Abstract
Despite improvements in clinical management, pregnancies complicated by pre-existing diabetes mellitus, gestational diabetes mellitus or obesity carry substantial risks for parent and offspring. Some of the endocrine and metabolic changes in parent and fetus in diabetes mellitus and obesity lead to fetal oxygen deficit, mostly due to insulin-induced accelerated fetal metabolism. The human fetus deals with reduced oxygenation through a wide range of adaptive responses that act at various levels in the placenta as well as the fetus. These responses ensure adequate oxygen delivery to the fetus, increase the oxygen transport capacity of fetal blood and redistribute oxygen-rich blood to vital organs such as the brain and heart. The liver has a central role in adapting to reduced oxygenation by increasing its oxygen extraction and stimulating erythropoietin synthesis to increase haematocrit. The type of adaptive response depends on the onset and duration of hypoxia and the severity of the metabolic disturbance. In pregnancies characterized by diabetes mellitus or obesity, these adaptive systems come under additional strain owing to the increased maternal supply of glucose and resultant fetal hyperinsulinaemia, both of which stimulate oxidative metabolism. In the rare situation that the adaptive responses are overwhelmed, stillbirth can ensue.
Key points
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Pre-existing diabetes mellitus and obesity during pregnancy can be associated with poor remodelling of the uterine spiral arteries and thus a reduction in oxygen delivery to the placenta, resulting in chronic fetal hypoxia.
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In pregnancies in people with diabetes mellitus, fetal hyperglycaemia and hyperinsulinaemia stimulate fetal metabolism and increase fetal oxygen uptake; this increase leads to metabolically induced oxygen deficit of varying degree and duration.
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Compensations for hypoxia include increasing oxygen delivery through an increase in fetal haematocrit and increasing fractional oxygen extraction as reflected in the decreased oxygen content of umbilical arterial blood.
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The fetal liver has a key role both in initiating hypoxia through increased metabolism and in compensation through increased secretion of erythropoietin and thus heightened haematopoiesis and increased haematocrit.
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Fetal outcomes will vary depending on the onset and duration of hypoxia and the degree of compensation but can include fetal growth restriction or even fetal demise.
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References
Feig, D. S. et al. Trends in incidence of diabetes in pregnancy and serious perinatal outcomes: a large, population-based study in Ontario, Canada, 1996–2010. Diabetes Care 37, 1590–1596 (2014).
Knorr, S. et al. Multisystem morbidity and mortality in offspring of women with type 1 diabetes (the EPICOM study): a register-based prospective cohort study. Diabetes Care 38, 821–826 (2015).
McIntyre, H. D. et al. Gestational diabetes mellitus. Nat. Rev. Dis. Primers 5, 47 (2019).
Godfrey, K. M. et al. Influence of maternal obesity on the long-term health of offspring. Lancet Diabetes Endocrinol. 5, 53–64 (2017).
Hjort, L. et al. Diabetes in pregnancy and epigenetic mechanisms — how the first 9 months from conception might affect the child’s epigenome and later risk of disease. Lancet Diabetes Endocrinol. 7, 796–806 (2019).
Desoye, G. & Herrera, E. Adipose tissue development and lipid metabolism in the human fetus: the 2020 perspective focusing on maternal diabetes and obesity. Prog. Lipid Res. 81, 101082 (2021).
Sacks, D. A. Etiology, detection, and management of fetal macrosomia in pregnancies complicated by diabetes mellitus. Clin. Obstet. Gynecol. 50, 980–989 (2007).
Teramo, K. A. Obstetric problems in diabetic pregnancy–the role of fetal hypoxia. Best Pract. Res. Clin. Endocrinol. Metab. 24, 663–671 (2010). A comprehensive discussion of reasons for fetal hypoxia and how it can be assessed.
Itskovitz, J., LaGamma, E. F. & Rudolph, A. M. Effects of cord compression on fetal blood flow distribution and O2 delivery. Am. J. Physiol. 252, H100–H109 (1987).
Edelstone, D. I., Darby, M. J., Bass, K. & Miller, K. Effects of reductions in hemoglobin-oxygen affinity and hematocrit level on oxygen consumption and acid-base state in fetal lambs. Am. J. Obstet. Gynecol. 160, 820–826 (1989); discussion 160, 826–828 (1989).
Lang, U., Baker, R. S., Khoury, J. & Clark, K. E. Effects of chronic reduction in uterine blood flow on fetal and placental growth in the sheep. Am. J. Physiol. Regul. Integr. Comp. Physiol. 279, R53–R59 (2000).
Jacobs, R., Robinson, J. S., Owens, J. A., Falconer, J. & Webster, M. E. The effect of prolonged hypobaric hypoxia on growth of fetal sheep. J. Dev. Physiol. 10, 97–112 (1988).
Moore, L. G. Hypoxia and reproductive health: reproductive challenges at high altitude: fertility, pregnancy and neonatal well-being. Reproduction 161, F81–F90 (2021).
Postigo, L. et al. Where the O2 goes to: preservation of human fetal oxygen delivery and consumption at high altitude. J. Physiol. 587, 693–708 (2009).
Susa, J. B. et al. Chronic hyperinsulinemia in the fetal rhesus monkey: effects of physiologic hyperinsulinemia on fetal substrates, hormones, and hepatic enzymes. Am. J. Obstet. Gynecol. 150, 415–420 (1984).
Hay, W. W. Jr & Sparks, J. W. Placental, fetal, and neonatal carbohydrate metabolism. Clin. Obstet. Gynecol. 28, 473–485 (1985).
Hoch, D., Gauster, M., Hauguel-de Mouzon, S. & Desoye, G. Diabesity-associated oxidative and inflammatory stress signalling in the early human placenta. Mol. Asp. Med. 66, 21–30 (2019).
Desoye, G. The human placenta in diabetes and obesity: friend or foe? The 2017 Norbert Freinkel award lecture. Diabetes care 41, 1362–1369 (2018).
Rys, P. M., Ludwig-Slomczynska, A. H., Cyganek, K. & Malecki, M. T. Continuous subcutaneous insulin infusion vs multiple daily injections in pregnant women with type 1 diabetes mellitus: a systematic review and meta-analysis of randomised controlled trials and observational studies. Eur. J. Endocrinol. 178, 545–563 (2018).
Murphy, H. R. et al. Characteristics and outcomes of pregnant women with type 1 or type 2 diabetes: a 5-year national population-based cohort study. Lancet Diabetes Endocrinol. 9, 153–164 (2021).
Hillier, T. A. et al. A pragmatic, randomized clinical trial of gestational diabetes screening. N. Engl. J. Med. 384, 895–904 (2021).
Nam, H. K. & Lee, K. H. Small for gestational age and obesity: epidemiology and general risks. Ann. Pediatr. Endocrinol. Metab. 23, 9–13 (2018).
Teramo, K. A. & Widness, J. A. Increased fetal plasma and amniotic fluid erythropoietin concentrations: markers of intrauterine hypoxia. Neonatology 95, 105–116 (2009).
