Placental Insufficiency

The gut microbiota operates at the interface of host-environment interactions to influence human homoeostasis and metabolic networks1-4. Environmental factors that unbalance gut microbial ecosystems can therefore shape physiological and disease-associated responses across somatic tissues5-9. However, the systemic impact of the gut microbiome on the germline-and consequently on the F1 offspring it gives rise to-is unexplored10. Here we show that the gut microbiota act as a key interface between paternal preconception environment and intergenerational health in mice. Perturbations to the gut microbiota of prospective fathers increase the probability of their offspring presenting with low birth weight, severe growth restriction and premature mortality. Transmission of disease risk occurs via the germline and is provoked by pervasive gut microbiome perturbations, including non-absorbable antibiotics or osmotic laxatives, but is rescued by restoring the paternal microbiota before conception. This effect is linked with a dynamic response to induced dysbiosis in the male reproductive system, including impaired leptin signalling, altered testicular metabolite profiles and remapped small RNA payloads in sperm. As a result, dysbiotic fathers trigger an elevated risk of in utero placental insufficiency, revealing a placental origin of mammalian intergenerational effects. Our study defines a regulatory 'gut-germline axis' in males, which is sensitive to environmental exposures and programmes offspring fitness through impacting placenta function.

Placental dysfunction underlies the cause of pregnancies complicated by preeclampsia. The use of placental magnetic resonance imaging to provide an insight into the pathophysiology of preeclampsia and thus assess its potential use to inform prognosis and clinical management was explored. In this prospective observational cohort study, 14 women with preterm preeclampsia and 48 gestation-matched controls using 3-Tesla magnetic resonance imaging at median of 31.6 weeks (interquartile range [IQR], 28.6-34.6) and 32.2 weeks (IQR, 28.6-33.8), respectively, were imaged. The acquired data included T2-weighted images and T2* maps of the placenta, the latter an indicative measure of placental oxygenation. Placentae in women with preeclampsia demonstrated advanced lobulation, varied lobule sizes, high granularity, and substantial areas of low-signal intensity on T2-weighted imaging, with reduced entire placental mean T2* values for gestational age (2 sample t test, t=7.49) correlating with a reduction in maternal PlGF (placental growth factor) concentrations (Spearman rank correlation coefficient 0.76) and increased lacunarity values (t=3.26). Median mean T2* reduced from 67 ms (IQR, 54-73) at 26.0 to 29.8 weeks' gestation to 38 ms (IQR, 28-40) at 34.0 to 37.9 weeks' gestation in the control group. In women with preeclampsia, median T2* was 23 ms (IQR, 20-23) at 26.0 to 29.8 weeks' gestation and remained low (22 ms [IQR, 20-26] at 34.0-37.8 weeks' gestation). Histological features of maternal vascular malperfusion were only found in placentae from women with preeclampsia. Placental volume did not differ between the control group and women with preeclampsia. Placental magnetic resonance imaging allows both objective quantification of placental function in vivo and elucidation of the complex mechanisms underlying preeclampsia development.

Fetal health is critically dependent on placental function, especially placental transport of oxygen from mother to fetus. When fetal growth is compromised, placental insufficiency must be distinguished from modest genetic growth potential. If placental insufficiency is present, the physician must trade off the risk of prolonged fetal exposure to placental insufficiency against the risks of preterm delivery. Current ultrasound methods to evaluate the placenta are indirect and insensitive. We propose to use Blood-Oxygenation-Level-Dependent (BOLD) MRI with maternal hyperoxia to quantitatively assess mismatch in placental function in seven monozygotic twin pairs naturally matched for genetic growth potential. In-utero BOLD MRI time series were acquired at 29 to 34 weeks gestational age. Maps of oxygen Time-To-Plateau (TTP) were obtained in the placentas by voxel-wise fitting of the time series. Fetal brain and liver volumes were measured based on structural MR images. After delivery, birth weights were obtained and placental pathological evaluations were performed. Mean placental TTP negatively correlated with fetal liver and brain volumes at the time of MRI as well as with birth weights. Mean placental TTP positively correlated with placental pathology. This study demonstrates the potential of BOLD MRI with maternal hyperoxia to quantify regional placental function in vivo.

BACKGROUNDPrenatal alcohol exposure (PAE) around conception in preclinical models results in placental insufficiency, likely contributing to offspring abnormalities. Altered placental DNA methylation (DNAm) and gene expression suggest epigenetic mechanisms, perhaps involving impacts on methyl donor levels. PAE around conception in women is common but placental effects are rarely examined. This cohort study investigated associations between PAE around conception and intake/plasma measures of the methyl donors folate and choline, feto-placental blood flow, and placental growth measures, gene expression, and DNAm.METHODSPregnant participants delivered at Mater Mothers' Hospital, Brisbane, Queensland, Australia (n = 411). Dietary intake of choline and folate were calculated and plasma concentrations measured using mass spectrometry (MS) and clinical immunoanalyzer, respectively. Cerebroplacental ratio (CPR) was calculated using Doppler measurements. Placentas were weighed/measured at delivery and samples used to quantify methyl donors (MS), global DNAm (ELISA), and gene expression (quantitative PCR). Data were compared between control/abstinent and PAE groups, by fetal sex.RESULTSA CPR <5th-centile, indicating fetal brain sparing because of placental insufficiency, was found in 2% of controls and 18% of the PAE group, mostly male fetuses (63%). Compared with controls, male PAE placentas had reduced mean thickness and placental growth factor mRNA and DNAm, whereas female PAE placentas had increased S-adenosylmethionine and a trend toward increased DNAm.CONCLUSIONPAE around conception is associated with reduced CPR and altered placental growth measures, particularly in males, with potential implications for future health.FUNDINGNational Health and Medical Research Council (APP1191217) and Mary McConnel Career Boost Program for Women in Paediatric Research (WIS132020).