Samantha C. Lean

Placental Adaptation: What Can We Learn from Birthweight:Placental Weight Ratio?

Appropriate fetal growth relies upon adequate placental nutrient transfer. Birthweight:placental weight ratio (BW:PW ratio) is often used as a proxy for placental efficiency, defined as the grams of fetus produced per gram placenta. An elevated BW:PW ratio in an appropriately grown fetus (small placenta) is assumed to be due to up-regulated placental nutrient transfer capacity i.e., a higher nutrient net flux per gram placenta. In fetal growth restriction (FGR), where a fetus fails to achieve its genetically pre-determined growth potential, placental weight and BW:PW ratio are often reduced which may indicate a placenta that fails to adapt its nutrient transfer capacity to compensate for its small size. This review considers the literature on BW:PW ratio in both large cohort studies of normal pregnancies and those studies offering insight into the relationship between BW:PW ratio and outcome measures including stillbirth, FGR, and subsequent postnatal consequences. The core of this review is the question of whether BW:PW ratio is truly indicative of altered placental efficiency, and whether changes in BW:PW ratio reflect those placentas which adapt their nutrient transfer according to their size. We consider this question using data from mice and humans, focusing upon studies that have measured the activity of the well characterized placental system A amino acid transporter, both in uncomplicated pregnancies and in FGR. Evidence suggests that BW:PW ratio is reduced both in FGR and in pregnancies resulting in a small for gestational age (SGA, birthweight < 10th centile) infant but this effect is more pronounced earlier in gestation (<28 weeks). In mice, there is a clear association between increased BW:PW ratio and increased placental system A activity. Additionally, there is good evidence in wild-type mice that small placentas upregulate placental nutrient transfer to prevent fetal undergrowth. In humans, this association between BW:PW ratio and placental system A activity is less clear and is worthy of further consideration, both in terms of system A and other placental nutrient transfer processes. This knowledge would help decide the value of measuring BW:PW ratio in terms of determining the risk of poor health outcomes, both in the neonatal period and long term.

Advanced maternal age and adverse pregnancy outcomes: A systematic review and meta-analysis.

Background Advanced maternal age (AMA; ≥35 years) is an increasing trend and is reported to be associated with various pregnancy complications. Objective To determine the risk of stillbirth and other adverse pregnancy outcomes in women of AMA. Search strategy Embase, Medline (Ovid), Cochrane Database of Systematic Reviews, ClinicalTrials.gov, LILACS and conference proceedings were searched from ≥2000. Selection criteria Cohort and case-control studies reporting data on one or more co-primary outcomes (stillbirth or fetal growth restriction (FGR)) and/or secondary outcomes in mothers ≥35 years and <35 years. Data collection and analysis The effect of age on pregnancy outcome was investigated by random effects meta-analysis and meta-regression. Stillbirth rates were correlated to rates of maternal diabetes, obesity, hypertension and use of assisted reproductive therapies (ART). Main results Out of 1940 identified titles; 63 cohort studies and 12 case-control studies were included in the meta-analysis. AMA increased the risk of stillbirth (OR 1.75, 95%CI 1.62 to 1.89) with a population attributable risk of 4.7%. Similar trends were seen for risks of FGR, neonatal death, NICU unit admission restriction and GDM. The relationship between AMA and stillbirth was not related to maternal morbidity or ART. Conclusions Stillbirth risk increases with increasing maternal age. This is not wholly explained by maternal co-morbidities and use of ART. We propose that placental dysfunction may mediate adverse pregnancy outcome in AMA. Further prospective studies are needed to directly test this hypothesis.

The influence of load carrying on the energetics and kinematics of terrestrial locomotion in a diving bird.

Summary The application of artificial loads to mammals and birds has been used to provide insight into the mechanics and energetic cost of terrestrial locomotion. However, only two species of bird have previously been used in loading experiments, the cursorial guinea fowl (Numida meleagris) and the locomotor-generalist barnacle goose (Branta leucopsis). Here, using respirometry and treadmill locomotion, we investigate the energetic cost of carrying trunk loads in a diving bird, the tufted duck (Aythya fuligula). Attachment of back loads equivalent to 10% and 20% of body mass increased the metabolic rate during locomotion (7.94% and 15.92%, respectively) while sternal loads of 5% and 10% had a greater proportional effect than the back loads (metabolic rate increased by 7.19% and 13.99%, respectively). No effect on locomotor kinematics was detected during any load carrying experiments. These results concur with previous reports of load carrying economy in birds, in that there is a less than proportional relationship between increasing load and metabolic rate (found previously in guinea fowl), while application of sternal loads causes an approximate doubling of metabolic rate compared to back loads (reported in an earlier study of barnacle geese). The increase in cost when carrying sternal loads may result from having to move this extra mass dorso-ventrally during respiration. Disparity in load carrying economy between species may arise from anatomical and physiological adaptations to different forms of locomotion, such as the varying uncinate process morphology and hindlimb tendon development in goose, guinea fowl and duck.

Placental dysfunction is associated with altered microRNA expression in pregnant women with low folate status

Scope Low maternal folate status during pregnancy increases the risk of delivering small for gestational age (SGA) infants, but the mechanistic link between maternal folate status, SGA, and placental dysfunction is unknown. microRNAs (miRNAs) are altered in pregnancy pathologies and by folate in other systems. We hypothesized that low maternal folate status causes placental dysfunction, mediated by altered miRNA expression. Methods and results A prospective observational study recruited pregnant adolescents and assessed third trimester folate status and placental function. miRNA array, QPCR, and bioinformatics identified placental miRNAs and target genes. Low maternal folate status is associated with higher incidence of SGA infants (28% versus 13%, p < 0.05) and placental dysfunction, including elevated trophoblast proliferation and apoptosis (p < 0.001), reduced amino acid transport (p < 0.01), and altered placental hormones (pregnancy‐associated plasma protein A, progesterone, and human placental lactogen). miR‐222‐3p, miR‐141‐3p, and miR‐34b‐5p were upregulated by low folate status (p < 0.05). Bioinformatics predicted a gene network regulating cell turnover. Quantitative PCR demonstrated that key genes in this network (zinc finger E‐box binding homeobox 2, v‐myc myelocytomatosis viral oncogene homolog (avian), and cyclin‐dependent kinase 6) were reduced (p < 0.05) in placentas with low maternal folate status. Conclusion This study supports that placental dysfunction contributes to impaired fetal growth in women with low folate status and suggests altered placental expression of folate‐sensitive miRNAs and target genes as a mechanistic link.

Placental Dysfunction Underlies Increased Risk of Fetal Growth Restriction and Stillbirth in Advanced Maternal Age Women

Pregnancies in women of advanced maternal age (AMA) are susceptible to fetal growth restriction (FGR) and stillbirth. We hypothesised that maternal ageing is associated with utero-placental dysfunction, predisposing to adverse fetal outcomes. Women of AMA (≥35 years) and young controls (20–30 years) with uncomplicated pregnancies were studied. Placentas from AMA women exhibited increased syncytial nuclear aggregates and decreased proliferation, and had increased amino acid transporter activity. Chorionic plate and myometrial artery relaxation was increased compared to controls. AMA was associated with lower maternal serum PAPP-A and sFlt and a higher PlGF:sFlt ratio. AMA mice (38–41 weeks) at E17.5 had fewer pups, more late fetal deaths, reduced fetal weight, increased placental weight and reduced fetal:placental weight ratio compared to 8–12 week controls. Maternofetal clearance of 14C-MeAIB and 3H-taurine was reduced and uterine arteries showed increased relaxation. These studies identify reduced placental efficiency and altered placental function with AMA in women, with evidence of placental adaptations in normal pregnancies. The AMA mouse model complements the human studies, demonstrating high rates of adverse fetal outcomes and commonalities in placental phenotype. These findings highlight placental dysfunction as a potential mechanism for susceptibility to FGR and stillbirth with AMA.

Infinity sperm storage: The gift that keeps on giving

© 2017 Wiley Periodicals, Inc. & M Female Drosophila retain sperm for up to two weeks post-copulation in a network of storage organs includng the bursa, the seminal receptacle, and the spermathecae. This image shows the seminal receptacle of a Drosophila melanogaster female, 2-hrs post-copulation between a LHM (wild-type) female with a male transgenic for fl uorescently tagged Protamine B (green), and -Tubulin (blue), whose sperm can be visualized within the female. This ‘infi nity’ structure of the seminal receptacle resembles the tubular coil that allows for the storage of very long sperm relative to female body size –up to 20 times the length of the female in some Drosophila species. These unusually long sperm carry essential seminal proteins from the male, which are gradually released from the gamete during their storage in the female (Adams and Wolfner. 2007. J. Insect Physiol. 53:319). These seminal proteins change female behavior, reducing the inclination to mate with other males; altering female feeding, immunity, longevity; and inducing relaxation of the oviduct for copulatory-induced ovulation (Mattei et al. 2015. PNAS. 112:8475). After these male-derived proteins modify her physiology, the female takes control and actively regulates the release of sperm from internal stores in time with ovulation. Gaining insight into the reproductive behavior of Drosophila provides a basic understanding of factors that regulate male and female reproductive success. This model could be translatable to population control of species that impact human health, including mosquitoes, which are vectors for diseases such as malaria, dengue fever, and Zika.

PP.08 Manchester Advanced Maternal Age Study (MAMAS) – Does an Ageing Maternal Environment and Altered Placental Function Explain Higher Risk of Poor Pregnancy Out Come in Advanced Maternal Age?

Background Women of advanced maternal age (AMA; ≥35 years) have increased risk of fetal growth restriction and stillbirth. The aetiology is unknown; however both conditions are linked with placental dysfunction, including reduced nutrient transport and altered placental morphology. Ageing is associated with increased systemic inflammation; whether this contributes to poor pregnancy outcome is unknown. We hypothesise an ageing maternal environment adversely affects placental function, resulting in poor pregnancy outcome. Methods Women (20–30, 35–39 and ≥40 years) with singleton pregnancies are being recruited to MAMAS. Maternal serum samples are collected at 28 and 36 weeks gestation for measurement of inflammatory markers by ELISA. Placental function is assessed by amino acid uptake by placental villous tissue. Placental morphology was quantified by density of Syncytial Nuclear Aggregates (SNA’s), fetal capillaries and quantification of proliferation. Results Preliminary ELISA analysis of 40 samples revealed lower anti-inflammatory cytokine interleukin-10 (IL-10) in maternal serum of women ≥35 (p = 0.016, Kruskal-Wallis test). Other cytokines were unchanged. Preliminary data suggests higher placental uptake of taurine in women ≥35, but system A activity appears unaltered. SNA’s were increased, but vascularity and proliferation were unchanged in placentas from women ≥35 (p < 0.05 Kruskal-Wallis test). Conclusion MAMAS is the only prospective observational study investigating AMA and placental function. Preliminary data indicate accelerated placental ageing with increased SNA and an altered maternal environment with reduced anti-inflammatory cytokines. Understanding the mechanisms underlying AMA and pregnancy complications may help improve outcome for these women. Measuring circulating biomarkers of ageing prenatally may enable detection of high risk pregnancies.