Basaran.
      The obvious response is that our recent paper
      • Liguori A.
      • D'Armiento F.P.
      • Palagiano A.
      • Palinski W.
      • Napoli C.
      Maternal C-reactive protein and developmental programming of atherosclerosis.
      used the patient population of the retrospective Fate of Early Lesions in Children study.
      • Napoli C.
      • Glass C.K.
      • Witztum J.L.
      • Deutsch R.
      • D'Armiento F.P.
      • Palinski W.
      Influence of maternal hypercholesterolaemia during pregnancy on progression of early atherosclerotic lesions in childhood: Fate of Early Lesions in Children (FELIC) study.
      The main criterion was to exclude pathologies suspected on the basis of epidemiological data to influence offspring cardiovascular disease by mechanisms independent of maternal hypercholesterolemia (ie, maternal diabetes and smoking).
      In addition, there are other maternal clinical conditions, many of which are known to be associated with dyslipidemia and inflammation, for which no such evidence exists, including CRP.
      • Napoli C.
      • Palinski W.
      Maternal hypercholesterolemia during pregnancy influences the later development of atherosclerosis: Clinical and pathogenic implications.
      The National Children's Study will test whether they do and also provide valuable data on the threshold of risk factors in childhood.
      • Mudd L.M.
      • Pham X.
      • Nechuta S.
      • et al.
      Prenatal care and delivery room staff attitudes toward research and The National Childrens Study.
      However, it is not very relevant to understand a precise threshold of maternal hypercholesterolemia.
      The same is true for CRP. Why define with rigidity the values of supposed normal ranges of maternal CRP levels? Again, the pathogenetically relevant question is whether increased CRP levels may indicate or promote subsequent vascular disease in children. It is well established that cholesterol levels may increase toward the third trimester and that the extent of this increase varies considerably from patient to patient.
      Prospective studies should obtain cholesterol and related values, including CRP, at a defined gestational age.
      Our retrospective studies utilized a composite value performed throughout pregnancy precisely to minimize the variability in the time of the prenatal exam. Dr Basaran states that “to call something abnormal, the norm must have been defined.” Indeed, our early studies were the first to define levels of hypercholesterolemia associated with increased atherosclerosis in fetuses
      • Napoli C.
      • D'Armiento F.P.
      • Mancini F.P.
      • et al.
      Fatty streak formation occurs in human fetal aortas and is greatly enhanced by maternal hypercholesterolemia: Intimal accumulation of low density lipoprotein and its oxidation precede monocyte recruitment into early atherosclerotic lesions.
      and during childhood,
      • Napoli C.
      • Glass C.K.
      • Witztum J.L.
      • Deutsch R.
      • D'Armiento F.P.
      • Palinski W.
      Influence of maternal hypercholesterolaemia during pregnancy on progression of early atherosclerotic lesions in childhood: Fate of Early Lesions in Children (FELIC) study.
      and the present paper does this for a surrogate parameter, CRP, but more practical definitions would have to be defined. Although it strikes us as exceptionally daring to expect evidence for causality from a human study on developmental programming,
      • Napoli C.
      • Palinski W.
      Maternal hypercholesterolemia during pregnancy influences the later development of atherosclerosis: Clinical and pathogenic implications.
      • Napoli C.
      • D'Armiento F.P.
      • Mancini F.P.
      • et al.
      Fatty streak formation occurs in human fetal aortas and is greatly enhanced by maternal hypercholesterolemia: Intimal accumulation of low density lipoprotein and its oxidation precede monocyte recruitment into early atherosclerotic lesions.
      extensive evidence for the atherogenic role of maternal hypercholesterolemia has been obtained in various experimental models.
      • Napoli C.
      • Witztum J.L.
      • Calara F.
      • de Nigris F.
      • Palinski W.
      Maternal hypercholesterolemia enhances atherogenesis in normocholesterolemic rabbits, which is inhibited by antioxidant or lipid-lowering intervention during pregnancy: An experimental model of atherogenic mechanisms in human fetuses.
      • Napoli C.
      • de Nigris F.
      • Welch J.S.
      • et al.
      Maternal hypercholesterolemia during pregnancy promotes early atherogenesis in LDL receptor-deficient mice and alters aortic gene expression determined by microarray.
      • Alkemade F.E.
      • Gittenberger-de Groot A.C.
      • Schiel A.E.
      • et al.
      Intrauterine exposure to maternal atherosclerotic risk factors increases the susceptibility to atherosclerosis in adult life.
      • Elahi M.M.
      • Cagampang F.R.
      • Anthony F.W.
      • et al.
      Statin treatment in hypercholesterolemic pregnant mice reduces cardiovascular risk factors in their offspring.

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