Mitochondria adapt their structure through fusion and fission, yet how their morphology and cristae architecture change as cells differentiate remains unclear. The human placenta is a valuable model for studying mitochondrial diversity within a single tissue. As epithelial trophoblast cells of the placenta differentiate, their accompanying mitochondria morphologically and functionally transform. We use array tomography to characterise mitochondrial volume and network complexity. Cryo-electron tomography reveals two distinct subpopulations of mitochondria within preparations enriched for progenitor cytotrophoblasts, and a singular, homogeneous population in the differentiated syncytiotrophoblast. We showcase the 3D topology of individual cristae through a standardised metric of "curvedness". Proteomic analysis of isolated mitochondria identifies reduced levels of proteins involved in mitochondrial dynamics and cristae organisation complexes in the syncytiotrophoblast, accompanied by variations in electron transport chain subunits, ATP synthase, and supercomplex components. This study highlights the advantages of combining multimodal imaging with proteomic analyses, to elucidate the process of mitochondrial morphology and cristae architecture remodelling as cells differentiate.

Background

Placental dysfunction underlies major obstetric complications, including preeclampsia, fetal growth restriction, preterm birth, and stillbirth. While early identification of pregnancies at high risk of complications enables preventive interventions, current screening methods based on traditional risk factors have limited accuracy.

Objective

This study aims to develop robust prediction models for placental dysfunction–related pregnancy disorders across 3 gestational windows and to determine the optimal delivery time by integrating maternal characteristics, biophysical measurements, and maternal circulating biomarkers.

Methods

The Placental Health Study is a prospective cohort study conducted at the Maternal Fetal Medicine Unit at Gold Coast University Hospital, Australia. Singleton pregnancies are enrolled at 11 to 13 weeks, 26 to 28 weeks, and 35 to 36 weeks of gestation and are followed until delivery. Exclusion criteria are multiple pregnancies, major fetal anomalies, maternal age below 18 years, and inability to provide informed consent. Clinical data, standardized ultrasound and Doppler measurements, hemodynamic parameters, and biospecimens (serum, plasma, whole blood RNA, and urine) are collected at each visit. Three gestational age-specific datasets (11‐13 weeks, 26‐28 weeks, and 35‐36 weeks) will be constructed for model development. Prediction models will be developed using multivariable logistic regression. Competing risks (Fine and Gray) models will be used as sensitivity analyses for outcomes related to gestational age at delivery. Bayesian updating will be applied to refine existing Fetal Medicine Foundation risk estimates using additional biomarkers or variables collected later in pregnancy. Developed models will undergo internal validation via 5-fold cross-validation, with performance assessed through model discrimination, calibration, and comparison against existing approaches. Collected biospecimens will also be analyzed for angiogenic markers and exploratory omics studies.

Results

Recruitment occurred from June 2022 to February 2026, enrolling 1267 participants. As of submission, 1072 (84.6%) participants have completed their pregnancies, 144 (11.4%) participants remain active in follow-up, and 51 (4%) were withdrawn or had missing or duplicated data. Clinical data have undergone preliminary cleaning and descriptive analysis. Biospecimens are being processed for biomarker quantification and exploratory molecular analyses. Two to three publications are anticipated in late 2026 or early 2027.

Conclusions

This cohort establishes a comprehensive database and biospecimen repository to advance prediction of placental dysfunction–related complications. Three-stage recruitment integrated into routine clinical care enhances feasibility and translation potential, enabling dynamic risk assessment and investigation of temporal biomarker changes. Although the single-center design may limit generalizability, warranting future external validation, the interdisciplinary research team brings diverse expertise that strengthens study depth and scope

Preeclampsia (PE) and small for gestational age/fetal growth restriction (SGA/FGR) are placental dysfunction-related disorders that often co-occur. First-trimester prediction remains challenging. This study characterized the maternal plasma proteome prior to clinical onset to identify candidate biomarkers for early risk stratification.

Objective

Placental dysfunction can result in small-for-gestational age (SGA) or fetal growth restriction (FGR). The aim of this prospective cohort study was to assess the association of the cerebroplacental ratio (CPR) and other more conventional fetoplacental Doppler indices, circulating placental growth factor (PlGF) levels and soluble fms-like tyrosine kinase-1 (sFlt-1)/PlGF ratio, with specific placental abnormalities in a large cohort of pregnancies with an SGA/FGR fetus.

