Skip to main content Accessibility help

Placental restriction in multi-fetal pregnancies and between-twin differences in size at birth alter neonatal feeding behaviour in the sheep

  • R. F. Peter (a1), J. Gugusheff (a1), A. L. Wooldridge (a2) (a3), K. L. Gatford (a2) (a3) and B. S. Muhlhausler (a1)...


Most individuals whose growth was restricted before birth undergo accelerated or catch-up neonatal growth. This is an independent risk factor for later metabolic disease, but the underlying mechanisms are poorly understood. This study aimed to test the hypothesis that natural and experimentally induced in utero growth restriction increase neonatal appetite and milk intake. Control (CON) and placentally restricted (PR) ewes carrying multiple fetuses delivered naturally at term. Outcomes were compared between CON (n=14) and PR (n=12) progeny and within twin lamb pairs. Lamb milk intake and feeding behaviour and ewe milk composition were determined using a modified weigh-suckle-weigh procedure on days 15 and 23. PR lambs tended to have lower birth weights than CON (−15%, P=0.052). Neonatal growth rates were similar in CON and PR, whilst heavier twins grew faster in absolute but not fractional terms than their co-twins. At day 23, milk protein content was higher in PR than CON ewes (P=0.038). At day 15, PR lambs had fewer suckling bouts than CON lambs and in females light twins had more suckling attempts than their heavier co-twins. Birth weight differences between twins positively predicted differences in milk intakes. Lactational constraint and natural prenatal growth restriction in twins may explain the similar milk intakes in CON and PR. Within twin comparisons support the hypothesis that prenatal constraint increases lamb appetite, although this did not increase milk intake. We suggest that future mechanistic studies of catch-up growth be performed in singletons and be powered to assess effects in each sex.


Corresponding author

*Address for correspondence: B. S. Muhlhausler, FOODplus Research Centre, The University of Adelaide, Adelaide, South Australia 5064, Australia. (Email


Hide All

Joint senior authors.