Davis, E. M. et al. Perinatal outcomes of two screening strategies for gestational diabetes mellitus: a randomized controlled trial. Obstet. Gynecol. 138, 6–15 (2021).
Aune, D., Saugstad, O. D., Henriksen, T. & Tonstad, S. Maternal body mass index and the risk of fetal death, stillbirth, and infant death: a systematic review and meta-analysis. JAMA 311, 1536–1546 (2014).
Carter, A. M. Placental gas exchange and the oxygen supply to the fetus. Compr. Physiol. 5, 1381–1403 (2015). A comprehensive account of the physiology of fetal oxygen homeostasis.
Carter, A. M., Enders, A. C. & Pijnenborg, R. The role of invasive trophoblast in implantation and placentation of primates. Phil. Trans. R. Soc. B 370, 20140070 (2015).
Aplin, J. D., Myers, J. E., Timms, K. & Westwood, M. Tracking placental development in health and disease. Nat. Rev. Endocrinol. 16, 479–494 (2020).
Stanley, J. L. et al. Effect of gestational diabetes on maternal artery function. Reprod. Sci. 18, 342–352 (2011).
Pietryga, M. et al. Abnormal uterine Doppler is related to vasculopathy in pregestational diabetes mellitus. Circulation 112, 2496–2500 (2005).
Pietryga, M., Brazert, J., Wender-Ozegowska, E., Dubiel, M. & Gudmundsson, S. Placental Doppler velocimetry in gestational diabetes mellitus. J. Perinat. Med. 34, 108–110 (2006).
Barth, W. H. Jr et al. Uterine arcuate artery Doppler and decidual microvascular pathology in pregnancies complicated by type I diabetes mellitus. Ultrasound Obstet. Gynecol. 8, 98–103 (1996).
Chen, C. Y., Chang, H. T., Chen, C. P. & Sun, F. J. First trimester placental vascular indices and volume by three-dimensional ultrasound in pre-gravid overweight women. Placenta 80, 12–17 (2019).
Castellana, B. et al. Maternal obesity alters uterine NK activity through a functional KIR2DL1/S1 imbalance. Immunol. Cell Biol. 96, 805–819 (2018).
Zamudio, S. et al. Hypoglycemia and the origin of hypoxia-induced reduction in human fetal growth. PLoS ONE 5, e8551 (2010).
Kitzmiller, J. L., Watt, N. & Driscoll, S. G. Decidual arteriopathy in hypertension and diabetes in pregnancy: immunofluorescent studies. Am. J. Obstet. Gynecol. 141, 773–779 (1981).
Grunewald, C., Divon, M. & Lunell, N. O. Doppler velocimetry in last trimester pregnancy complicated by insulin-dependent diabetes mellitus. Acta Obstet. Gynecol. Scand. 75, 804–808 (1996).
van den Elzen, H. J., Cohen-Overbeek, T. E., Grobbee, D. E., Quartero, R. W. & Wladimiroff, J. W. Early uterine artery Doppler velocimetry and the outcome of pregnancy in women aged 35 years and older. Ultrasound Obstet. Gynecol. 5, 328–333 (1995).
Golinska-Grzybala, K. et al. Subclinical cardiac performance in obese and overweight women as a potential risk factor of preeclampsia. Pregnancy Hypertens. 23, 131–135 (2021).
De Rosa, M. C. et al. Glycated human hemoglobin (HbA1c): functional characteristics and molecular modeling studies. Biophys. Chem. 72, 323–335 (1998).
Bell, A. W., Kennaugh, J. M., Battaglia, F. C., Makowski, E. L. & Meschia, G. Metabolic and circulatory studies of fetal lamb at midgestation. Am. J. Physiol. 250, E538–E544 (1986).
Bonds, D. R. et al. Estimation of human fetal-placental unit metabolic rate by application of the Bohr principle. J. Dev. Physiol. 8, 49–54 (1986).
Mackay, R. B. Observations of the oxygenation of the foetus in normal and abnormal pregnancy. J. Obstet. Gynaecol. Br. Emp. 64, 185–197 (1957).
Bianchi, C. et al. The role of obesity and gestational diabetes on placental size and fetal oxygenation. Placenta 103, 59–63 (2021).
Taricco, E. et al. Effects of gestational diabetes on fetal oxygen and glucose levels in vivo. BJOG 116, 1729–1735 (2009).
Salvesen, D. R. et al. Placental and fetal Doppler velocimetry in pregnancies complicated by maternal diabetes mellitus. Am. J. Obstet. Gynecol. 168, 645–652 (1993).
Michelsen, T. M. et al. Uteroplacental glucose uptake and fetal glucose consumption: a quantitative study in human pregnancies. J. Clin. Endocrinol. Metab. 104, 873–882 (2019). Clinical data that show that placental utilization of glucose is a modulator of the glucose supply to the human fetus.
Aldoretta, P. W. & Hay, W. W. Jr Metabolic substrates for fetal energy metabolism and growth. Clin. Perinatol. 22, 15–36 (1995).
Hay, W. W. Jr, DiGiacomo, J. E., Meznarich, H. K., Hirst, K. & Zerbe, G. Effects of glucose and insulin on fetal glucose oxidation and oxygen consumption. Am. J. Physiol. 256, E704–E713 (1989).
Capkova, A. & Jirasek, J. E. Glycogen reserves in organs of human foetuses in the first half of pregnancy. Biol. Neonat. 13, 129–142 (1968).
Shelley, H. J. Carbohydrate reserves in the newborn infant. Br. Med. J. 1, 273–275 (1964).
Char, V. C. & Creasy, R. K. Lactate and pyruvate as fetal metabolic substrates. Pediatr. Res. 10, 231–234 (1976).
Burd, L. I. et al. Placental production and foetal utilisation of lactate and pyruvate. Nature 254, 710–711 (1975).
Gresham, E. L. et al. Production and excretion of urea by the fetal lamb. Pediatrics 50, 372–379 (1972).
Hay, W. W. Jr et al. Glucose and lactate oxidation rates in the fetal lamb. Proc. Soc. Exp. Biol. Med. 173, 553–563 (1983).
Sparks, J. W., Hay, W. W. Jr, Bonds, D., Meschia, G. & Battaglia, F. C. Simultaneous measurements of lactate turnover rate and umbilical lactate uptake in the fetal lamb. J. Clin. Invest. 70, 179–192 (1982).
Loy, G. L. et al. Fetoplacental deamination and decarboxylation of leucine. Am. J. Physiol. 259, E492–E497 (1990).
van den Akker, C. H. et al. Amino acid metabolism in the human fetus at term: leucine, valine, and methionine kinetics. Pediatr. Res. 70, 566–571 (2011).
Cetin, I. Amino acid interconversions in the fetal-placental unit: the animal model and human studies in vivo. Pediatr. Res. 49, 148–154 (2001).
Chien, P. F. et al. Protein turnover in the human fetus studied at term using stable isotope tracer amino acids. Am. J. Physiol. 265, E31–E35 (1993).