Methods

This was a prospective cohort study of singleton pregnancies with a SGA/FGR fetus conducted at the Centre for Maternal and Fetal Medicine at the Mater Mother's Hospital, Queensland, Australia. Multivariable logistic regression with adjustment for pre-eclampsia was used to evaluate the effect of CPR < 5th centile, umbilical artery Doppler abnormality (defined as umbilical artery (UA) pulsatility index (PI) > 95th centile, or absent or reversed end-diastolic flow), mean uterine artery (UtA) PI > 95th centile and abnormal placental biomarkers (PlGF level < 100 ng/L and sFlt-1/PlGF ratio > 5.78 if gestational age < 28 weeks or > 38 if gestational age ≥ 28 weeks) on the following placental abnormalities, classified based on the Amsterdam Placental Workshop Group Consensus criteria: placental maternal vascular malperfusion (MVM), fetal vascular malperfusion (FVM), villitis of unknown etiology (VUE), chronic histiocytic intervillositis (CHI) and delayed villous maturation (DVM).

Results

Among the 367 women included in this study, MVM was present in 159 (43.3%) placentae, FVM in 20 (5.4%), VUE in 49 (13.4%), DVM in 19 (5.2%) and CHI in six (1.6%). Compared to SGA controls with normal fetoplacental Doppler and placental biomarkers, CPR < 5th centile (adjusted odds ratio (aOR), 3.17 (95% CI, 1.95–5.16); P < 0.001), abnormal UA Doppler (aOR, 2.97 (95% CI, 1.80–4.90); P < 0.001) and mean UtA-PI > 95th centile (aOR, 5.42 (95% CI 2.75–10.70); P < 0.001) were associated with higher odds of placental abnormality. The odds of MVM specifically were significantly higher when CPR < 5th centile (aOR, 2.47 (95% CI, 1.64–4.33); P < 0.001), abnormal UA Doppler (aOR, 3.13 (95% CI, 1.91–5.12); P < 0.001) or mean UtA-PI > 95th centile (aOR, 4.01 (95% CI, 2.25–7.13); P < 0.001) was present. The odds of placental abnormality were also significantly higher if PlGF levels were < 100 ng/L (aOR, 3.66 (95% CI, 2.22–6.06); P < 0.001) or the sFlt-1/PlGF ratio was elevated (aOR, 3.74 (95% CI, 2.17–6.43); P < 0.001). The odds of MVM were also higher in women with PlGF < 100 ng/L (aOR, 2.89 (95% CI, 1.72–4.85); P < 0.001) and elevated sFlt-1/PlGF ratio (aOR, 3.15 (95% CI, 1.83–5.45); P < 0.001).

Conclusion

In pregnancies with SGA/FGR fetus, mean UtA-PI > 95th centile, abnormal UA Doppler, CPR < 5th centile, PlGF < 100 ng/L and elevated sFlt-1/PlGF ratio were all strongly associated with placental abnormality, particularly MVM.

Introduction

The aim of this study was to evaluate differences in circulating maternal placental biomarkers and fetoplacental Dopplers in women with diabetes mellitus in pregnancy (DIP) with prenatally identified small fetuses (defined as <20th centile for gestational age) compared to women with small fetuses without DIP.

Methods

This was a prospective cohort study of women with DIP with small infants compared to a non-diabetic cohort with similarly small fetuses. Multivariable logistic regression was used to evaluate the effect of DIP on placental biomarkers, fetoplacental Dopplers, and adverse perinatal outcomes.

Results

There were 447 pregnancies in this study – 117 (26.2 %) had DIP and 330 (73.8 %) did not have diabetes. Of the DIP cohort, 57 (48.7 %) had early-onset and 27 (23.1 %) had late-onset FGR. Higher rates of low PlGF levels<100 ng/L (42.1 % vs. 25.7 %,p = 0.002), high sFlt-1/PlGF ratio (39.6 % vs. 25.4 %,p = 0.006), low MCA PI < 5th centile at recruitment (18.8 % vs. 7.6 %,p < 0.001, OR 2.37 95%CI 1.25, 4.46,p = 0.008), abnormal UA Doppler before delivery (OR 1.63 95%CI 1.00, 2.66,p = 0.048) were seen in the DIP cohort. DIP was associated with higher rates of emergency cesarean section (43.6 % vs. 26.7 %,p = 0.001) and lower birthweight (2300 (1558, 2610g) vs. 2447 (2050, 2690g),p = 0.003). The odds of early FGR (OR 1.90 95%CI 1.20, 2.98,p = 0.006), PTB<37 weeks (OR 1.66 95%CI 1.02, 2.70,p = 0.039), PTB<34 weeks’ gestation (OR 3.00 95%CI 1.51, 5.96,p = 0.002), composite non-neurological neonatal morbidity (OR 1.86 95%CI 1.04, 3.33,p = 0.037), and hypoglycemia (OR 3.69 95%CI 1.59, 8.54,p = 0.002) were significantly higher in DIP.

Conclusions

DIP is associated with increased risks of early-onset FGR, PTB, composite severe non-neurological neonatal morbidity, and neonatal hypoglycemia in women with small infants. DIP was significantly associated with increased odds of MCA PI < 5th centile at diagnosis and abnormal UA Doppler before birth.