Hide All
1. Rosenberg, A. The IUGR newborn. Semin Perinatol. 2008; 32, 219224.
2. Sharma, D, Shastri, S, Farahbakhsh, N, Sharma, P. Intrauterine growth restriction – Part 1. J Matern Fetal Neonatal Med. 2016; 29, 39773987.
3. Sankaran, S, Kyle, PM. Aetiology and pathogenesis of IUGR. Best Pract Res Clin Obstet Gynaecol. 2009; 23, 765777.
4. Tenovuo, A, Kero, P, Piekkala, P, et al. Growth of 519 small for gestational age infants during the first two years of life. Acta Paed Scand. 1987; 76, 636646.
5. Albertsson-Wikland, K, Karlberg, J. Postnatal growth of children born small for gestational age. Acta Paediatrica. 1997; 423, 193195.
6. Eriksson, JG, Forsen, T, Tuomilehto, J, et al. Catch-up growth in childhood and death from coronary heart disease: longitudinal study. BMJ. 1999; 318, 427431.
7. Forsen, T, Eriksson, J, Tuomilehto, J, et al. The fetal and childhood growth of persons who develop type 2 diabetes. Ann Intern Med. 2000; 133, 176182.
8. Huxley, RR, Shiell, AW, Law, CM. The role of size at birth and postnatal catch-up growth in determining systolic blood pressure: a systematic review of the literature. J Hypertens. 2000; 18, 815831.
9. Ong, KK, Ahmed, ML, Emmett, PM, Preece, MA, Dunger, DB. Association between postnatal catch-up growth and obesity in childhood: prospective cohort study. BMJ. 2000; 320, 967971.
10. Ounsted, M, Sleigh, G. The infant’s self-regulation of food intake and weight gain. Difference in metabolic balance after growth constraint or acceleration in utero. Lancet. 1975; 1, 13931397.
11. Greenwood, PL, Hunt, AS, Hermanson, JW, Bell, AW. Effects of birth weight and postnatal nutrition on neonatal sheep: I. Body growth and composition, and some aspects of energetic efficiency. J Anim Sci. 1998; 76, 23542367.
12. Vickers, MH, Breier, BH, Cutfield, WS, Hofman, PL, Gluckman, PD. Fetal origins of hyperphagia, obesity, and hypertension and postnatal amplification by hypercaloric nutrition. Am J Physiol. 2000; 279, E83E87.
13. Laporte-Broux, B, Roussel, S, Ponter, AA, et al. Long-term consequences of feed restriction during late pregnancy in goats on feeding behavior and emotional reactivity of female offspring. Physiol Behav. 2012; 106, 178184.
14. Laporte-Broux, B, Roussel, S, Ponter, AA, et al. Short-term effects of maternal feed restriction during pregnancy on goat kid morphology, metabolism, and behavior. J Anim Sci. 2011; 89, 21542163.
15. Alexander, G. Studies on the placenta of the sheep. J Reprod Fertil. 1964; 7, 289305.
16. Robinson, JS, Kingston, EJ, Jones, CT, Thorburn, GD. Studies on experimental growth retardation in sheep. The effect of removal of endometrial caruncles on fetal size and metabolism. J Develop Physiol. 1979; 1, 379398.
17. De Blasio, MJ, Gatford, KL, McMillen, IC, Robinson, JS, Owens, JA. Placental restriction of fetal growth increases insulin action, growth and adiposity in the young lamb. Endocrinology. 2006; 148, 13501358.
18. De Blasio, MJ, Gatford, KL, Robinson, JS, Owens, JA. Placental restriction of fetal growth reduces size at birth and alters postnatal growth, feeding activity, and adiposity in the young lamb. Am J Physiol Regul Integr Comp Physiol. 2007; 292, R875R886.
19. O’Dowd, R, Kent, JC, Moseley, JM, Wlodek, ME. Effects of uteroplacental insufficiency and reducing litter size on maternal mammary function and postnatal offspring growth. Am J Physiol Regul Integr Comp Physiol. 2008; 294, R539R548.
20. National Health and Medical Research Council. Australian Code for the Care and Use of Animals for Scientific Purposes, 8th edn, 2013. National Health and Medical Research Council: Canberra.
21. Kaur, M, Wooldridge, AL, Wilkes, MJ, et al. Placental restriction in multi-fetal pregnancies increases spontaneous ambulatory activity during daylight hours in young adult female sheep. J Dev Orig Health Dis. 2016; 7, 525537.
22. Vonnahme, KA, Arndt, WJ, Johnson, ML, Borowicz, PP, Reynolds, LP. Effect of morphology on placentome size, vascularity, and vasoreactivity in late pregnant sheep. Biol Reprod. 2008; 79, 976982.
23. Muhlhausler, BS, Adam, CL, Findlay, PA, Duffield, JA, McMillen, IC. Increased maternal nutrition alters development of the appetite-regulating network in the brain. FASEB J. 2006; 20, 12571259.