Philipps, A. F., Porte, P. J., Stabinsky, S., Rosenkrantz, T. S. & Raye, J. R. Effects of chronic fetal hyperglycemia upon oxygen consumption in the ovine uterus and conceptus. J. Clin. Invest. 74, 279–286 (1984).
Philipps, A. F., Dubin, J. W., Matty, P. J. & Raye, J. R. Arterial hypoxemia and hyperinsulinemia in the chronically hyperglycemic fetal lamb. Pediatr. Res. 16, 653–658 (1982).
Philipson, E. H., Kalhan, S. C., Riha, M. M. & Pimentel, R. Effects of maternal glucose infusion on fetal acid-base status in human pregnancy. Am. J. Obstet. Gynecol. 157, 866–873 (1987).
Simmons, M. A., Jones, M. D. Jr, Battaglia, F. C. & Meschia, G. Insulin effect on fetal glucose utilization. Pediatr. Res. 12, 90–92 (1978).
Hay, W. W. Jr, Meznarich, H. K., DiGiacomo, J. E., Hirst, K. & Zerbe, G. Effects of insulin and glucose concentrations on glucose utilization in fetal sheep. Pediatr. Res. 23, 381–387 (1988).
Milley, J. R., Papacostas, J. S. & Tabata, B. K. Effect of insulin on uptake of metabolic substrates by the sheep fetus. Am. J. Physiol. 251, E349–E356 (1986).
Pedersen, J. Diabetes mellitus and pregnancy: present status of the hyperglycaemia–hyperinsulinism theory and the weight of the newborn baby. Postgrad. Med. J. 47 (Suppl.), 66–67 (1971).
Desoye, G. & Nolan, C. J. The fetal glucose steal: an underappreciated phenomenon in diabetic pregnancy. Diabetologia 59, 1089–1094 (2016).
Brown, L. D. & Hay, W. W. Jr Effect of hyperinsulinemia on amino acid utilization and oxidation independent of glucose metabolism in the ovine fetus. Am. J. Physiol. Endocrinol. Metab. 291, E1333–E1340 (2006).
Milley, J. R. et al. The effect of insulin on ovine fetal oxygen extraction. Am. J. Obstet. Gynecol. 149, 673–678 (1984).
Stonestreet, B. S. Effects of prolonged fetal hyperinsulinemia on plasma catecholamines, circulation and oxygen metabolism in utero. Dev. Pharmacol. Ther. 15, 35–44 (1990).
Carson, B. S., Philipps, A. F., Simmons, M. A., Battaglia, F. C. & Meschia, G. Effects of a sustained insulin infusion upon glucose uptake and oxygenation of the ovine fetus. Pediatr. Res. 14, 147–152 (1980).
Philipps, A. F., Dubin, J. W. & Raye, J. R. Fetal metabolic response to endogenous insulin release. Am. J. Obstet. Gynecol. 139, 441–445 (1981).
Stonestreet, B. S., Goldstein, M., Oh, W. & Widness, J. A. Effects of prolonged hyperinsulinemia on erythropoiesis in fetal sheep. Am. J. Physiol. 257, R1199–R1204 (1989).
Georgieff, M. K., Widness, J. A., Mills, M. M. & Stonestreet, B. S. The effect of prolonged intrauterine hyperinsulinemia on iron utilization in fetal sheep. Pediatr. Res. 26, 467–469 (1989).
Hay, W. W. Jr Recent observations on the regulation of fetal metabolism by glucose. J. Physiol. 572, 17–24 (2006).
Richardson, B. S., Ruttinger, S., Brown, H. K., Regnault, T. R. H. & de Vrijer, B. Maternal body mass index impacts fetal-placental size at birth and umbilical cord oxygen values with implications for regulatory mechanisms. Early Hum. Dev. 112, 42–47 (2017).
Sosenko, I. R. et al. The infant of the diabetic mother: correlation of increased cord C-peptide levels with macrosomia and hypoglycemia. N. Engl. J. Med. 301, 859–862 (1979).
Walsh, J. M., Segurado, R., Mahony, R. M., Foley, M. E. & McAuliffe, F. M. The effects of fetal gender on maternal and fetal insulin resistance. PLoS ONE 10, e0137215 (2015).
Shields, B. M. et al. Measurement of cord insulin and insulin-related peptides suggests that girls are more insulin resistant than boys at birth. Diabetes Care 30, 2661–2666 (2007).
Wilkin, T. J. & Murphy, M. J. The gender insulin hypothesis: why girls are born lighter than boys, and the implications for insulin resistance. Int. J. Obes. 30, 1056–1061 (2006).
Dong, Y. et al. Large-for-gestational-age may be associated with lower fetal insulin sensitivity and beta-cell function linked to leptin. J. Clin. Endocrinol. Metab. 103, 3837–3844 (2018).
Wang, X. et al. Correlation between maternal and fetal insulin resistance in pregnant women with gestational diabetes mellitus. Clin. Lab. 64, 945–953 (2018).
Hay, W. W. Jr, Meznarich, H. K., Sparks, J. W., Battaglia, F. C. & Meschia, G. Effect of insulin on glucose uptake in near-term fetal lambs. Proc. Soc. Exp. Biol. Med. 178, 557–564 (1985).
Hay, W. W. Jr, Lin, C. C. & Meznarich, H. K. Effect of high levels of insulin on glucose utilization and glucose production in pregnant and nonpregnant sheep. Proc. Soc. Exp. Biol. Med. 189, 275–284 (1988).
Dickinson, J. E., Meyer, B. A. & Palmer, S. M. Fetal vascular responses to maternal glucose administration in streptozocin-induced ovine diabetes mellitus. J. Obstet. Gynaecol. Res. 24, 325–333 (1998).
Cook, G. A. & Park, E. A. Expression and regulation of carnitine palmitoyltransferase-Ialpha and -Ibeta genes. Am. J. Med. Sci. 318, 43–48 (1999).
Nold, J. L. & Georgieff, M. K. Infants of diabetic mothers. Pediatr. Clin. North Am. 51, 619–637 (2004).
Kiserud, T. Diabetes in pregnancy: scanning the wrong horizon? Ultrasound Obstet. Gynecol. 36, 266–267 (2010).
Lund, A. et al. Altered development of fetal liver perfusion in pregnancies with pregestational diabetes. PLoS ONE 14, e0211788 (2019). Clinical data indicating that umbilical venous blood flow does not always keep pace with fetal growth in pregnancies with diabetes mellitus.
Neufeld, N. D., Scott, M. & Kaplan, S. A. Ontogeny of the mammalian insulin receptor. Studies of human and rat fetal liver plasma membranes. Dev. Biol. 78, 151–160 (1980).
Bonder, M. J. et al. Genetic and epigenetic regulation of gene expression in fetal and adult human livers. BMC Genomics 15, 860 (2014).
McCormick, K. L. et al. Chronic hyperinsulinemia in the fetal rhesus monkey: effects on hepatic enzymes active in lipogenesis and carbohydrate metabolism. Diabetes 28, 1064–1068 (1979).
