Journal of Developmental Origins of Health and Disease (2010), 1(6), 360–364. & Cambridge University Press and the International Society for Developmental Origins of Health and Disease 2010 doi:10.1017/S2040174410000280
REVIEW
Beyond birthweight: the maternal and placental origins of chronic disease D. J. P. Barker1,2,3*, K. L. Thornburg2, C. Osmond1, E. Kajantie4,5 and J. G. Eriksson4,6,7,8,9 1
MRC Epidemiology Resource Centre, Southampton General Hospital, University of Southampton, Southampton, UK Heart Research Center, Oregon Health and Science University, Portland, OR, USA 3 Fetal Programming Research Chair, King Saud University, Saudi Arabia 4 Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland 5 Hospital for Children and Adolescents, Helsinki University Central Hospital, Helsinki, Finland 6 Department of General Practice and Primary Health Care, University of Helsinki, Helsinginyliopisto, Finland 7 Vasa Central Hospital, Sandviksgatan 2–4, Vasa, Finland 8 Folkha¨lsan Research Centre, Helsinki, Helsingfors Universitet, Finland 9 Unit of General Practice, Helsinki University Central Hospital, Finland 2
New findings on the maternal and placental programming of chronic disease lead to four conclusions: (1) Growth of the placental surface is polarized from the time of implantation, so that growth along the major axis, the length, is qualitatively different from growth along the minor axis, the breadth. (2) The human fetus may attempt to compensate for undernutrition by expansion of the placental surface along its minor axis. This only occurs if the mother was well nourished before conception, and may have long-term costs that include hypertension. (3) The effects of placental size on long-term health are conditioned by the mother’s nutritional state, as indicated by her socio-economic status, height and body mass index. (4) The maternal–placental programming of chronic disease differs in boys and girls. Boys invest less than girls in placental growth but more readily expand the placental surface if they become undernourished in mid-late gestation. Boys are more responsive to their mothers’ current diets while girls respond more to their mothers’ lifetime nutrition and metabolism. Received 9 March 2010; Revised 28 April 2010; Accepted 10 May 2010; First published online 10 June 2010 Key words: placental size, maternal body size, chronic disease
Introduction
Measurements of placental size that reflect function
To date, most epidemiological observations that have shown a link between prenatal life and later chronic disease have used birthweight as a marker of early life. A baby’s birthweight reflects its success in obtaining nutrients from its mother.1 The source of these nutrients is not only the mother’s daily diet, but her nutritional stores and metabolism, which are the product of her lifetime nutrition.2 We have previously reviewed how the nutrition and growth of girls during infancy, childhood and at puberty influence chronic disease in the next generation.3 A baby’s nutrition also depends on the placenta’s ability to transport nutrients to it from the mother.1 We here use new data from the Helsinki Birth Cohort to review three questions: (1) What measures of placental size can be used as markers of its function? (2) Is a large placenta always beneficial? (3) Are there sex differences in the maternal–placental phenotypes that predict chronic disease?
Low placental weight at birth has been shown to predict hypertension and coronary heart disease in later life.4,5 Placental weight, however, does not distinguish the surface area of the placenta from its thickness. In order to increase the surface for nutrient and oxygen exchange, the placenta can increase the surface area of its villi, or expand its invasion across the surface of the uterine lining or invade the maternal spiral arteries more deeply. The long-term consequences may be different. Textbooks of midwifery written early in the last century describe the placental surface as being either ‘oval’ or ‘round’.6,7 In order to measure the extent to which the surface was more oval than round, two so-called ‘diameters’ of the surface were routinely recorded in some hospitals in the past: a maximal diameter, the length, and a lesser one bisecting it at right angles, the width. These measurements are available for the Helsinki Birth Cohort that comprises 20,436 men and women born in the city during 1924–1944.8 The mean sizes of the length and breadth were 19.5 and 16.9 cm, and the sizes were highly correlated (correlation coefficient 5 0.63). We used the length and breadth to estimate the surface area. How closely this area reflects the total surface area for maternal–fetal exchange through the gestational period is not known. A thin placenta with a large surface area could have
*Address for correspondence: Prof. D. J. P. Barker, MRC Epidemiology Resource Centre, Southampton General Hospital, University of Southampton, Southampton, SO16 6YD, UK. (Email [email protected])
Beyond birthweight
361
Table 1. Mean systolic blood pressure of men and women, aged 50 years, born at term Placental weight (pounds) Birthweight (pounds)
1.0
1.25
1.5
.1.5
6.5 7.5 .7.5
149 139 131
152 148 143
151 146 148
167 159 153
the major axis is aligned to the rostro-caudal axis of the embryo, while the minor axis is more important for nutrient transfer to the fetus. Fig. 1. Odds ratios for preeclampsia according to the diameters of the placental surface.