24. Hinch, GN. The suckling behaviour of triplet, twin and single lambs at pasture. Appl Anim Behav Sci. 1989; 22, 3948.
25. Nommsen, LA, Lovelady, CA, Heinig, MJ, Lonnerdal, B, Dewey, KG. Determinants of energy, protein, lipid, and lactose concentrations in human milk during the first 12 mo of lactation: the DARLING Study. Am J Clin Nutr. 1991; 53, 457465.
26. Falconer, J, Owens, JA, Allotta, E, Robinson, JS. Effect of restriction of placental growth on the concentrations of insulin, glucose and placental lactogen in the plasma of sheep. J Endocrinol. 1985; 106, 711.
27. Hayden, TJ, Thomas, CR, Forsyth, IA. Effect of number of young born (litter size) on milk yield of goats: role for placental lactogen. J Dairy Sci. 1979; 62, 5363.
28. Martal, J, Djiane, J. Mammotrophic and growth promoting activities of a placental hormone in sheep. J Steroid Biochem. 1977; 8, 415417.
29. Leibovich, H, Gertler, A, Bazer, F, Gootwine, E. Effects of recombinant ovine placental lactogen and recombinant ovine growth hormone on growth of lambs and milk production of ewes. Livestock Production Sci. 2001; 68, 7986.
30. Prentice, P, Ong, KK, Schoemaker, MH, et al. Breast milk nutrient content and infancy growth. Acta Paediatr. 2016; 105, 641647.
31. Koletzko, B, von Kries, R, Closa, R, et al. Lower protein in infant formula is associated with lower weight up to age 2 y: a randomized clinical trial. Am J Clin Nutr. 2009; 89, 18361845.
32. Torres-Hernandez, G, Hohenboken, W. Relationships between ewe milk production and composition and preweaning lamb weight gain. J Anim Sci. 1980; 50, 597603.
33. Domany, KA, Mandel, D, Hausman Kedem, M, Lubetzky, R. Breast milk fat content of mothers to small-for-gestational-age infants. J Perinatol. 2015; 35, 444446.
34. Bobinski, R, Mikulska, M, Mojska, H, Simon, M. Comparison of the fatty acid composition of transitional and mature milk of mothers who delivered healthy full-term babies, preterm babies and full-term small for gestational age infants. Eur J Clin Nutr. 2013; 67, 966971.
35. Daly, SE, Di Rosso, A, Owens, RA, Hartmann, PE. Degree of breast emptying explains changes in the fat content, but not fatty acid composition, of human milk. Exp Physiol. 1993; 78, 741755.
36. Jaquiery, AL, Oliver, MH, Bloomfield, FH, Harding, JE. Periconceptional events perturb postnatal growth regulation in sheep. Pediatr Res. 2011; 70, 261266.
37. Cameron, EZ. Is suckling behaviour a useful predictor of milk intake? A review. Animal Behaviour. 1998; 56, 521532.
38. van der Linden, DS, Sciascia, Q, Sales, F, McCoard, SA. Placental nutrient transport is affected by pregnancy rank in sheep. J Anim Sci. 2013; 91, 644653.
39. Muhlhausler, BS, Hancock, SN, Bloomfield, FH, Harding, R. Are twins growth restricted? Pediatr Res. 2011; 70, 117122.
40. Hancock, SN, Oliver, MH, McLean, C, Jaquiery, AL, Bloomfield, FH. Size at birth and adult fat mass in twin sheep are determined in early gestation. J Physiol. 2012; 590, 12731285.
41. Davies, MJ. Fetal programming: the perspective of single and twin pregnancies. Reprod Fertil Dev. 2005; 17, 379386.
42. Morrison, JL. Sheep models of intrauterine growth restriction: fetal adaptations and consequences. Clin Exp Pharmacol Physiol. 2008; 35, 730743.
43. Benson, ME, Henry, MJ, Cardellino, RA. Comparison of weigh-suckle-weigh and machine milking for measuring ewe milk production. J Anim Sci. 1999; 77, 23302335.
44. Muhlhausler, BS, Duffield, JA, Ozanne, SE, et al. The transition from fetal growth restriction to accelerated postnatal growth: a potential role for insulin signalling in skeletal muscle. J Physiol. 2009; 587, 41994211.
45. Gruenwald, P. Growth of the human fetus. II. Abnormal growth in twins and infants of mothers with diabetes, hypertension, or isoimmunization. Am J Obstet Gynecol. 1966; 94, 11201132.
46. Thompson, GE. The intake of milk by suckled, newborn lambs and the effects of twinning and cold exposure. Br J Nutr. 1983; 50.
47. Dove, H. Estimation of the intake of milk by lambs, from the turnover of deuterium- or tritium-labelled water. Br J Nutr. 1988; 60, 375387.



Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed