Anthony V Perkins

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

Background: Preeclampsia (PE) is a multisystemic pregnancy syndrome that presents in different clinical subtypes. While placental dysfunction is a critical feature of PE, its contribution to different PE subtypes remains unclear. This study aims to use integrated bioinformatics analysis of placental transcriptomics to investigate subtype-specific molecular mechanisms associated with PE.

Methods: A systematic search of the Gene Expression Omnibus (GEO) repository identified two datasets (GSE234729, n = 123; GSE75010, n = 157) for integrated Weighted Gene Co-expression Network Analysis (WGCNA) and differential gene expression analysis. We constructed co-expression networks and identified gene modules correlated with three PE subtypes (severe, early-onset and late-onset). Differential gene expression analysis was conducted using the “limma” R package. Differentially expressed genes (DEGs) overlapping with PE subtype-correlated WGCNA modules underwent Gene Ontology (GO) enrichment analysis. Consistently dysregulated genes were validated in an additional external dataset (GSE25906) and RT-PCR analysis of placental samples from 21 PE cases and 21 uncomplicated controls.

Results: We identified distinct molecular signatures associated with each PE subtype. The green gene module was positively correlated with severe PE (r = 0.63, p = 4e-15), containing 179 DEGs primarily involved in lipid metabolism and hypoxia response processes. Early-onset PE had two highly significant gene modules: the yellow module (r = 0.73, p = 4e-15) with 112 DEGs enriched in biological processes related to gonadotrophin secretion and lipid storage, and the black module (r = −0.55, p = 5e-08) with 47 DEGs significantly enriched in chronic inflammation responses. Late-onset PE showed moderate correlation with the ivory module (r = 0.46, p = 5e-05), containing 23 DEGs enriched in p38MAPK stress-response signalling. Cross-subtype analysis identified 20 consistently dysregulated genes across three PE subtypes, with four upregulated genes (LEP, FSTL3, HTRA4, and HK2) confirmed in the external dataset GSE25906. However, RT-PCR validation showed only moderate upregulation without statistical significance.

Conclusion: Though placental dysfunction occurs across all subtypes with a core set of upregulated genes, variation exits in placental gene expression patterns among PE subtypes. Severe and early-onset PE exhibit large molecular perturbations, while late-onset PE presents more subtle alterations. Aberrant placental lipid storage may contribute to disease severity and early manifestation.

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.

Introduction
The aim of this study was to evaluate the association between placental abnormalities, placental biomarkers, and fetoplacental Dopplers in a cohort of pregnancies complicated by fetal growth restriction (FGR). We also ascertained the risk of perinatal mortality, severe neurological morbidity, and severe non-neurological morbidity by type of placental abnormality.

Methods
This was a prospective cohort study. Multivariable logistic regression was used to evaluate the effect of early vs. late FGR, placental biomarkers and fetoplacental Dopplers on Maternal Vascular Malperfusion (MVM) which was the commonest placental abnormality identified.

Results
There were 161 (53.5 %) early FGR and 140 (46.5 %) late FGR cases. MVM abnormalities were present in 154 (51.2 %), VUE in 45 (14.6 %), FVM in 16 (5.3 %), DVM in 14 (4.7 %) and CHI in 4 (1.3 %) cases. The odds of MVM were higher in early compared to late FGR cohort (OR 1.89, 95%CI 1.14, 3.14, p = 0.01). Low maternal PlGF levels <100 ng/L (OR 2.34, 95%CI 1.27,4.31, p = 0.01), high sFlt-1 level (OR 2.13, 95%CI 1.35, 3.36, p = 0.001) or elevated sFlt-1/PlGF ratio (OR 3.48, 95%CI 1.36, 8.91, p = 0.01) were all associated with MVM. Increased UA PI > 95th centile (OR 2.91, 95%CI 1.71, 4.95, p=<0.001) and mean UtA PI z-score (OR 1.74, 95%CI 1.15, 2.64, p = 0.01) were associated with higher odds of MVM. Rates of severe non-neurological morbidity were highest in the MVM, FVM, and CHI cohorts (44.8 %, 50 %, and 50 % respectively).

Conclusion
MVM was the commonest placental abnormality in FGR, particularly in early-onset disease. Low maternal PlGF levels, high sFlt-1 levels, elevated sFlt-1/PlGF ratio, and abnormal fetoplacental Dopplers were also significantly associated with MVM. MVM, FVM, and CHI abnormalities were associated with lower median birthweight, higher rates of preterm birth, operative birth for non-reassuring fetal status, and severe neonatal non-neurological morbidity.

Linoleic acid (LA) is required for neuronal development. We have previously demonstrated sex-specific changes in cardiovascular and hepatic function in rat offspring from mothers consuming a high-LA diet, with some effects associated with reduced LA concentration in the postnatal diet. At this time, the impact of a high-maternal-LA diet on offspring brain development and the potential for the postnatal diet to alter any adverse changes are unknown. Rat offspring from mothers fed low- (LLA) or high-LA (HLA) diets during pregnancy and lactation were weaned at postnatal day 25 (PN25) and fed LLA or HLA diets until sacrifice in adulthood (PN180). In the offspring’s brains, the postnatal HLA diet increased docosapentaenoate in males. The maternal HLA diet increased LA, arachidonate, docosapentaenoate, C18:0 dimethylacetal (DMA), C16:0 DMA, C16:0 DMA/C16:0, and C18:0 DMA/C18:0, but decreased eoicosenoate, nervoniate, lignocerate, and oleate in males. Maternal and postnatal HLA diets reduced oleate and vaccenate and had an interaction effect on myristate, palmitoleate, and eicosapentaenoate in males. In females, maternal HLA diet increased eicosadienoate. Postnatal HLA diet increased stearate and docosapentaenoate. Maternal and postnatal HLA diets had an interaction effect on oleate, arachidate, and docosahexaenoic acid (DHA)/omega (n)-6 docosapentaenoic acid (DPA) in females. Postnatal HLA diet decreased DHA/n-6 DPA in males and females. Postnatal HLA diet increased plasma endocannabinoids (arachidonoyl ethanolamide and 2-arachidonoyl glycerol), as well as other N-acyl ethanolamides and testosterone. HLA diet alters brain fatty acids, plasma endocannabinoids, and plasmalogen concentrations in a development-specific and sex-specific manner.