a smaller villous exchange surface than a thick placenta with a small surface area. Nevertheless, it seems reasonable to suppose that the surface area measured in the Helsinki data correlates with the exchange area. We combined the two diameters and placental weight to estimate thickness. Preeclampsia is associated with abnormal placentation as a result of impaired invasion of the maternal spiral arteries by the trophoblast at implantation.9 We examined the effect of preeclampsia on placental area and thickness.10 In all, 6410 of the mothers of the younger part of the Helsinki birth cohort, born 1934–1944, had their blood pressures and the results of urinary protein tests recorded after 20 weeks of pregnancy; 284 of these pregnancies were complicated by preeclampsia. Compared to normotensive pregnancies, the placentas from these pregnancies had a reduced surface area, but the thickness was increased. We speculated that the increase in thickness in preeclampsia was compensatory for restricted expansion of the surface. Placentas from pregnancies complicated by preeclampsia had a more oval surface than those from normotensive pregnancies because of a disproportionate reduction in the breadth. When the length and breadth were analyzed together, preeclampsia was not associated with the size of the length, but was strongly associated with a short breadth. This is shown in Figure 1. The relationship with the breadth was graded: the shorter the breadth, the greater the risk for, and severity of, preeclampsia. This association with short breadth depended on its absolute size rather on its size in relation to the size of the length. Processes that underlie the disease may therefore be closely linked to the absolute amount of placental tissue on the breadth of the placental surface. This link must be through a structure or function that it does not share with tissue along the length. We postulated that placental growth is polarized from the time of implantation, so that growth along the major axis, defined by the length, is qualitatively different from growth along the minor axis.10 One possibility is that
Large placentas The ability of the placenta to transfer nutrients from the mother to the baby is reflected in its overall size.11 Babies whose birthweights are toward the lower end of the normal range generally have small placentas, and low placental weight is associated with hypertension in later life.4 However, a study of men and women born in a maternity hospital in Preston, UK, showed that high placental weight in relation to birthweight is also associated with later hypertension.12 Table 1 shows that whereas people who had both low placental weight and low birthweight had higher mean systolic blood pressures than those who had low placental weight but high birthweight, the highest mean systolic pressures occurred in people who had high placental weight but low birthweight. This observation has been replicated, and high placental weight in relation to birthweight has also been shown to predict coronary heart disease.4,13 An additional point made by Table 1 is that the ability of birthweight to predict blood pressure is enhanced if the size of the placenta is taken into account.12 The associations with large placental size shown in Table 1 suggest that cardiovascular disease can be initiated through placental overgrowth as well as through restricted placental growth. Observations in sheep show that in response to undernutrition a fetus is able to extend the area of the placenta by expanding the individual cotyledons.14,15 This increases the area available for nutrient and oxygen exchange, and results in a larger lamb than there would otherwise have been. This is profitable for the farmer, and manipulation of placental size by changing the pasture of pregnant ewes is standard practice in sheep farming. Placental overgrowth in response to undernutrition in mid-gestation can only occur, however, if the ewe was well nourished before conception.15 There is evidence of a similar phenomenon in humans. 2003 members of the Helsinki Birth Cohort were randomly selected to attend a clinic; 644 were being treated for hypertension.8 We found that the effects of placental size on hypertension depended on the mother’s socio-economic status, a marker of her current
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Fig. 2. Prevalence of hypertension according to placental area in the offspring of short and tall mothers.
nutrition, and on her height, which reflected her nutrition and metabolism in childhood and adolescence.8,16 In people whose mothers were of low socio-economic status or below average height, hypertension was associated with low placental weight and area. In people whose mothers were likely to have been the best nourished, being tall and middle class, hypertension was predicted by large placental size in relation to birthweight. Figure 2 shows the trends in the prevalence of hypertension in people divided according to whether their mother’s height was above or below the median of 160 cm. In people whose mothers were short, the prevalence of hypertension fell progressively with increasing placental area. In people with tall mothers, the association was U-shaped, the prevalence initially falling as area increased but thereafter rising. Therefore, while the effect of small placental area on hypertension was similar in the two maternal height groups, a large area was associated with almost double the prevalence of hypertension in the offspring of tall mothers when compared with the offspring of short mothers. These different trends in hypertension with placental area in people born to short or tall mothers suggest a link between hypertension and the lifetime nutrition of the mother. Short maternal stature is a product of poor fetal or childhood nutrition, or recurrent exposure to infections, though there are also genetic influences.16 Protein metabolism is established in early life and is related to visceral mass. Short women have less visceral mass than tall women and have reduced rates of protein synthesis in pregnancy.2,17 In short mothers, an increased placental surface for protein transport might offset reduced rates of synthesis. Among people with tall mothers, there was no overall effect of placental area on hypertension (Fig. 2). When, however, these offspring were subdivided by the family’s socioeconomic status, two opposing trends were revealed. In lower social class families, hypertension was associated with small placental area and low weight. In middle class families, hypertension was associated with large placental area and high placental weight in relation to birthweight. Tall mothers in
