Linking intrauterine growth restriction and blood pressure: insight into the human origins of cardiovascular disease.

Abnormal perfusion to the fetus can slow fetal growth and result in intrauterine growth restriction (IUGR)1. IUGR, or failure to reach one's birth potential, is one of the most common complications during pregnancy and generally results from placental insufficiency1. IUGR is generally not recognized prior to delivery and treatment options for IUGR are limited with early delivery the most common1. Preeclampsia is often a contributory cause of IUGR and numerous studies indicate that individuals exposed to a preeclamptic pregnancy exhibit a higher body mass index (BMI) and blood pressure during childhood and adult life2. Individuals born IUGR also demonstrate an increase in blood pressure later in life3. This association forms the basis for the developmental origins of health and disease and indicates that adverse influences during fetal life that slow fetal growth program an individual for greater cardiovascular risk in later life4,5. Experimental models of placental insufficiency provide proof of principle that IUGR induced by reduced uterine perfusion programs an increase in blood pressure and cardiovascular risk in later life5. However, in this issue of Circulation Gaillard et al. provide a direct link between reduced uterine perfusion and IUGR with increased cardiovascular risk6. Utilizing a large, prospective longitudinal cohort, Gaillard and colleagues report that an increase in third trimester feto-placental vascular resistance indicative of reduced perfusion was associated with a decrease in size at birth and a later increase in total fat mass and systolic blood pressure at 6 years of age6. Thus, this study indicates that assessment of fetal growth characteristics via Doppler flow velocity waveforms in the umbilical artery may not only be indicative of IUGR, but may also identify an individual at greater risk for cardiovascular disease in later life. IUGR in this study occurred in a relatively low risk population of age-appropriate mothers that were in good health, of European descent, and were from a middle class to an upper middle class socioeconomic background6. Based on the socioeconomic background and health of the mother, this would suggest that mothers in this cohort had adequate access to proper nutrition. IUGR in this cohort was associated with higher umbilical artery vascular resistance6. Thus, these findings suggest that the causative factors contributing to IUGR in this cohort were most likely not due to maternal undernutrition per se, but improper remodeling of the utero-placental circulation. The original hypothesis for the developmental origins of health and disease was based on a geographical association correlating high rates of infant mortality with high rates of death from coronary heart disease4. However, the original observation noted by Barker was from an area of depressed socioeconomic status4 leading Barker to hypothesize that fetal undernutrition due to poor living conditions was a causative factor in the etiology of fetal programming of cardiovascular risk. Since that original observation and formulation of what is now referred to as the developmental origins of health and disease, numerous population-based studies note an inverse relationship between birth weight as a crude marker of slow fetal growth and blood pressure as an indicator of increased cardiovascular risk that is present regardless of socioeconomic status7. Therefore, significant evidence exists that poor nutrition to the fetus regardless of the etiology, poverty versus placental insufficiency, contributes to the developmental origins of chronic disease. Notably, this study by Galliard et al. clearly demonstrates that the origins of increased programmed cardiovascular risk that arise from IUGR may require more than adequate nutrition to reverse the etiology of slow fetal growth that originates from improper remodeling of the maternal/utero-placental vasculature. To date, it is not possible to reverse IUGR that results from utero-placental insufficiency8. Pregnancies complicated by IUGR are associated with increased risk of perinatal morbidity and mortality with early delivery considered the main treatment option8,9. Infants delivered preterm often have serious, long-term health problems including respiratory distress, problems with vision and hearing, cerebral palsy, developmental delays and infection8. In addition, individuals born preterm also exhibit a moderate increase in blood pressure in later life10. Thus, early delivery to prevent the immediate demise of the IUGR fetus is not only associated with the early morbidities that accompany preterm birth, but individuals born preterm may also have an increased risk for the development of hypertension and cardiovascular disease in later life. There are multiple causes of IUGR; yet, most are thought to result from the improper modification of the spiral arteries and resulting increased placental resistance1. Ultrasound technologies are advancing in their ability to detect resistance within the uterine and umbilical arteries as methods for identification of IUGR and evaluation of fetal healt1. However, use is generally not indicated for routine screening in low-risk populations9. Although Doppler evaluation is used for the assessment and management of high-risk pregnancies, detection rates during the first and second trimester remain low1. Thus, reliable markers that exhibit an adequate positive predictive value for early detection of IUGR are needed. Numerous serum markers of angiogenic factors, growth factors, placental proteins and hormones have been evaluated11. However, to date, none of these have exhibited a strong predictive accuracy11. Additionally, treatment options for IUGR have not been effective8. Proper development of the utero-placental circulation is critical for adequate transfer of oxygen and nutrients to the fetus and removal of wastes from the fetus12. Development of the utero-placental circulation occurs in order to convert high-resistance vessels to low-resistance vessels to facilitate the growing needs of the developing fetus12. Pijnenborg et al. propose that this conversion occurs in two stages12. The first stage initiates from 8 to 10 weeks of age and involves endovascular plugging of the spiral arteries followed by shallow invasion of the spiral arteries by trophoblast cells12. The second stage occurs from 12 to 14 weeks of age and involves deeper trophoblast invasion of the spiral arteries to complete remodeling of the utero-placental circulation12. Therefore, based on the direct link between reduced uterine perfusion and later cardiovascular risk reported by Galliard et al, early detection of pregnancies destined to be complicated by IUGR and the development of viable options to prevent impaired utero-placental perfusion and subsequent IUGR are crucial not only the for the health of the fetus and infant, but also the cardiovascular health of the IUGR individual throughout life. An additional finding of merit in this study by Galliard et al. involves the reported sex difference in the association between higher umbilical artery vascular resistance and IUGR with increased total fat mass and blood pressure with girls at 6 years of age more impacted than boys6. Very few studies have examined whether sex impacts programmed cardiovascular risk in children. Additionally, studies of children under 11 years of age differ in their findings reporting that the inverse association between birth weight, as a crude marker for slow fetal growth, and systolic blood pressure is stronger in boys than girls13, or present in girls but not boys14. Differences in methods for measure of blood pressure and whether birth records or recall were used for birth weights may contribute to these discrepancies. However, clearly further studies are needed to elucidate the impact of sex on programmed cardiovascular risk. To summarize, Gaillard et al. provide a definitive link between impaired placental perfusion and slow fetal growth with programmed CV risk6. Their study also indicates that sex impacts cardiovascular outcome at 6 years of age following IUGR during fetal life6. In conclusion, findings from this study by Galliard and colleagues in this issue of Circulation clearly demonstrate a need for the development of reliable early markers that can identify pregnancies at risk prior to the initiation of events leading to IUGR and preventative or treatment options to avert the adverse impact of IUGR on gestational outcome and the long-term health of the individual. Furthermore, this study also provides merit for continued monitoring of this cohort to further investigate how IUGR impacts cardiovascular risk with age and how changes in the hormonal milieu via transitions through puberty, middle age and menopause impact the sex difference in programmed risk. Clearly, additional longitudinal cohort studies are needed to clarify the long-term impact of the developmental origins of cardiovascular disease across the lifespan.