Susa, J. B. et al. Chronic hyperinsulinemia in the fetal rhesus monkey: effects on fetal growth and composition. Diabetes 28, 1058–1063 (1979).
Rozance, P. J. et al. Effects of chronic hyperinsulinemia on metabolic pathways and insulin signaling in the fetal liver. Am. J. Physiol. Endocrinol. Metab. 319, E721–E733 (2020).
Radovic, S. M. et al. Insulin/IGF1 signaling regulates the mitochondrial biogenesis markers in steroidogenic cells of prepubertal testis, but not ovary. Biol. Reprod. 100, 253–267 (2019).
Emery, J. L. Functional asymmetry of the liver. Ann. NY Acad. Sci. 111, 37–44 (1963).
Cox, L. A. et al. Gene expression profile differences in left and right liver lobes from mid-gestation fetal baboons: a cautionary tale. J. Physiol. 572, 59–66 (2006).
Kiserud, T., Rasmussen, S. & Skulstad, S. Blood flow and the degree of shunting through the ductus venosus in the human fetus. Am. J. Obstet. Gynecol. 182, 147–153 (2000).
Botti, J. J., Edelstone, D. I., Caritis, S. N. & Mueller-Heubach, E. Portal venous blood flow distribution to liver and ductus venosus in newborn lambs. Am. J. Obstet. Gynecol. 144, 303–308 (1982).
Edelstone, D. I., Rudolph, A. M. & Heymann, M. A. Liver and ductus venosus blood flows in fetal lambs in utero. Circ. Res. 42, 426–433 (1978).
Rudolph, A. M. Hepatic and ductus venosus blood flows during fetal life. Hepatology 3, 254–258 (1983). Fundamental account of the distribution of umbilical venous blood flow and the shunting of blood through the ductus venosus and foramen ovale.
Kunisaki, S. M. et al. Fetal hepatic haematopoiesis is modulated by arterial blood flow to the liver. Br. J. Haematol. 134, 330–332 (2006).
Bristow, J., Rudolph, A. M., Itskovitz, J. & Barnes, R. Hepatic oxygen and glucose metabolism in the fetal lamb. Response to hypoxia. J. Clin. Invest. 71, 1047–1061 (1983).
Gruenwald, P. Degenerative changes in the right half of the liver resulting from intra-uterine anoxia. Am. J. Clin. Pathol. 19, 801–813 (1949).
Kilavuz, O. & Vetter, K. Is the liver of the fetus the 4th preferential organ for arterial blood supply besides brain, heart, and adrenal glands? J. Perinat. Med. 27, 103–106 (1999). Suggests that the fetal liver is an important regulatory site for the distribution of oxygenated blood between other organs.
Dubiel, M., Breborowicz, G. H. & Gudmundsson, S. Evaluation of fetal circulation redistribution in pregnancies with absent or reversed diastolic flow in the umbilical artery. Early Hum. Dev. 71, 149–156 (2003).
Tchirikov, M., Schroder, H. J. & Hecher, K. Ductus venosus shunting in the fetal venous circulation: regulatory mechanisms, diagnostic methods and medical importance. Ultrasound Obstet. Gynecol. 27, 452–461 (2006).
Ebbing, C., Rasmussen, S., Godfrey, K. M., Hanson, M. A. & Kiserud, T. Hepatic artery hemodynamics suggest operation of a buffer response in the human fetus. Reprod. Sci. 15, 166–178 (2008).
Zvanca, M., Gielchinsky, Y., Abdeljawad, F., Bilardo, C. M. & Nicolaides, K. H. Hepatic artery Doppler in trisomy 21 and euploid fetuses at 11–13 weeks. Prenat. Diagn. 31, 22–27 (2011).
Lund, A., Ebbing, C., Rasmussen, S., Kiserud, T. & Kessler, J. Maternal diabetes alters the development of ductus venosus shunting in the fetus. Acta Obstet. Gynecol. Scand. 97, 1032–1040 (2018).
Shannon, K., Davis, J. C., Kitzmiller, J. L., Fulcher, S. A. & Koenig, H. M. Erythropoiesis in infants of diabetic mothers. Pediatr. Res. 20, 161–165 (1986).
Salvesen, D. R., Brudenell, J. M., Snijders, R. J., Ireland, R. M. & Nicolaides, K. H. Fetal plasma erythropoietin in pregnancies complicated by maternal diabetes mellitus. Am. J. Obstet. Gynecol. 168, 88–94 (1993).
Widness, J. A. et al. Increased erythropoiesis and elevated erythropoietin in infants born to diabetic mothers and in hyperinsulinemic rhesus fetuses. J. Clin. Invest. 67, 637–642 (1981).
Roberts, A. B., Mitchell, J. M. & Pattison, N. S. Fetal liver length in normal and isoimmunized pregnancies. Am. J. Obstet. Gynecol. 161, 42–46 (1989).
Mirghani, H., Zayed, R., Thomas, L. & Agarwal, M. Gestational diabetes mellitus: fetal liver length measurements between 21and 24 weeks’ gestation. J. Clin. Ultrasound 35, 34–37 (2007).
Boito, S. M., Struijk, P. C., Ursem, N. T., Stijnen, T. & Wladimiroff, J. W. Assessment of fetal liver volume and umbilical venous volume flow in pregnancies complicated by insulin-dependent diabetes mellitus. BJOG 110, 1007–1013 (2003).
Naeye, R. L. Infants of diabetic mothers: a quantitative, morphologic study. Pediatrics 35, 980–988 (1965).
Yamane, T. Cellular basis of embryonic hematopoiesis and its implications in prenatal erythropoiesis. Int. J. Mol. Sci. 21, 9346 (2020).
Manesia, J. K. et al. Highly proliferative primitive fetal liver hematopoietic stem cells are fueled by oxidative metabolic pathways. Stem Cell Res. 15, 715–721 (2015).
Ratajczak, J. et al. The role of insulin (INS) and insulin-like growth factor-I (IGF-I) in regulating human erythropoiesis. Studies in vitro under serum-free conditions-comparison to other cytokines and growth factors. Leukemia 12, 371–381 (1998).
Perrine, S. P., Greene, M. F., Lee, P. D., Cohen, R. A. & Faller, D. V. Insulin stimulates cord blood erythroid progenitor growth: evidence for an aetiological role in neonatal polycythaemia. Br. J. Haematol. 64, 503–511 (1986).
Kurtz, A., Jelkmann, W. & Bauer, C. Insulin stimulates erythroid colony formation independently of erythropoietin. Br. J. Haematol. 53, 311–316 (1983).
Jelkmann, W. Physiology and pharmacology of erythropoietin. Transfus. Med. Hemother. 40, 302–309 (2013). A comprehensive discussion of erythropoietin.
Dame, C. et al. Erythropoietin mRNA expression in human fetal and neonatal tissue. Blood 92, 3218–3225 (1998).
Dame, C. & Juul, S. E. The switch from fetal to adult erythropoiesis. Clin. Perinatol. 27, 507–526 (2000).
Gonzalez, F. J., Xie, C. & Jiang, C. The role of hypoxia-inducible factors in metabolic diseases. Nat. Rev. Endocrinol. 15, 21–32 (2018).
Widness, J. A. et al. Temporal response of immunoreactive erythropoietin to acute hypoxemia in fetal sheep. Pediatr. Res. 20, 15–19 (1986).
Schneider, H. & Malek, A. Lack of permeability of the human placenta for erythropoietin. J. Perinat. Med. 23, 71–76 (1995).
Ruth, V., Widness, J. A., Clemons, G. & Raivio, K. O. Postnatal changes in serum immunoreactive erythropoietin in relation to hypoxia before and after birth. J. Pediatr. 116, 950–954 (1990).
Thilaganathan, B., Salvesen, D. R., Abbas, A., Ireland, R. M. & Nicolaides, K. H. Fetal plasma erythropoietin concentration in red blood cell-isoimmunized pregnancies. Am. J. Obstet. Gynecol. 167, 1292–1297 (1992).
Madazli, R. et al. The incidence of placental abnormalities, maternal and cord plasma malondialdehyde and vascular endothelial growth factor levels in women with gestational diabetes mellitus and nondiabetic controls. Gynecol. Obstet. Invest. 65, 227–232 (2008).
Ibrahim, M. H., Moustafa, A. N., Saedii, A. A. F. & Hassan, E. E. Cord blood erythropoietin and cord blood nucleated red blood cells for prediction of adverse neonatal outcome associated with maternal obesity in term pregnancy: prospective cohort study. J. Matern. Fetal Neonatal Med. 30, 2237–2242 (2017).
Amark, H., Sirotkina, M., Westgren, M., Papadogiannakis, N. & Persson, M. Is obesity in pregnancy associated with signs of chronic fetal hypoxia? Acta Obstet. Gynecol. Scand. 99, 1649–1656 (2020).
Cetin, H., Yalaz, M., Akisu, M. & Kultursay, N. Polycythaemia in infants of diabetic mothers: beta-hydroxybutyrate stimulates erythropoietic activity. J. Int. Med. Res. 39, 815–821 (2011).
Green, D. W., Khoury, J. & Mimouni, F. Neonatal hematocrit and maternal glycemic control in insulin-dependent diabetes. J. Pediatr. 120, 302–305 (1992).
Mimouni, F. et al. Neonatal polycythemia in infants of insulin-dependent diabetic mothers. Obstet. Gynecol. 68, 370–372 (1986).
Riskin, A. et al. Perinatal outcomes in infants of mothers with diabetes in pregnancy. Isr. Med. Assoc. J. 22, 569–575 (2020).
Green, D. W. & Mimouni, F. Nucleated erythrocytes in healthy infants and in infants of diabetic mothers. J. Pediatr. 116, 129–131 (1990).
Yeruchimovich, M., Mimouni, F. B., Green, D. W. & Dollberg, S. Nucleated red blood cells in healthy infants of women with gestational diabetes. Obstet. Gynecol. 95, 84–86 (2000).
Tsakalakos, N., Macfarlane, C. M. & Taljaard, J. J. Evidence of hypoxaemia and distribution of minor haemoglobin components in the cord blood of neonates born to diabetic mothers. S. Afr. Med. J. 67, 628–632 (1985).
Bard, H. & Prosmanne, J. Relative rates of fetal hemoglobin and adult hemoglobin synthesis in cord blood of infants of insulin-dependent diabetic mothers. Pediatrics 75, 1143–1147 (1985).
Perrine, S. P., Greene, M. F. & Faller, D. V. Delay in the fetal globin switch in infants of diabetic mothers. N. Engl. J. Med. 312, 334–338 (1985).
Sosenko, J. M. et al. Umbilical cord glycosylated hemoglobin in infants of diabetic mothers: relationships to neonatal hypoglycemia, macrosomia, and cord serum C-peptide. Diabetes Care 5, 566–570 (1982).
Salvesen, D. R., Freeman, J., Brudenell, J. M. & Nicolaides, K. H. Prediction of fetal acidaemia in pregnancies complicated by maternal diabetes mellitus by biophysical profile scoring and fetal heart rate monitoring. Br. J. Obstet. Gynaecol. 100, 227–233 (1993).
Salvesen, D. R., Brudenell, M. J. & Nicolaides, K. H. Fetal polycythemia and thrombocytopenia in pregnancies complicated by maternal diabetes mellitus. Am. J. Obstet. Gynecol. 166, 1287–1293 (1992).
Russell, N. E., Higgins, M. F., Kinsley, B. F., Foley, M. E. & McAuliffe, F. M. Heart rate variability in neonates of type 1 diabetic pregnancy. Early Hum. Dev. 92, 51–55 (2016).
Bradley, R. J., Brudenell, J. M. & Nicolaides, K. H. Fetal acidosis and hyperlacticaemia diagnosed by cordocentesis in pregnancies complicated by maternal diabetes mellitus. Diabet. Med. 8, 464–468 (1991).
Salvesen, D. R., Brudenell, J. M., Proudler, A. J., Crook, D. & Nicolaides, K. H. Fetal pancreatic beta-cell function in pregnancies complicated by maternal diabetes mellitus: relationship to fetal acidemia and macrosomia. Am. J. Obstet. Gynecol. 168, 1363–1369 (1993).
Robillard, J. E., Sessions, C., Kennedy, R. L. & Smith, F. G. Jr Metabolic effects of constant hypertonic glucose infusion in well-oxygenated fetuses. Am. J. Obstet. Gynecol. 130, 199–203 (1978).
Desoye, G. & Wells, J. C. K. Pregnancies in diabetes and obesity: the capacity-load model of placental adaptation. Diabetes 70, 823–830 (2021). Introduces the concept of limitations to placental adaptation as a cause of adverse pregnancy outcomes.
Desoye, G. & Shafrir, E. Placental metabolism and its regulation in health and diabetes. Mol. Asp. Med. 15, 505–682 (1994).
Higgins, M., Felle, P., Mooney, E. E., Bannigan, J. & McAuliffe, F. M. Stereology of the placenta in type 1 and type 2 diabetes. Placenta 32, 564–569 (2011).
Carrasco-Wong, I. et al. Placental structure in gestational diabetes mellitus. Biochim. Biophys. Acta Mol. Basis Dis. 1866, 165535 (2020).
Calderon, I. M. et al. Morphometric study of placental villi and vessels in women with mild hyperglycemia or gestational or overt diabetes. Diabetes Res. Clin. Pract. 78, 65–71 (2007).
Mayhew, T. M., Sorensen, F. B., Klebe, J. G. & Jackson, M. R. The effects of mode of delivery and sex of newborn on placental morphology in control and diabetic pregnancies. J. Anat. 183, 545–552 (1993).
Dahlstrom, J. E., Nolan, C. J. & Desoye, G. in Benirschke’s Pathology of the Human Placenta Ch. 20 (eds Baergen, R. N., Burton, G. J., & Kaplan, C. G.) 555–575 (Springer Nature, 2022).
Gauster, M., Desoye, G., Totsch, M. & Hiden, U. The placenta and gestational diabetes mellitus. Curr. Diab. Rep. 12, 16–23 (2012).
Mayhew, T. M., Sorensen, F. B., Klebe, J. G. & Jackson, M. R. Oxygen diffusive conductance in placentae from control and diabetic women. Diabetologia 36, 955–960 (1993). Demonstrates that hypervascularization of the placenta, and associated anatomical changes, facilitates oxygen diffusion.
Jauniaux, E. & Burton, G. J. Villous histomorphometry and placental bed biopsy investigation in type I diabetic pregnancies. Placenta 27, 468–474 (2006).
Nelson, S. M., Coan, P. M., Burton, G. J. & Lindsay, R. S. Placental structure in type 1 diabetes: relation to fetal insulin, leptin, and IGF-I. Diabetes 58, 2634–2641 (2009).
Jackson, M. R., Mayhew, T. M. & Haas, J. D. On the factors which contribute to thinning of the villous membrane in human placentae at high altitude. I. Thinning and regional variation in thickness of trophoblast. Placenta 9, 1–8 (1988).
Jackson, M. R., Mayhew, T. M. & Haas, J. D. On the factors which contribute to thinning of the villous membrane in human placentae at high altitude. II. An increase in the degree of peripheralization of fetal capillaries. Placenta 9, 9–18 (1988).
Reshetnikova, O. S., Burton, G. J. & Milovanov, A. P. Effects of hypobaric hypoxia on the fetoplacental unit: the morphometric diffusing capacity of the villous membrane at high altitude. Am. J. Obstet. Gynecol. 171, 1560–1565 (1994).
Reshetnikova, O. S., Burton, G. J., Milovanov, A. P. & Fokin, E. I. Increased incidence of placental chorioangioma in high-altitude pregnancies: hypobaric hypoxia as a possible etiologic factor. Am. J. Obstet. Gynecol. 174, 557–561 (1996).
Bjork, O. & Persson, B. Villous structure in different parts of the cotyledon in placentas of insulin-dependent diabetic women. A morphometric study. Acta Obstet. Gynecol. Scand. 63, 37–43 (1984).
Moeller, S. L. et al. Anemia in late pregnancy induces an adaptive response in fetoplacental vascularization. Placenta 80, 49–58 (2019).
Burton, G. J., Charnock-Jones, D. S. & Jauniaux, E. Regulation of vascular growth and function in the human placenta. Reproduction 138, 895–902 (2009).
Cvitic, S., Desoye, G. & Hiden, U. Glucose, insulin, and oxygen interplay in placental hypervascularisation in diabetes mellitus. Biomed. Res. Int. 2014, 145846 (2014).
Hiden, U. et al. Fetal insulin and IGF-II contribute to gestational diabetes mellitus (GDM)-associated up-regulation of membrane-type matrix metalloproteinase 1 (MT1-MMP) in the human feto-placental endothelium. J. Clin. Endocrinol. Metab. 97, 3613–3621 (2012).
Lassance, L. et al. Hyperinsulinemia stimulates angiogenesis of human fetoplacental endothelial cells: a possible role of insulin in placental hypervascularization in diabetes mellitus. J. Clin. Endocrinol. Metab. 98, E1438–E1447 (2013).
Loegl, J. et al. GDM alters paracrine regulation of feto-placental angiogenesis via the trophoblast. Lab. Invest. 97, 409–418 (2017).
Loegl, J. et al. Hofbauer cells of M2a, M2b and M2c polarization may regulate feto-placental angiogenesis. Reproduction 152, 447–455 (2016).
Roberts, K. A. et al. Placental structure and inflammation in pregnancies associated with obesity. Placenta 32, 247–254 (2011).
Brouwers, L. et al. Association of maternal prepregnancy body mass index with placental histopathological characteristics in uncomplicated term pregnancies. Pediatr. Dev. Pathol. 22, 45–52 (2019).
Camaschella, C. & Pagani, A. Iron and erythropoiesis: a dual relationship. Int. J. Hematol. 93, 21–26 (2011).
Nogueira-Pedro, A., dos Santos, G. G., Oliveira, D. C., Hastreiter, A. A. & Fock, R. A. Erythropoiesis in vertebrates: from ontogeny to clinical relevance. Front. Biosci. 8, 100–112 (2016).
McArdle, H. J., Andersen, H. S., Jones, H. & Gambling, L. Copper and iron transport across the placenta: regulation and interactions. J. Neuroendocrinol. 20, 427–431 (2008).
Petry, C. D. et al. Placental transferrin receptor in diabetic pregnancies with increased fetal iron demand. Am. J. Physiol. 267, E507–E514 (1994).
Georgieff, M. K., Petry, C. D., Mills, M. M., McKay, H. & Wobken, J. D. Increased N-glycosylation and reduced transferrin-binding capacity of transferrin receptor isolated from placentae of diabetic women. Placenta 18, 563–568 (1997).
McDonald, E. A. et al. Iron transport across the human placenta is regulated by hepcidin. Pediatr. Res. https://doi.org/10.1038/s41390-020-01201-y (2020).
Yang, A. et al. Expression of hepcidin and ferroportin in the placenta, and ferritin and transferrin receptor 1 levels in maternal and umbilical cord blood in pregnant women with and without gestational diabetes. Int. J. Env. Res. Public Health 13, 766 (2016).
Jones, A. D. et al. Maternal obesity during pregnancy is negatively associated with maternal and neonatal iron status. Eur. J. Clin. Nutr. 70, 918–924 (2016).
Phillips, A. K. et al. Neonatal iron status is impaired by maternal obesity and excessive weight gain during pregnancy. J. Perinatol. 34, 513–518 (2014).
Korlesky, C. et al. Cord blood erythropoietin and hepcidin reflect lower newborn iron stores due to maternal obesity during pregnancy. Am. J. Perinatol. 36, 511–516 (2019).
Georgieff, M. K. et al. Abnormal iron distribution in infants of diabetic mothers: spectrum and maternal antecedents. J. Pediatr. 117, 455–461 (1990).
Petry, C. D. et al. Iron deficiency of liver, heart, and brain in newborn infants of diabetic mothers. J. Pediatr. 121, 109–114 (1992).
Giussani, D. A. The fetal brain sparing response to hypoxia: physiological mechanisms. J. Physiol. 594, 1215–1230 (2016). An excellent review of the physiological responses to fetal hypoxia.
Wei, Z., Mu, M., Li, M., Li, J. & Cui, Y. Color Doppler ultrasound detection of hemodynamic changes in pregnant women with GDM and analysis of their influence on pregnancy outcomes. Am. J. Transl. Res. 13, 3330–3336 (2021).
Challis, D. E., Warren, P. S. & Gill, R. W. The significance of high umbilical venous blood flow measurements in a high-risk population. J. Ultrasound Med. 14, 907–912 (1995).
Olofsson, P., Lingman, G., Marsal, K. & Sjoberg, N. O. Fetal blood flow in diabetic pregnancy. J. Perinat. Med. 15, 545–553 (1987).