middle class families are likely to have been the best nourished before conception. During pregnancy, however, they would have been subject to the food scarcities that occurred in Finland around the time of the Second World War.18 We speculate that, similar to sheep, their fetuses responded to this by expansion of the placental surface. Compensatory placental growth may be beneficial in some circumstances, but if the compensation is inadequate and the fetus continues to be undernourished, the need to share its nutrients with an enlarged placenta may become an added metabolic burden. A long-term cost of this added burden is hypertension, possibly as a result of impaired development of low priority organs like the kidney.19 Among the offspring of tall, middle class mothers, hypertension was associated with above average birthweight. This suggests that, as in sheep, placental enlargement in response to fetoplacental malnutrition leads to increased body size at birth. Epidemiological studies that include large numbers of tall, middle class mothers may therefore fail to show the well-known association between low birthweight and later hypertension. A general point made by Figure 2 is that, just as the ability of birthweight to predict long-term outcomes is enhanced if the size of the placenta is taken into account, the ability of placental size to predict outcomes is enhanced if maternal body size is known. Of the two diameters of the surface, breadth was more closely associated with hypertension.8 The interaction between the effects of mother’s height and placental area (Fig. 2) was reflected in a similar interaction between the effects of mother’s height and the breadth of the surface, but there was no interaction between mother’s height and the length. These findings are consistent with the idea that placental tissue along the breadth of the surface is more important for nutrient transfer to the fetus than tissue along the length, and expansion of the placental surface along its minor axis is one way in which a fetus may compensate for malnutrition. The findings on hypertension show that the effects of placental size on the fetus are conditioned by the mother’s height. Studies of lung cancer show that they are also conditioned by the mother’s body mass index in pregnancy height/weight2, a marker for her glucose and lipid metabolism.20,21 Sex differences in the placenta Boys grow faster than girls from an early stage of gestation, even from before implantation, and this makes them more vulnerable if their nutrition is compromised.16,22 We have examined the differences in fetal and placental size at birth among boys and girls in the Helsinki Birth Cohort.23 We found that the small differences in average body measurements concealed large differences in body proportions. At any placental weight, boys tended to be taller than girls; and boys’ placentas were smaller than girls’ placentas when related to the weight of the baby.23 This suggests that boys’ placentas are more efficient but may have less reserve capacity, which therefore increases their
Beyond birthweight
Fig. 3. Odds ratios for hypertension in women according to mother’s height and placental weight.
vulnerability to undernutrition. Boys tend to have larger head circumferences at birth but are thinner than girls.24 This suggests that they may more readily trade off visceral development to protect brain growth. The growth of every human fetus is constrained by the limited capacity of the mother and placenta to deliver nutrients to it.25 The male fetus, by growing more rapidly and investing in brain growth rather than placental growth, is adopting a more dangerous strategy that puts it at greater risk of becoming undernourished. We found that the relationship between placental diameters and later hypertension was different in the two sexes.24 In women, hypertension was associated with short breadth and small placental area. In men, it was associated with large breadth in relation to birthweight. This suggests that compensatory expansion of the placental breadth may occur more readily in boys. Direct evidence for this comes from findings in the Dutch famine (van Abeleen et al., personal communication). The dangerous growth strategy of boys may therefore be compounded by the costs of compensatory placental enlargement in mid-late gestation. Among women the trends in hypertension with small placental area and low placental weight were stronger in those whose mothers were short (Fig. 3).24 The trends did not differ with the mother’s social class. In contrast, among men the trend in hypertension with a greater breadth in relation to birthweight was not influenced by the mother’s height but differed according to the mother’s social class. Figure 4 shows that the trend was confined to men whose mothers were middle class (Fig. 4). An interpretation of these findings is that during development in the womb, girls respond more to their mother’s lifetime nutrition and metabolism, indicated by her height, whereas boys respond more to their mother’s current diet, indicated by her social class. The greater effect of the Dutch famine on the numbers of boys supports this,26 as do the greater effects of experimental alterations in maternal diet on male animals.27–29 While boys’
363
Fig. 4. Odds ratios for hypertension in men according to the mother’s socio-economic status and the ratio of the lesser placental diameter to birthweight.
responsiveness to their mothers’ current diet enables them to capitalize on improving food supply, and promotes their agenda of rapid growth, it makes them vulnerable to food shortages. Conclusions Birthweight is a crude marker of fetal nutrition. The same weight may result from a variety of different nutritional circumstances. A priori, it was likely that epidemiological associations between birthweight and later disease would not always be consistent. To some extent, these inconsistencies can be reduced by using additional measures of body size at birth, including length and head circumference. This study suggests that the size and shape of the placental surface is a new epidemiological marker. There is already a body of knowledge about the maternal determinants of normal placental structure.30 The biological functions that underlie the associations between different maternal–placental phenotypes and later disease now need to be explored. This study leads to four conclusions about the maternal– placental programming of chronic disease: (1) Growth of the placental surface is polarized from the time of implantation, so that growth along the major axis is qualitatively different from growth along the minor axis. (2) The human fetus may attempt to compensate for undernutriton by expansion of the placental surface along its minor axis. (3) The effects of placental size on long-term health are conditioned by the mother’s nutritional state, as indicated by her socio-economic status and height. (4) The maternal–placental programming of chronic disease differs in boys and girls. Acknowledgements This study was supported by the British Heart Foundation, the Academy of Finland, the Paivikki and Sakari Sohlberg
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Foundation, the Finnish Diabetes Research Foundation, the Finnish Foundation for Cardiovascular Research, the Finnish Medical Society Duodecim, Yrjo Jahnsson Foundation, Finska Lakaresa¨llskapet. References 1. Harding JE. The nutritional basis of the fetal origins of adult disease. Int J Epidemiol. 2001; 30, 15–23. 2. Jackson AA. All that glitters. British Nutrition Foundation Annual Lecture. Nutr Bull. 2000; 25, 11–24. 3. Barker DJP, Osmond C, Kajantie E, Eriksson JG. Growth and chronic disease: findings in the Helsinki Birth Cohort. Ann Hum Biol. 2009; 36, 445–458. 4. Eriksson J, Forsen T, Toumilheto J, Osmond C, Barker D. Fetal and childhood growth and hypertension in adult life. Hypertension. 2000; 36, 790–794. 5. Forse´n T, Eriksson JG, Tuomilehto J, et al. ‘Mother’s weight in pregnancy and coronary heart disease in a cohort of Finnish men: follow up study’. BMJ. 1997; 315, 837–840. 6. Anderson MC. Lessons in Midwifery for Nurses and Midwifes, 1930. A & C Black: London. 7. Hinselmann H. Biologie und Pathologie des Weibes, 1925. Urban & Schwarzenberg: Berlin. 8. Barker DJP, Thornburg KL, Osmond C, Kajantie E, Eriksson JG. The surface area of the placenta and hypertension in the offspring in later life. Int J Dev Biol. 2010; 54, 525–530. 9. Roberts JM, Cooper DW. Pathogenesis and genetics of preeclampsia. Lancet. 2001; 357, 53–56. 10. Kajantie E, Barker DJP, Osmond C, Kajantie E, Eriksson JG. In pre-eclampsia the placenta grows slowly along its minor axis. Int J Dev Biol. 2010; 54, 469–473. 11. Sibley CP. The pregnant woman. In Human Physiology: Age, Stress, and the Environment (eds. Case RM, Waterhouse JM), 1994; pp. 3–27. Oxford University Press: Oxford. 12. Barker DJP, Bull AR, Osmond C, Simmonds S. Fetal and placental size and risk of hypertension in adult life. BMJ. 1990; 301, 259–262. 13. Martyn CN, Barker DJP, Osmond C. Mothers pelvic size, fetal growth and death from stroke in men. Lancet. 1996; 348, 1264–1268. 14. McCrabb GJ, Egan AR, Hosking BJ. Maternal undernutrition during mid-pregnancy in sheep. Placental size and its relationship to calcium transfer during late pregnancy. Br J Nutr. 1991; 65, 157–168. 15. McCrabb GJ, Egan AR, Hosking BJ. Maternal undernutrition during mid-pregnancy in sheep: variable effects on placental growth. J Agric Sci. 1992; 118, 127–132.
16. Tanner JM. Fetus into Man, 2nd edn, 1989. Castlemead, Ware. 17. Duggleby SL, Jackson AA. Relationship of maternal protein turnover and lean body mass during pregnancy and birth length. Clin Sci (Lond). 2001; 101, 65–72. 18. Pesonen AK, Raikkonen K, Heinonen K, et al. Depressive symptoms in adults separated from their parents as children: a natural experiment during World War II. Am J Epidemiol. 2007; 166, 1126–1133. 19. Barker DJP, Bagby S, Hanson MA. Mechanisms of disease: in utero programming in the pathogenesis of hypertension. Nature Clin Pract Nephrol. 2006; 2, 700–707. 20. Eriksson JG, Thornburg KL, Osmond C, Kajantie E, Barker DJP. The prenatal origins of lung cancer: I. The fetus. Am J Hum Biol 2010; doi:10.1002/ajhb.21041. 21. Barker DJP, Thornburg KL, Osmond C, Kajantie E, Eriksson JG . The prenatal origins of lung cancer: II. The placenta. Am J Hum Biol 2010; doi:10.1002/ajhb.21041. 22. Pedersen JF. Ultrasound evidence of sexual difference in fetal size in first trimester. BMJ. 1980; 281, 1253. 23. Forse´n T, Eriksson JG, Tuomilehto J, Osmond C, Barker DJP. Growth in utero and during childhood among women who develop coronary heart disease: longitudinal study. BMJ. 1999; 319, 1403–1407. 24. Eriksson JG, Kajantie E, Osmond C, Thornburg K, Barker DJP. Boys live dangerously in the womb. Am J Hum Biol. 2010; doi:10.1002/ajhb.20995. 25. Ounsted M, Scott A, Ounsted C. Transmission through the female line of a mechanism constraining human fetal growth. Ann Hum Biol. 1986; 13, 143–151. 26. Ravelli AC, van der Meulen JHP, Osmond C, Barker DJP, Bleker OP. Obesity at the age of 50 y in men and women exposed to famine prenatally. Am J Clin Nutr. 1999; 70, 811–816. 27. Ozaki T, Nishina H, Hanson MA, Poston L. Dietary restriction in pregnant rats causes gender-related hypertension and vascular dysfunction in offspring. J Physiol. 2001; 530, 141–152. 28. Woods LL, Ingelfinger JR, Rasch R. Modest maternal protein restriction fails to program adult hypertension in female rats. Am J Physiol Regul Integr Comp Physiol. 2005; 289, R1131–R1136. 29. Grigore D, Ojeda NB, Alexander BT. Sex differences in the fetal programming of hypertension. Gend Med. 2008; 5(Suppl. A), S121–S132. 30. Coall DA, Charles AK, Salafia CM. Gross placental structure in a low-risk population of singleton, term, first born infants. Ped Develop Path. 2009; 12, 200–210.
REVIEW
Beyond birthweight: the maternal and placental origins of chronic disease D. J. P. Barker1,2,3*, K. L. Thornburg2, C. Osmond1, E. Kajantie4,5 and J. G. Eriksson4,6,7,8,9 1
MRC Epidemiology Resource Centre, Southampton General Hospital, University of Southampton, Southampton, UK Heart Research Center, Oregon Health and Science University, Portland, OR, USA 3 Fetal Programming Research Chair, King Saud University, Saudi Arabia 4 Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland 5 Hospital for Children and Adolescents, Helsinki University Central Hospital, Helsinki, Finland 6 Department of General Practice and Primary Health Care, University of Helsinki, Helsinginyliopisto, Finland 7 Vasa Central Hospital, Sandviksgatan 2–4, Vasa, Finland 8 Folkha¨lsan Research Centre, Helsinki, Helsingfors Universitet, Finland 9 Unit of General Practice, Helsinki University Central Hospital, Finland 2
New findings on the maternal and placental programming of chronic disease lead to four conclusions: (1) Growth of the placental surface is polarized from the time of implantation, so that growth along the major axis, the length, is qualitatively different from growth along the minor axis, the breadth. (2) The human fetus may attempt to compensate for undernutrition by expansion of the placental surface along its minor axis. This only occurs if the mother was well nourished before conception, and may have long-term costs that include hypertension. (3) The effects of placental size on long-term health are conditioned by the mother’s nutritional state, as indicated by her socio-economic status, height and body mass index. (4) The maternal–placental programming of chronic disease differs in boys and girls. Boys invest less than girls in placental growth but more readily expand the placental surface if they become undernourished in mid-late gestation. Boys are more responsive to their mothers’ current diets while girls respond more to their mothers’ lifetime nutrition and metabolism. Received 9 March 2010; Revised 28 April 2010; Accepted 10 May 2010; First published online 10 June 2010 Key words: placental size, maternal body size, chronic disease
Introduction
Measurements of placental size that reflect function
To date, most epidemiological observations that have shown a link between prenatal life and later chronic disease have used birthweight as a marker of early life. A baby’s birthweight reflects its success in obtaining nutrients from its mother.1 The source of these nutrients is not only the mother’s daily diet, but her nutritional stores and metabolism, which are the product of her lifetime nutrition.2 We have previously reviewed how the nutrition and growth of girls during infancy, childhood and at puberty influence chronic disease in the next generation.3 A baby’s nutrition also depends on the placenta’s ability to transport nutrients to it from the mother.1 We here use new data from the Helsinki Birth Cohort to review three questions: (1) What measures of placental size can be used as markers of its function? (2) Is a large placenta always beneficial? (3) Are there sex differences in the maternal–placental phenotypes that predict chronic disease?
