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Fetoplacental oxygen homeostasis in pregnancies with maternal diabetes mellitus and obesity

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

  • 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.

  • 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.

  • 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.

  • 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.

  • 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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Fig. 1: Overview of the fetoplacental circulation.
Fig. 2: Interaction of pathways leading to increased number of red blood cells.
Fig. 3: Schematic depicting potential reasons for oxygen deficit in the fetus in pregnancies with diabetes mellitus and/or obesity.
Fig. 4: Adaptive responses of the fetoplacental unit to hypoxia and metabolically induced oxygen deficit in diabetes mellitus and obesity.
Fig. 5: Schematic linking various forms of metabolic disturbance in the mother with adaptations in fetus and placenta.

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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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Nature Reviews Endocrinology thanks Helen Murphy, who co-reviewed the manuscript with Tara Lee, Thomas Jansson and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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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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