Rurak, D. W. & Gruber, N. C. The effect of neuromuscular blockade on oxygen consumption and blood gases in the fetal lamb. Am. J. Obstet. Gynecol. 145, 258–262 (1983).
Richardson, B. S., Hohimer, A. R., Bissonnette, J. M. & Machida, C. M. Insulin hypoglycemia, cerebral metabolism, and neural function in fetal lambs. Am. J. Physiol. 248, R72–R77 (1985).
Carroll, L., Gallagher, L. & Smith, V. Risk factors for reduced fetal movements in pregnancy: a systematic review and meta-analysis. Eur. J. Obstet. Gynecol. Reprod. Biol. 243, 72–82 (2019).
Yates, D. T. et al. Hypoxaemia-induced catecholamine secretion from adrenal chromaffin cells inhibits glucose-stimulated hyperinsulinaemia in fetal sheep. J. Physiol. 590, 5439–5447 (2012).
Chen, X. et al. Enhanced insulin secretion responsiveness and islet adrenergic desensitization after chronic norepinephrine suppression is discontinued in fetal sheep. Am. J. Physiol. Endocrinol. Metab. 306, E58–E64 (2014).
Tchirikov, M., Kertschanska, S., Sturenberg, H. J. & Schroder, H. J. Liver blood perfusion as a possible instrument for fetal growth regulation. Placenta 23 (Suppl. A), S153–S158 (2002).
Tchirikov, M., Kertschanska, S. & Schroder, H. J. Obstruction of ductus venosus stimulates cell proliferation in organs of fetal sheep. Placenta 22, 24–31 (2001). Demonstrates that liver perfusion contributes to regulation of fetal organ growth.
Economides, D. L., Proudler, A. & Nicolaides, K. H. Plasma insulin in appropriate- and small-for-gestational-age fetuses. Am. J. Obstet. Gynecol. 160, 1091–1094 (1989).
Giudice, L. C. et al. Insulin-like growth factors and their binding proteins in the term and preterm human fetus and neonate with normal and extremes of intrauterine growth. J. Clin. Endocrinol. Metab. 80, 1548–1555 (1995).
Hooper, S. B., Bocking, A. D., White, S., Challis, J. R. & Han, V. K. DNA synthesis is reduced in selected fetal tissues during prolonged hypoxemia. Am. J. Physiol. 261, R508–R514 (1991).
Gutaj, P. & Wender-Ozegowska, E. Diagnosis and management of IUGR in pregnancy complicated by type 1 diabetes mellitus. Curr. Diab. Rep. 16, 39 (2016).
Jensen, D. M. et al. Microalbuminuria, preeclampsia, and preterm delivery in pregnant women with type 1 diabetes: results from a nationwide Danish study. Diabetes Care 33, 90–94 (2010).
White, P. Pregnancy complicating diabetes. Am. J. Med. 7, 609–616 (1949).
Marchi, J., Berg, M., Dencker, A., Olander, E. K. & Begley, C. Risks associated with obesity in pregnancy, for the mother and baby: a systematic review of reviews. Obes. Rev. 16, 621–638 (2015).
Mathiesen, E. R., Ringholm, L. & Damm, P. Stillbirth in diabetic pregnancies. Best Pract. Res. Clin. Obstet. Gynaecol. 25, 105–111 (2011).
Ptacek, I. et al. Quantitative assessment of placental morphology may identify specific causes of stillbirth. BMC Clin. Pathol. 16, 1 (2016).
Dudley, D. J. Diabetic-associated stillbirth: incidence, pathophysiology, and prevention. Obstet. Gynecol. Clin. North Am. 34, 293–307 (2007).
Feig, D. S. & Palda, V. A. Type 2 diabetes in pregnancy: a growing concern. Lancet 359, 1690–1692 (2002).
Westgate, J. A. et al. Hyperinsulinemia in cord blood in mothers with type 2 diabetes and gestational diabetes mellitus in New Zealand. Diabetes Care 29, 1345–1350 (2006).
Norgan, N. G. The beneficial effects of body fat and adipose tissue in humans. Int. J. Obes. Relat. Metab. Disord. 21, 738–746 (1997).
Wells, J. C. K. The Evolutionary Biology of Human Body Fatness: Thrift and Control (Cambridge Univ. Press, 2010).
Kuzawa, C. W. Adipose tissue in human infancy and childhood: an evolutionary perspective. Am. J. Phys. Anthropol. 107 (Suppl. 27), 177–209 (1998).
Wesolowski, S. R. et al. Switching obese mothers to a healthy diet improves fetal hypoxemia, hepatic metabolites, and lipotoxicity in non-human primates. Mol. Metab. 18, 25–41 (2018). Shows that fetal hypoxia can be reversed by improving the quality of maternal diet and might establish the scientific basis for future dietary interventions to improve fetal outcome in pregnancies complicated by diabetes mellitus and/or pregnancies in people with obesity.
Kiserud, T. Physiology of the fetal circulation. Semin. Fetal Neonatal Med. 10, 493–503 (2005).
Kiserud, T. & Acharya, G. The fetal circulation. Prenat. Diagn. 24, 1049–1059 (2004). An excellent account of the human fetal circulation.
Edelstone, D. I. & Rudolph, A. M. Preferential streaming of ductus venosus blood to the brain and heart in fetal lambs. Am. J. Physiol. 237, H724–H729 (1979).
Kiserud, T., Kessler, J., Ebbing, C. & Rasmussen, S. Ductus venosus shunting in growth-restricted fetuses and the effect of umbilical circulatory compromise. Ultrasound Obstet. Gynecol. 28, 143–149 (2006).
Bellotti, M. et al. Simultaneous measurements of umbilical venous, fetal hepatic, and ductus venosus blood flow in growth-restricted human fetuses. Am. J. Obstet. Gynecol. 190, 1347–1358 (2004).
Ganong, W. F. Ganong’s Review of Medical Physiology 20th edn (McGraw Hill, 2001).
Philipps, A. F., Widness, J. A., Garcia, J. F., Raye, J. R. & Schwartz, R. Erythropoietin elevation in the chronically hyperglycemic fetal lamb. Proc. Soc. Exp. Biol. Med. 170, 42–47 (1982).
Wong, S. F., Chan, F. Y., Cincotta, R. B., McIntyre, D. H. & Stone, M. Use of umbilical artery Doppler velocimetry in the monitoring of pregnancy in women with pre-existing diabetes. Aust. N. Z. J. Obstet. Gynaecol. 43, 302–306 (2003).
Haugen, G. et al. Fetal liver-sparing cardiovascular adaptations linked to mother’s slimness and diet. Circ. Res. 96, 12–14 (2005).
Barbera, A. et al. Relationship of umbilical vein blood flow to growth parameters in the human fetus. Am. J. Obstet. Gynecol. 181, 174–179 (1999).
Cohn, H. E., Sacks, E. J., Heymann, M. A. & Rudolph, A. M. Cardiovascular responses to hypoxemia and acidemia in fetal lambs. Am. J. Obstet. Gynecol. 120, 817–824 (1974).