Low placental weight at birth has been shown to predict hypertension and coronary heart disease in later life.4,5 Placental weight, however, does not distinguish the surface area of the placenta from its thickness. In order to increase the surface for nutrient and oxygen exchange, the placenta can increase the surface area of its villi, or expand its invasion across the surface of the uterine lining or invade the maternal spiral arteries more deeply. The long-term consequences may be different. Textbooks of midwifery written early in the last century describe the placental surface as being either ‘oval’ or ‘round’.6,7 In order to measure the extent to which the surface was more oval than round, two so-called ‘diameters’ of the surface were routinely recorded in some hospitals in the past: a maximal diameter, the length, and a lesser one bisecting it at right angles, the width. These measurements are available for the Helsinki Birth Cohort that comprises 20,436 men and women born in the city during 1924–1944.8 The mean sizes of the length and breadth were 19.5 and 16.9 cm, and the sizes were highly correlated (correlation coefficient 5 0.63). We used the length and breadth to estimate the surface area. How closely this area reflects the total surface area for maternal–fetal exchange through the gestational period is not known. A thin placenta with a large surface area could have
*Address for correspondence: Prof. D. J. P. Barker, MRC Epidemiology Resource Centre, Southampton General Hospital, University of Southampton, Southampton, SO16 6YD, UK. (Email [email protected])
Beyond birthweight
361
Table 1. Mean systolic blood pressure of men and women, aged 50 years, born at term Placental weight (pounds) Birthweight (pounds)
1.0
1.25
1.5
.1.5
6.5 7.5 .7.5
149 139 131
152 148 143
151 146 148
167 159 153
the major axis is aligned to the rostro-caudal axis of the embryo, while the minor axis is more important for nutrient transfer to the fetus. Fig. 1. Odds ratios for preeclampsia according to the diameters of the placental surface.
a smaller villous exchange surface than a thick placenta with a small surface area. Nevertheless, it seems reasonable to suppose that the surface area measured in the Helsinki data correlates with the exchange area. We combined the two diameters and placental weight to estimate thickness. Preeclampsia is associated with abnormal placentation as a result of impaired invasion of the maternal spiral arteries by the trophoblast at implantation.9 We examined the effect of preeclampsia on placental area and thickness.10 In all, 6410 of the mothers of the younger part of the Helsinki birth cohort, born 1934–1944, had their blood pressures and the results of urinary protein tests recorded after 20 weeks of pregnancy; 284 of these pregnancies were complicated by preeclampsia. Compared to normotensive pregnancies, the placentas from these pregnancies had a reduced surface area, but the thickness was increased. We speculated that the increase in thickness in preeclampsia was compensatory for restricted expansion of the surface. Placentas from pregnancies complicated by preeclampsia had a more oval surface than those from normotensive pregnancies because of a disproportionate reduction in the breadth. When the length and breadth were analyzed together, preeclampsia was not associated with the size of the length, but was strongly associated with a short breadth. This is shown in Figure 1. The relationship with the breadth was graded: the shorter the breadth, the greater the risk for, and severity of, preeclampsia. This association with short breadth depended on its absolute size rather on its size in relation to the size of the length. Processes that underlie the disease may therefore be closely linked to the absolute amount of placental tissue on the breadth of the placental surface. This link must be through a structure or function that it does not share with tissue along the length. We postulated that placental growth is polarized from the time of implantation, so that growth along the major axis, defined by the length, is qualitatively different from growth along the minor axis.10 One possibility is that
Large placentas The ability of the placenta to transfer nutrients from the mother to the baby is reflected in its overall size.11 Babies whose birthweights are toward the lower end of the normal range generally have small placentas, and low placental weight is associated with hypertension in later life.4 However, a study of men and women born in a maternity hospital in Preston, UK, showed that high placental weight in relation to birthweight is also associated with later hypertension.12 Table 1 shows that whereas people who had both low placental weight and low birthweight had higher mean systolic blood pressures than those who had low placental weight but high birthweight, the highest mean systolic pressures occurred in people who had high placental weight but low birthweight. This observation has been replicated, and high placental weight in relation to birthweight has also been shown to predict coronary heart disease.4,13 An additional point made by Table 1 is that the ability of birthweight to predict blood pressure is enhanced if the size of the placenta is taken into account.12 The associations with large placental size shown in Table 1 suggest that cardiovascular disease can be initiated through placental overgrowth as well as through restricted placental growth. Observations in sheep show that in response to undernutrition a fetus is able to extend the area of the placenta by expanding the individual cotyledons.14,15 This increases the area available for nutrient and oxygen exchange, and results in a larger lamb than there would otherwise have been. This is profitable for the farmer, and manipulation of placental size by changing the pasture of pregnant ewes is standard practice in sheep farming. Placental overgrowth in response to undernutrition in mid-gestation can only occur, however, if the ewe was well nourished before conception.15 There is evidence of a similar phenomenon in humans. 2003 members of the Helsinki Birth Cohort were randomly selected to attend a clinic; 644 were being treated for hypertension.8 We found that the effects of placental size on hypertension depended on the mother’s socio-economic status, a marker of her current
362
D. J. P. Barker et al.
Fig. 2. Prevalence of hypertension according to placental area in the offspring of short and tall mothers.
