Fetal Fornix and Hippocampus in Pregnant Women With Early-Onset Preeclampsia

Hypertensive disorders complicate approximately 5-10% of all pregnancies and account for nearly 16% of maternal mortality. Preeclampsia (PE) occurs in 4-5% of pregnancies, and in the United States, preeclampsia or eclampsia contributed to 7.4% of the 2,009 pregnancy-related maternal deaths reported between 2011 and 2013. Preeclampsia is defined by new-onset hypertension and proteinuria, or new-onset hypertension with or without proteinuria, accompanied by evidence of significant end-organ dysfunction. It is a progressive, multisystem disorder that generally develops after 20 weeks of gestation or during the postpartum period.

Preeclampsia is also considered a pregnancy-specific syndrome capable of affecting every organ system. Because of its significant maternal and perinatal morbidity and mortality, PE represents a major public health concern. The condition is commonly described as a two-stage disease. Stage 1 (placental syndrome) is characterized by early placental ischemia/reperfusion, oxidative stress, and the release of toxic factors, primarily due to abnormal endovascular trophoblastic remodeling, primigravidity, trophoblast load, genetic predisposition, and maternal immunologic maladaptation. Stage 2 (maternal syndrome) represents the clinical phase, driven by an exaggerated maternal systemic inflammatory response and endothelial dysfunction. Maternal genetic susceptibility and underlying vascular disease may further contribute.

Overall, the etiopathogenesis of PE involves abnormal trophoblastic invasion, maternal-fetal immunologic incompatibility, maladaptation to normal cardiovascular and inflammatory changes of pregnancy, systemic vascular dysfunction, genetic influences, and epigenetic mechanisms. Approximately 90% of preeclampsia cases occur in the late-preterm (34-37 weeks), term, or postpartum period and generally have more favorable outcomes. However, severe morbidity and mortality may still occur. The remaining 10% of cases present as early-onset preeclampsia (EOPE, <34 weeks), in which abnormal placentation and defective trophoblastic invasion are more pronounced and closely correlate with disease severity. EOPE carries a markedly higher risk of serious perinatal complications, largely due to its strong association with preterm delivery. Consequently, the study of EOPE remains clinically important.

The hippocampus is a seahorse-shaped structure located within the medial temporal lobe, protruding laterally toward the temporal horn of the lateral ventricle. It plays essential roles in memory processing (dorsal hippocampus) and regulation of stress responses (ventral hippocampus). Fetal hippocampal development involves progressive inward folding of the dentate gyrus, cornu ammonis, subiculum, and parahippocampal gyrus around the shrinking hippocampal sulcus.

Experimental studies have demonstrated that adverse maternal conditions may affect hippocampal development. In rodent models, uncontrolled maternal diabetes reduces hippocampal volume and neuronal density during early postnatal life, leading to delayed development and motor, behavioral, and cognitive deficits in offspring. In an experimental preeclampsia model induced with a cholesterol-based diet, hippocampal arteriolar vasoreactivity to neurovascular coupling mediators was impaired, resulting in deficits in long-term-but not spatial-memory. These findings may parallel long-term cardiovascular and neurocognitive outcomes observed in women with a history of preeclampsia and eclampsia. Persistent endothelial and vascular smooth muscle dysfunction in hippocampal vessels may contribute to disrupted hippocampal networks and early cognitive impairment.

Clinical and experimental data also suggest that children born to preeclamptic mothers have higher rates of neurodevelopmental disorders, including cognitive impairments, autism spectrum disorder, depressive disorders, attention-deficit/hyperactivity disorder, and cerebral palsy. Reported neuronal abnormalities include impaired neurogenesis, reduced neuronal integrity, accumulation of cellular debris, decreased synaptogenesis and myelination, and abnormal neurite outgrowth, potentially mediated by microglial activation, inflammation, and reduced angiogenesis.

Since EOPE is frequently associated with inadequate placentation, placental insufficiency, chronic fetal hypoxia, oxidative stress, and inflammation, these pathophysiologic processes may interfere with fetal hippocampal neuronal development and maturation of the fornix. These mechanisms support our hypothesis that fetal fornix and hippocampus dimensions may be reduced in EOPE.

Ultrasonographic literature on fetal hippocampal imaging is limited. Gindes et al. demonstrated that the fetal hippocampus and fornix can be identified as a C-shaped structure on sagittal three-dimensional (3D) ultrasound. Toprak et al. reported that the fetal fornix and hippocampus can be rapidly visualized using two-dimensional (2D) ultrasound during midtrimester anomaly screening. Sahin et al. confirmed that the bilateral fornix-hippocampus complex can be visualized between 18 and 36 weeks of gestation and proposed sonographic reference values.

Research Hypothesis:

Is there a difference in fetal fornix and hippocampus dimensions in pregnancies complicated by early-onset preeclampsia compared with healthy controls? Our primary hypothesis is that fetal fornix and hippocampus dimensions are reduced in EOPE.

Expected Benefits:

By assessing the relationship between fetal fornix and hippocampus size and EOPE, and evaluating potential associations with pregnancy prognosis and complications, this study may contribute to improved understanding and management of the condition and support future prospective research. The study poses no risk to pregnant women or fetuses.

The study will enroll 42 pregnant women diagnosed with EOPE (aged 18-45 years, 20-34 weeks of gestation) presenting to the Perinatology Clinic of Ankara Etlik City Hospital, along with 42 healthy controls. Sample size calculation using G*Power 3.1.9.7 indicated that a minimum of 84 participants would provide 95% statistical power (effect size d = 0.8, α = 0.05, 1-β = 0.95). Participants will be included after informed consent is obtained, and confidentiality will be ensured.

Demographic and routinely collected clinical data-including age, gestational age, height, weight, BMI, weight gain, gravidity, parity, obstetric history, comorbidities, medications, prior surgeries, tobacco and alcohol use-will be recorded. Routine laboratory parameters and ultrasonographic measurements (biometry, amniotic fluid index, umbilical artery Doppler systolic/diastolic (S/D) ratio and pulsatility index (PI), middle cerebral artery Doppler peak systolic velocity (PSV) and PI, uterine artery Doppler PI, cerebroplacental ratio (CPR), and cerebro-placento-uterine ratio (CPUR)) will also be obtained.

For this study, fetal fornix and hippocampus dimensions will be measured by 2D ultrasound in both EOPE and control groups using standard clinic equipment. All findings will be compiled into a detailed report including statistical analyses, comparisons between groups, and evaluation of the relationship between EOPE and fetal fornix/hippocampus measurements.

Inclusion criteria

• Women aged 18-45 years
• Gestational age between 20 and 34 weeks
• Diagnosis of early-onset preeclampsia (EOPE)
• Singleton pregnancy

Exclusion criteria

• Multiple pregnancies
• Presence of chronic or significant comorbid conditions other than maternal early-onset preeclampsia, including: Chronic, mental, or physical illnesses, severe renal, hepatic, or gastrointestinal acute or chronic inflammatory diseases, hyperthyroidism or hypothyroidism, chronic hypertension, type 1 or type 2 diabetes mellitus, history of polycystic ovary syndrome (PCOS), history of malignancy
• Fetal congenital or chromosomal anomalies
• Chronic medication use
• Tobacco or alcohol use during pregnancy
• Maternal late-onset preeclampsia (≥34 weeks gestation)