Comparative intrauterine development and placental function of ART concepti: implications for human reproductive medicine and animal breeding

Abstract

Background: The number of children conceived using assisted reproductive technologies (ART) has reached >5 million worldwide and continues to increase. Although the great majority of ART children are healthy, many reports suggest a forthcoming risk of metabolic complications, which is further supported by the Developmental Origins of Health and Disease hypothesis of suboptimal embryo/fetal conditions predisposing adult cardiometabolic pathologies. Accumulating evidence suggests that fetal and placental growth kinetics are important features predicting post-natal health, but the relationship between ART and intrauterine growth has not been systematically reviewed.

Methods: Relevant studies describing fetoplacental intrauterine phenotypes of concepti generated by in vitro fertilization (IVF), intracytoplasmic sperm injection (ICSI) and somatic cell nuclear transfer (SCNT) in the mouse, bovine and human were comprehensively researched using PubMed and Google Scholar. Intrauterine growth plots were created from tabular formatted data available in selected reports.

Results: ART pregnancies display minor but noticeable alterations in fetal and placental growth curves across mammalian species. In all species, there is evidence of fetal growth restriction in the earlier stages of pregnancy, followed by significant increases in placental size and accelerated fetal growth toward the end of gestation. However, there is a species-specific effect of ART on birthweights, that additionally vary in a culture condition-, strain-, and/or stage at transfer-specific manner. We discuss the potential mechanisms that underlie these changes, and how they are affected by specific components of ART procedures.

Conclusions: ART may promote measurable alterations to intrauterine growth trajectory and placental function. Key findings include evidence that birthweight is not a reliable marker of fetal stress, and that increases in embryo manipulation result in more deviant fetal growth curves. Because growth kinetics in early life are particularly relevant to adult metabolic physiology, we advise more rigorous assessment of fetal growth and placental function in human ART pregnancies, as well as continued follow-up of ART offspring throughout post-natal life. Finally, strategies to minimize embryo manipulations should be adopted whenever possible.

Keywords: Developmental Origins of Health and Disease; IVF; assisted reproductive technology; fetal and placental growth.

Figure 1

Critical period of developmental sensitivity. Schematic illustrating the windows of human pregnancy most susceptible for influencing the development of components of metabolic syndrome later in life. Metabolic stress, including defects in glucose handling, is a common outcome of stress in utero and is less dependent on the specific timing of the stress occurrence. In addition to increased vulnerability during organogenesis, the preimplantation period is a time of extensive epigenetic remodeling and therefore may be particularly susceptible to stress.

Figure 2

Preimplantation development and IVF. Overview of the stages of preimplantation embryo development from ovulation and fertilization of the oocyte in the oviduct, through cleavage divisions and embryo polarization, to blastocyst formation and implantation into the uterus. In vitro, gametes are isolated for co-incubation, and fertilized zygotes are cultured 3–5 days prior to transfer back into the uterus.

Figure 3

Intrauterine growth restriction, placentomegaly and accelerated fetal growth in mammalian ART pregnancy. Mean fetal and placental ART weights relative to spontaneously conceived concepti, with corresponding placental:fetal weight ratios in mouse (A and B), bovine (C and D) and human (E and F) pregnancies. Adapted from mouse: Delle Piane et al. (2010) and Bloise et al. (2012); bovine: Bertolini et al. (2004); human: Haavaldsen et al. (2012). *P < 0.05. E, embryonic day. Gestational age is days for mouse (A,B) and bovine (C,D) and weeks for humans (E,F).

Figure 4

Increased IVF stress exacerbates fetoplacental phenotype. Mouse E12.5 mean fetal weight (red line), placental weight (red dotted line), and corresponding placental:fetal (P:F) weight ratio (blue line) of concepti conceived by IVF and cultured either under optimized conditions (KSOM medium with amino acids under 5% O₂, IVF_KAA) or suboptimal culture conditions (Whitten's medium under 20% O₂, IVF_WM), normalized to in vivo-derived blastocysts transferred to surrogate damns (flushed blastocyst control, FB). Different superscripts indicate statistical significance between spontaneously conceived pregnancies and IVF concepti produced in different media as shown in the original reports (P < 0.05). Adapted from Delle Piane et al. (2010).

Figure 5

Mechanisms by which ART procedures affect acute and long-term growth. Both ovarian stimulation with exogenous gonadotrophins as well as assorted components of IVF and embryo culture conditions, including oxygen tension, culture medium composition, culture substrate rigidity, pH and the duration of embryo culture, can affect oocyte and embryo developmental competence. This can lead to epigenetic errors, cell mosaicism and ploidy defects, while also inducing adjustments to embryo metabolism, transcription and proliferation. Cumulatively, these acute outcomes can influence intrauterine growth kinetics, leading to the fetal and placental phenotypes observed in ART offspring, and possibly subsequent increased risk of metabolic disease in adulthood. ICM, inner cell mass; TE, trophectoderm.