nutrition, and on her height, which reflected her nutrition and metabolism in childhood and adolescence.8,16 In people whose mothers were of low socio-economic status or below average height, hypertension was associated with low placental weight and area. In people whose mothers were likely to have been the best nourished, being tall and middle class, hypertension was predicted by large placental size in relation to birthweight. Figure 2 shows the trends in the prevalence of hypertension in people divided according to whether their mother’s height was above or below the median of 160 cm. In people whose mothers were short, the prevalence of hypertension fell progressively with increasing placental area. In people with tall mothers, the association was U-shaped, the prevalence initially falling as area increased but thereafter rising. Therefore, while the effect of small placental area on hypertension was similar in the two maternal height groups, a large area was associated with almost double the prevalence of hypertension in the offspring of tall mothers when compared with the offspring of short mothers. These different trends in hypertension with placental area in people born to short or tall mothers suggest a link between hypertension and the lifetime nutrition of the mother. Short maternal stature is a product of poor fetal or childhood nutrition, or recurrent exposure to infections, though there are also genetic influences.16 Protein metabolism is established in early life and is related to visceral mass. Short women have less visceral mass than tall women and have reduced rates of protein synthesis in pregnancy.2,17 In short mothers, an increased placental surface for protein transport might offset reduced rates of synthesis. Among people with tall mothers, there was no overall effect of placental area on hypertension (Fig. 2). When, however, these offspring were subdivided by the family’s socioeconomic status, two opposing trends were revealed. In lower social class families, hypertension was associated with small placental area and low weight. In middle class families, hypertension was associated with large placental area and high placental weight in relation to birthweight. Tall mothers in
middle class families are likely to have been the best nourished before conception. During pregnancy, however, they would have been subject to the food scarcities that occurred in Finland around the time of the Second World War.18 We speculate that, similar to sheep, their fetuses responded to this by expansion of the placental surface. Compensatory placental growth may be beneficial in some circumstances, but if the compensation is inadequate and the fetus continues to be undernourished, the need to share its nutrients with an enlarged placenta may become an added metabolic burden. A long-term cost of this added burden is hypertension, possibly as a result of impaired development of low priority organs like the kidney.19 Among the offspring of tall, middle class mothers, hypertension was associated with above average birthweight. This suggests that, as in sheep, placental enlargement in response to fetoplacental malnutrition leads to increased body size at birth. Epidemiological studies that include large numbers of tall, middle class mothers may therefore fail to show the well-known association between low birthweight and later hypertension. A general point made by Figure 2 is that, just as the ability of birthweight to predict long-term outcomes is enhanced if the size of the placenta is taken into account, the ability of placental size to predict outcomes is enhanced if maternal body size is known. Of the two diameters of the surface, breadth was more closely associated with hypertension.8 The interaction between the effects of mother’s height and placental area (Fig. 2) was reflected in a similar interaction between the effects of mother’s height and the breadth of the surface, but there was no interaction between mother’s height and the length. These findings are consistent with the idea that placental tissue along the breadth of the surface is more important for nutrient transfer to the fetus than tissue along the length, and expansion of the placental surface along its minor axis is one way in which a fetus may compensate for malnutrition. The findings on hypertension show that the effects of placental size on the fetus are conditioned by the mother’s height. Studies of lung cancer show that they are also conditioned by the mother’s body mass index in pregnancy height/weight2, a marker for her glucose and lipid metabolism.20,21 Sex differences in the placenta Boys grow faster than girls from an early stage of gestation, even from before implantation, and this makes them more vulnerable if their nutrition is compromised.16,22 We have examined the differences in fetal and placental size at birth among boys and girls in the Helsinki Birth Cohort.23 We found that the small differences in average body measurements concealed large differences in body proportions. At any placental weight, boys tended to be taller than girls; and boys’ placentas were smaller than girls’ placentas when related to the weight of the baby.23 This suggests that boys’ placentas are more efficient but may have less reserve capacity, which therefore increases their
Beyond birthweight
Fig. 3. Odds ratios for hypertension in women according to mother’s height and placental weight.
vulnerability to undernutrition. Boys tend to have larger head circumferences at birth but are thinner than girls.24 This suggests that they may more readily trade off visceral development to protect brain growth. The growth of every human fetus is constrained by the limited capacity of the mother and placenta to deliver nutrients to it.25 The male fetus, by growing more rapidly and investing in brain growth rather than placental growth, is adopting a more dangerous strategy that puts it at greater risk of becoming undernourished. We found that the relationship between placental diameters and later hypertension was different in the two sexes.24 In women, hypertension was associated with short breadth and small placental area. In men, it was associated with large breadth in relation to birthweight. This suggests that compensatory expansion of the placental breadth may occur more readily in boys. Direct evidence for this comes from findings in the Dutch famine (van Abeleen et al., personal communication). The dangerous growth strategy of boys may therefore be compounded by the costs of compensatory placental enlargement in mid-late gestation. Among women the trends in hypertension with small placental area and low placental weight were stronger in those whose mothers were short (Fig. 3).24 The trends did not differ with the mother’s social class. In contrast, among men the trend in hypertension with a greater breadth in relation to birthweight was not influenced by the mother’s height but differed according to the mother’s social class. Figure 4 shows that the trend was confined to men whose mothers were middle class (Fig. 4). An interpretation of these findings is that during development in the womb, girls respond more to their mother’s lifetime nutrition and metabolism, indicated by her height, whereas boys respond more to their mother’s current diet, indicated by her social class. The greater effect of the Dutch famine on the numbers of boys supports this,26 as do the greater effects of experimental alterations in maternal diet on male animals.27–29 While boys’
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Fig. 4. Odds ratios for hypertension in men according to the mother’s socio-economic status and the ratio of the lesser placental diameter to birthweight.
responsiveness to their mothers’ current diet enables them to capitalize on improving food supply, and promotes their agenda of rapid growth, it makes them vulnerable to food shortages. Conclusions Birthweight is a crude marker of fetal nutrition. The same weight may result from a variety of different nutritional circumstances. A priori, it was likely that epidemiological associations between birthweight and later disease would not always be consistent. To some extent, these inconsistencies can be reduced by using additional measures of body size at birth, including length and head circumference. This study suggests that the size and shape of the placental surface is a new epidemiological marker. There is already a body of knowledge about the maternal determinants of normal placental structure.30 The biological functions that underlie the associations between different maternal–placental phenotypes and later disease now need to be explored. This study leads to four conclusions about the maternal– placental programming of chronic disease: (1) Growth of the placental surface is polarized from the time of implantation, so that growth along the major axis is qualitatively different from growth along the minor axis. (2) The human fetus may attempt to compensate for undernutriton by expansion of the placental surface along its minor axis. (3) The effects of placental size on long-term health are conditioned by the mother’s nutritional state, as indicated by her socio-economic status and height. (4) The maternal–placental programming of chronic disease differs in boys and girls. Acknowledgements This study was supported by the British Heart Foundation, the Academy of Finland, the Paivikki and Sakari Sohlberg
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Foundation, the Finnish Diabetes Research Foundation, the Finnish Foundation for Cardiovascular Research, the Finnish Medical Society Duodecim, Yrjo Jahnsson Foundation, Finska Lakaresa¨llskapet. References 1. Harding JE. The nutritional basis of the fetal origins of adult disease. Int J Epidemiol. 2001; 30, 15–23. 2. Jackson AA. All that glitters. British Nutrition Foundation Annual Lecture. Nutr Bull. 2000; 25, 11–24. 3. Barker DJP, Osmond C, Kajantie E, Eriksson JG. Growth and chronic disease: findings in the Helsinki Birth Cohort. Ann Hum Biol. 2009; 36, 445–458. 4. Eriksson J, Forsen T, Toumilheto J, Osmond C, Barker D. Fetal and childhood growth and hypertension in adult life. Hypertension. 2000; 36, 790–794. 5. Forse´n T, Eriksson JG, Tuomilehto J, et al. ‘Mother’s weight in pregnancy and coronary heart disease in a cohort of Finnish men: follow up study’. BMJ. 1997; 315, 837–840. 6. Anderson MC. Lessons in Midwifery for Nurses and Midwifes, 1930. A & C Black: London. 7. Hinselmann H. Biologie und Pathologie des Weibes, 1925. Urban & Schwarzenberg: Berlin. 8. Barker DJP, Thornburg KL, Osmond C, Kajantie E, Eriksson JG. The surface area of the placenta and hypertension in the offspring in later life. Int J Dev Biol. 2010; 54, 525–530. 9. Roberts JM, Cooper DW. Pathogenesis and genetics of preeclampsia. Lancet. 2001; 357, 53–56. 10. Kajantie E, Barker DJP, Osmond C, Kajantie E, Eriksson JG. In pre-eclampsia the placenta grows slowly along its minor axis. Int J Dev Biol. 2010; 54, 469–473. 11. Sibley CP. The pregnant woman. In Human Physiology: Age, Stress, and the Environment (eds. Case RM, Waterhouse JM), 1994; pp. 3–27. Oxford University Press: Oxford. 12. Barker DJP, Bull AR, Osmond C, Simmonds S. Fetal and placental size and risk of hypertension in adult life. BMJ. 1990; 301, 259–262. 13. Martyn CN, Barker DJP, Osmond C. Mothers pelvic size, fetal growth and death from stroke in men. Lancet. 1996; 348, 1264–1268. 14. McCrabb GJ, Egan AR, Hosking BJ. Maternal undernutrition during mid-pregnancy in sheep. Placental size and its relationship to calcium transfer during late pregnancy. Br J Nutr. 1991; 65, 157–168. 15. McCrabb GJ, Egan AR, Hosking BJ. Maternal undernutrition during mid-pregnancy in sheep: variable effects on placental growth. J Agric Sci. 1992; 118, 127–132.
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