Effects of vitrification and the superovulated environment on placental function and fetal growth in an IVF mouse model

2020 ◽  
Vol 26 (8) ◽  
pp. 624-635
Author(s):  
C Roeca ◽  
E Silva ◽  
C Barentsen ◽  
T L Powell ◽  
T Jansson
Keyword(s):  
Mouse Model ◽  
Fetal Growth ◽  
Gestational Age ◽  
Large For Gestational Age ◽  
Placental Development ◽  
Developmental Potential ◽  
Placental Function ◽  
Uterine Environment ◽  
Embryonic Viability ◽  
Human Ivf

Abstract In studies of human IVF, as compared to frozen embryo transfer (ET), fresh ET is associated with smaller infants and higher risk of small for gestational age infants. Recent observations suggest that ET using vitrified embryos is associated with higher pregnancy and live birth rates compared to fresh ET, but increased rates of large for gestational age infants. The mechanisms underlying these associations are largely unknown, and available evidence suggests that the influence of IVF, vitrification and the superovulated (SO) uterine environment on placental function and fetal growth is complex. This warrants further investigation given the prevalent practice in human IVF of both fresh ET into a SO uterine environment, and vitrification with ET into a more physiologic uterine environment. Using a mouse model that closely resembles human IVF, we investigated if vitrification of IVF embryos better preserves placental function and results in better pregnancy outcomes as compared to fresh ET because of transfer into a more physiologic endometrium. We found that the SO environment, independent of vitrification status, reduced implantation rates, inhibited placental mechanistic target of rapamycin signaling and induced placental stress signaling, resulting in fetal growth restriction (1.080 ± 0.05 g estrous fresh (n = 17 litters), 1.176 ± 0.05 g estrous vitrified (n = 12), 0.771 ± 0.06 g SO fresh (n = 15), 0.895 ± 0.08 g SO vitrified (n = 10), P < 0.0001). In addition, our study suggests that vitrification impairs the developmental potential of IVF blastocysts that resulted in a significantly smaller litter size (2.6 ± 2.3 fresh estrous vs 2.5 ± 2.4 fresh SO vs 1.6 ± 1.7 estrous vitrified vs 1.7 ± 1.8 SO vitrified, P = 0.019), with no effect on fetal growth or placental function at term. Our findings suggest that vitrification may negatively impact early embryonic viability, while the SO maternal uterine environment impairs both placental development and fetal growth in IVF.

Fetal growth and development following temporary exposure of Day 3 ovine embryos to an advanced uterine environment

1998 ◽  
Vol 10 (3) ◽  
pp. 263 ◽  
Author(s):  
K. D. Sinclair ◽  
L. D. Dunne ◽  
E. K. Maxfield ◽  
C. A. Maltin ◽  
L. E. Young ◽  
...  
Keyword(s):  
Fetal Growth ◽  
Gestational Age ◽  
Fetal Development ◽  
Growth And Development ◽  
Allometric Equation ◽  
Organ Weight ◽  
Fetal Weight ◽  
Fetal Sex ◽  
Uterine Environment ◽  
Day 3 Embryos

The effect of exposing Day 3 ovine embryos to an advanced uterine environment for a period of 3 days on subsequent fetal growth and development between Day 35 and Day 135 of gestation was studied. Day 3 embryos were recovered from superovulated donor ewes and transferred to synchronous final or asynchronous temporary recipients for 3 days. Embryos were recovered from these temporary recipients and transferred to Day 6 final recipients. Gravid uteri were recovered, weighed and dissected on Days 35, 45, 60, 90, 110, 125 and 135 of gestation. Fetal weight and length data were analysed by fitting non-linear Gompertz models of the form loge y = a – be–ct, where y is fetal size and t is time from conception. Various terms including treatment, gestational age, embryo stage at transfer and fetal sex were fitted to this model. Fetal development was assessed by relating organ weight to fetal bodyweight using the linear allometric equation loge y = loge a + b loge x, where y is organ weight and x is fetal weight. Temporary exposure of Day 3 embryos to an advanced uterine environment did not increase the rate of embryo development and had no effect on fetal growth and development between Days 35 and 135 of gestation in this study. A single Gompertz model (loge y = 10.134 – 17.047e –0.01733t) explained 99.8% of the variation in fetal weight. Of terms fitted to this model only gestational age and fetal sex influenced fetal weight, with male fetuses being 5% heavier (P<0.05) than female fetuses. Fetal development was also unaffected by experimental treatment in this study. Allometric coefficients established for various fetal components agreed well with those from previously published studies.