Jensen, A. & Berger, R. Fetal circulatory responses to oxygen lack. J. Dev. Physiol. 16, 181–207 (1991).
Milley, J. R. Effect of insulin on the distribution of cardiac output in the fetal lamb. Pediatr. Res. 22, 168–172 (1987).
Stonestreet, B. S., Widness, J. A. & Berard, D. J. Circulatory and metabolic effects of hypoxia in the hyperinsulinemic ovine fetus. Pediatr. Res. 38, 67–75 (1995).
Pilania, R., Sikka, P., Rohit, M. K., Suri, V. & Kumar, P. Fetal cardiodynamics by echocardiography in insulin dependent maternal diabetes and its correlation with pregnancy outcome. J. Clin. Diagn. Res. 10, QC01–QC04 (2016).
Lisowski, L. A., Verheijen, P. M., De Smedt, M. M., Visser, G. H. & Meijboom, E. J. Altered fetal circulation in type-1 diabetic pregnancies. Ultrasound Obstet. Gynecol. 21, 365–369 (2003). Finds significant differences in the fetal circulation in pregnancies with T1DM and those without T1DM and suggests the existence of compensatory mechanisms.
Bravo-Valenzuela, N. J. et al. Fetal cardiac function and ventricular volumes determined by three-dimensional ultrasound using STIC and VOCAL methods in fetuses from pre-gestational diabetic women. Pediatr. Cardiol. 41, 1125–1134 (2020).
Winter, J. et al. Depressed left and right ventricular cardiac output in fetuses of diabetic mothers. Echo Res. Pract. 5, 19–26 (2018).
Brooks, G. A. The science and translation of lactate shuttle theory. Cell Metab. 27, 757–785 (2018).
Gladden, L. B. Lactate metabolism: a new paradigm for the third millennium. J. Physiol. 558, 5–30 (2004).
Ma, L. N., Huang, X. B., Muyayalo, K. P., Mor, G. & Liao, A. H. Lactic acid: a novel signaling molecule in early pregnancy? Front. Immunol. 11, 279 (2020).
Hunt, T. K., Aslam, R., Hussain, Z. & Beckert, S. Lactate, with oxygen, incites angiogenesis. Adv. Exp. Med. Biol. 614, 73–80 (2008).
Di Renzo, G. C., Rosati, A., Sarti, R. D., Cruciani, L. & Cutuli, A. M. Does fetal sex affect pregnancy outcome? Gend. Med. 4, 19–30 (2007).
van Poppel, M. N., Eder, M., Lang, U. & Desoye, G. Sex-specific associations of insulin-like peptides in cord blood with size at birth. Clin. Endocrinol. 89, 187–193 (2018).
Jagota, D. et al. Sex differences in fetal Doppler parameters during gestation. Biol. Sex. Differ. 12, 26 (2021).
Basak, K., Luis Dean-Ben, X., Gottschalk, S., Reiss, M. & Razansky, D. Non-invasive determination of murine placental and foetal functional parameters with multispectral optoacoustic tomography. Light Sci. Appl. 8, 71 (2019).
Arthuis, C. J. et al. Real-time monitoring of placental oxygenation during maternal hypoxia and hyperoxygenation using photoacoustic imaging. PLoS ONE 12, e0169850 (2017).
Karlas, A., Pleitez, M. A., Aguirre, J. & Ntziachristos, V. Optoacoustic imaging in endocrinology and metabolism. Nat. Rev. Endocrinol. 17, 323–335 (2021).
Schrauben, E. M. et al. Technique for comprehensive fetal hepatic blood flow assessment in sheep using 4D flow MRI. J. Physiol. 598, 3555–3567 (2020).
Roberts, V. H. et al. Quantitative assessment of placental perfusion by contrast-enhanced ultrasound in macaques and human subjects. Am. J. Obstet. Gynecol. 214, 369.e1–8 (2016).
Anderson, K. B. et al. Placental transverse relaxation time (T2) estimated by MRI: normal values and the correlation with birthweight. Acta Obstet. Gynecol. Scand. 100, 934–940 (2020).
Sinding, M. et al. Prediction of low birth weight: comparison of placental T2* estimated by MRI and uterine artery pulsatility index. Placenta 49, 48–54 (2017).
Sorensen, A., Hutter, J., Seed, M., Grant, P. E. & Gowland, P. T2*-weighted placental MRI: basic research tool or emerging clinical test for placental dysfunction? Ultrasound Obstet. Gynecol. 55, 293–302 (2020).
Seidmann, L., Kamyshanskiy, Y., Wagner, D. C., Zimmer, S. & Roth, W. CD15 immunostaining improves placental diagnosis of fetal hypoxia. Placenta 105, 41–49 (2021).
Acknowledgements
The authors thank P. Damm, Rigshospitalet, University of Copenhagen, Denmark, for critical reading of the manuscript and valuable input. The authors also thank the reviewers for their helpful comments and suggestions on a previous version of the manuscript. G.D. was supported by a visiting professorship grant from the Danish Diabetes Academy, which is funded by the Novo Nordisk Foundation, grant number NNF17SA0031406. G.D also received funds from the Österreichische Nationalbank (Anniversary Fund, project number: 17950).
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Glossary
- Fetal macrosomia
-
Fetal overgrowth often found in diabetes mellitus and obesity resulting in excessive birthweight, defined as either >4,000 g or >4,500 g depending on the clinical centre.
- Small for gestational age
-
(SGA). Commonly defined as growth at the 10th percentile or less for weight of all fetuses at that gestational age.
- Fetal growth restriction
-
(FGR). Refers to a fetus that does not achieve the expected in utero growth potential owing to genetic or environmental factors.
- Metabolically induced oxygen deficit
-
Hypoxia due to an imbalance between fetal oxygen demand and oxygen supply owing to an increase in fetal metabolic rate.
- Cytotrophoblast
-
Mononuclear cell of the trophoblast cell lineage, which can either fuse to form a syncytium, the placental surface exposed to maternal blood, or invade the maternal decidua.
- Cytotrophoblast invasion
-
The process by which fetal trophoblast cells invade the maternal decidua to anchor the feto-placental unit and to transform the spiral arteries into low-resistance vessels.
- Atheromas
-
Degenerations of the walls of the arteries caused by accumulated fatty deposits and scar tissue.
- Pulsatility indices
-
The uterine artery pulsatility index is a measure of uteroplacental perfusion derived from measurements of flow velocity made with Doppler ultrasound.
- Partial pressure of oxygen
-
(pO2). The independent pressure exerted by an individual gas (here oxygen) in a mixture of gases.
- Carotid chemoreflex
-
Reflex activation of the sympathetic nervous system in response to an alteration in the composition of the blood sensed by receptors in the carotid bodies.
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Desoye, G., Carter, A.M. Fetoplacental oxygen homeostasis in pregnancies with maternal diabetes mellitus and obesity. Nat Rev Endocrinol 18, 593–607 (2022). https://doi.org/10.1038/s41574-022-00717-z
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DOI: https://doi.org/10.1038/s41574-022-00717-z
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