scholarly journals Placental and fetal characteristics of the Ohia mouse line recapitulate outcomes in human hypoplastic left heart syndrome

2020 ◽  
Author(s):  
Rebecca L Wilson ◽  
Weston Troja ◽  
Jennifer Courtney ◽  
Helen N Jones
Keyword(s):  
Mouse Model ◽  
Mrna Expression ◽  
Hypoplastic Left Heart Syndrome ◽  
Fetal Growth ◽  
Fetal Weight ◽  
Left Heart ◽  
Heterozygous Genotype ◽  
Placental Development ◽  
Hypoplastic Left Heart ◽  
Left Heart Syndrome

AbstractCongenital heart defects (CHDs) are one of the most common birth defects worldwide. The morbidity and mortality associated with these defects is compounded by increased frequency of fetal growth abnormalities in the newborns. Inappropriate placental development and function has been implicated as a contributing factor to poor fetal growth in pregnancies complicated by CHDs however, the exact mechanisms are poorly understood. In the Ohia mouse model of hypoplastic left heart syndrome (HLHS), the double homozygous genotype had previously been shown to be embryonically lethal at mid-pregnancy; a time in which optimal establishment of the placenta is crucial to fetal survival. We aimed to characterize placental and fetal growth and development in the double heterozygous genotype to determine whether the genetic mutations associated with HLHS in the Ohia mouse also affect the placenta. The frequency of fetuses with reduced weight near term was shifted in the double heterozygous genotype compared to wildtype fetuses. This shift in fetal weight distribution was associated with reduced fetal capillary density in the placentas of the double heterozygotes as well as a reduction in placental mRNA expression of angiogenic factors placenta growth factor (Pgf) and fms-like tyrosine kinase-1 (Flt1) suggesting abhorrent placental angiogenesis. Positive correlations were observed between fetal weight and placenta mRNA expression of several nutrient transporters in the double heterozygous genotype but not observed in the wildtype. This data shows changes to placental angiogenesis and nutrient transport that are likely to contribute to inadequate fetal growth in the Ohia mouse model. Such differences are similar to findings in studies of human placentas from pregnancies with a fetus with HLHS and highlights the importance of this mouse model in continuing to understand the link between placental development and CHDs such as HLHS.New and NoteworthyWe used the Ohia mouse line, which is characterized with a hypoplastic left heart syndrome (HLHS)-like phenotype to investigate the contribution of placental development and function to fetal growth abnormalities associated with congenital heart defects (CHDs). We demonstrate an increase in the frequency of fetuses with lower fetal weight in the double heterozygous genotype which is associated with abnormalities to the placental microstructure, reduced placental fetal capillary density and placental mRNA expression of angiogenic factors Pgf and Flt1. These results are supported by similar studies of human placentas from HLHS pregnancies and highlights the usefulness of this model in furthering our understanding of abnormal fetal growth in CHDs.

scholarly journals Differential Changes in Akt and AMPK Phosphorylation Regulating mTOR Activity in the Placentas of Pregnancies Complicated by Fetal Growth Restriction and Gestational Diabetes Mellitus With Large-For-Gestational Age Infants

2021 ◽  
Vol 8 ◽  
Author(s):  
Tai-Ho Hung ◽  
Chung-Pu Wu ◽  
Szu-Fu Chen
Keyword(s):  
Diabetes Mellitus ◽  
Gestational Diabetes ◽  
Gestational Diabetes Mellitus ◽  
Pregnant Women ◽  
Fetal Growth ◽  
Gestational Age ◽  
Fetal Growth Restriction ◽  
Large For Gestational Age ◽  
Mtor Phosphorylation ◽  
Mtor Activity

Background: Dysregulation of placental mechanistic target of rapamycin (mTOR) activity has been implicated in the pathophysiology of pregnancies complicated by idiopathic fetal growth restriction (FGR) and gestational diabetes mellitus (GDM) with large-for-gestational-age (LGA) infants. However, the underlying mechanisms remain unclear.Methods: We obtained placentas from women with normal pregnancies (n = 11) and pregnancies complicated by FGR (n = 12) or GDM with LGA infants (n = 12) to compare the levels of total and phosphorylated forms of Akt, AMPK, TSC2, and mTOR among the three groups and used primary cytotrophoblast cells isolated from 30 normal term placentas to study the effects of oxygen–glucose deprivation (OGD) and increasing glucose concentrations on the changes of these factors in vitro.Results: Placentas from FGR pregnancies had lower phosphorylated Akt (p-Akt) levels (P &lt; 0.05), higher p-AMPKα levels (P &lt; 0.01), and lower mTOR phosphorylation (P &lt; 0.05) compared to that of normal pregnant women. Conversely, women with GDM and LGA infants had higher p-Akt (P &lt; 0.001), lower p-AMPKα (P &lt; 0.05), and higher p-mTOR levels (P &lt; 0.05) in the placentas than normal pregnant women. Furthermore, primary cytotrophoblast cells subjected to OGD had lower p-Akt and p-mTOR (both P &lt; 0.05) and higher p-AMPKα levels (P &lt; 0.05) than those cultured under standard conditions, but increasing glucose concentrations had opposite effects on the respective levels. Administering compound C, an AMPK inhibitor, did not significantly affect Akt phosphorylation but partially reversed mTOR phosphorylation. Administering LY294002, an Akt inhibitor, decreased p-mTOR levels, but did not change the levels of total and phosphorylated AMPKα.Conclusion: These results suggest that Akt and AMPK are involved in the regulation of trophoblast mTOR activity in the placentas of pregnancies complicated by FGR and GDM with LGA infants.

scholarly journals Uterine distention as a factor in birth timing: retrospective nationwide cohort study in Sweden

BMJ Open ◽  
2018 ◽  
Vol 8 (10) ◽  
pp. e022929 ◽  
Author(s):  
Jonas Bacelis ◽  
Julius Juodakis ◽  
Kristina M Adams Waldorf ◽  
Verena Sengpiel ◽  
Louis J Muglia ◽  
...  
Keyword(s):  
Cohort Study ◽  
Preterm Birth ◽  
Fetal Growth ◽  
Gestational Age ◽  
Large For Gestational Age ◽  
Maternal Height ◽  
Birth Timing ◽  
Gestational Age At Birth ◽  
Age At Birth ◽  
Singleton Pregnancies

ObjectivesTo determine whether uterine distention is associated with human pregnancy duration in a non-invasive observational setting.DesignRetrospective cohort study modelling uterine distention by interaction between maternal height and uterine load.SettingThe study is based on the 1990–2013 population data from all delivery units in Sweden.ParticipantsUncomplicated first pregnancies of healthy Nordic-born mothers with spontaneous onset of labour. Pregnancies were classified as twin (n=2846) or singleton (n=527 868). Singleton pregnancies were further classified as carrying a large for gestational age fetus (LGA, n=24 286) or small for gestational age fetus (SGA, n=33 780).Outcome measuresStatistical interaction between maternal height and uterine load categories (twin vs singleton pregnancies, and LGA vs SGA singleton pregnancies), where the outcome is pregnancy duration.ResultsIn all models, statistically significant interaction was found. Mothers carrying twins had 2.9 times larger positive linear effect of maternal height on gestational age than mothers carrying singletons (interaction p=5e−14). Similarly, the effect of maternal height was strongly modulated by the fetal growth rate in singleton pregnancies: the effect size of maternal height on gestational age in LGA pregnancies was 2.1 times larger than that in SGA pregnancies (interaction p<1e−11). Preterm birth OR was 1.4 when the mother was short, and 2.8 when the fetus was extremely large for its gestational age; however, when both risk factors were present together, the OR for preterm birth was larger than expected, 10.2 (interaction p<0.0005).ConclusionsAcross all classes, maternal height was significantly associated with child’s gestational age at birth. Interestingly, in short-statured women with large uterine load (twins, LGA), spontaneous delivery occurred much earlier than expected. The interaction between maternal height, uterine load size and gestational age at birth strongly suggests the effect of uterine distention imposed by fetal growth on birth timing.

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