Although there are many theories regarding the pathogenesis of preeclampsia, its exact etiology remains unknown and seems to be a multifactorial condition involving fetal/placental and maternal factors [8]^[1]. The most prominently accepted theory concerns the abnormal development of the placental vasculature in early pregnancy due to defective trophoblast differentiation and invasion [8]^[1], causing abnormal remodeling of the spiral arteries, which leads to the perpetuation of a high-resistance and low-flow uteroplacental unit [9]^[2]. In turn, this results in diminished placental perfusion, hypoxia, and ischemia, which lead to the release of antiangiogenic factors into the maternal circulation, an imbalance between vasodilating and vasoconstrictive factors, increased vascular reactivity, and excessive inflammation [10]^[3]. The immunologic theory supports the hypothesis that immunologic intolerance between the mother and the paternal/fetal antigens may contribute to the pathogenesis of preeclampsia. This immunologic imbalance is believed to increase natural killer (NK) cell activity and decrease levels of regulatory T cells and other mediators of the immune response, thus inducing abnormal placental implantation [10]^[3]. Finally, numerous other theories cast the following features as etiologic or triggering factors: genetic factors, environmental and maternal susceptibility factors (such as IVF, high maternal BMI), increased sensitivity to angiotensin II, complement activation disorders, and endothelial cell dysfunction [8]^[1].

2. Outcome in Offspring

2.1. Neurodevelopment

There is evidence that Hypertensive Disorders of Pregnancy (HDP) and Preeclampsia (PE) have been associated with adverse outcomes and an increased risk of neurodevelopmental disorders in the mother’s offspring. Neurodevelopmental disorders (NDs) are a group of conditions with an onset in a child’s developmental period and comprise Autism Spectrum Disorder (ASD); intellectual disability (ID); Communication Disorders; Attention-Deficit/Hyperactivity Disorder (ADHD); Neurodevelopmental Motor Disorders, including Tic Disorders; and Specific Learning Disorders. All NDs have a strong genetic background, as they are associated with environmental parameters that affect early brain development. A broad range of environmental perinatal parameters may affect neurodevelopment, including prematurity, low birthweight, and maternal exposure to certain environmental contaminants and/or drugs, alcohol, or tobacco [16,17]^[4][5]. Hypertensive disorders of pregnancy and preeclampsia are leading causes of several obstetric complications related to adverse neurodevelopmental outcomes. These complications mainly include preterm birth and fetal growth restriction, both of which are considered well-recognized perinatal risk factors for neurodevelopmental disorders [18,19]^[6][7]. However, hypertensive disorders of pregnancy and preeclampsia have been relatively recently added to these perinatal risk factors (independently of their effects on gestational age and birth weight) [20]^[8]. Indeed, the “preeclamptic” environment may alter the structure and function of the central nervous system and affect fetal brain development [21]^[9]. Although the exact mechanisms associating PE and neurodevelopmental outcomes are still under investigation [22^[10][11],23], it has been postulated that both inflammation and oxidative stress, the two main pathophysiological mechanisms of PE, may contribute considerably to this association. Potentiated inflammatory processes and oxidative stress affect maternal, placental, and fetal circulation in PE and expose the fetus to both maternal immune activation and increased concentrations of pro-inflammatory cytokines. The fetal brain is directly exposed to deleterious factors that adversely affect neuronal development. The final impacts of these changes are the interaction of hypoxia and placental ischemia, oxidative stress, angiogenic and growth-factor-related changes, and inflammation. Changes of the neuroanatomy and the cerebrovasculature [9,24,25]^[2][12][13] may be associated with a higher risk of developing all NDs [26]^[14].

2.2. Eye Disorders

Preeclampsia is associated with an increased risk of ophthalmic morbidity. A population-based cohort analysis compared the risk of long-term ophthalmic morbidity among children who had been born via a preeclamptic pregnancy and those who had not. The results showed a significant association between severe preeclampsia or eclampsia and the risk of long-term, vascularly associated ophthalmic morbidity in offspring (no preeclampsia 0.3%, mild preeclampsia 0.2%, and severe preeclampsia or eclampsia 0.5%, p = 0.008). However, there is insufficient evidence regarding the association between eye disease and mild preeclampsia [52]^[15]. The underlying mechanisms by which PE affects the eyes of newborns are not well understood. It is possible that abnormal placentation results in placental hypoperfusion and hypoxia, which, in turn, intensifies the expression of hypoxia-inducible factor-1 (HIF-1), a transcription factor that is causally associated with systemic endothelial dysfunction in the fetus and the mother, which affects the visual system [53,54,55]^[16][17][18]. Intrauterine stress related to PE is an additional contributing factor that triggers fetal adaptive epigenetic reprogramming, thereby increasing the susceptibility of a child to vascular diseases later in life, through a permanent alteration of gene expression [56,57,58,59]^{[19][20][21][22]}. Furthermore, preeclampsia-associated iatrogenic preterm birth and may lead to short-term visual morbidity, such as retinopathy of prematurity (ROP) [60,61]^[23][24].

2.3. Immune System and Susceptibility to Infections

It has been suggested that abnormal immune function may contribute to the pathophysiology and clinical presentation of PE. Furthermore, it has been proposed that PE reflects an exaggerated maternal inflammatory response to pregnancy and is associated with immune processes similar to organ rejection after allograft transplantation and in graft-versus-host diseases (GVHD) [62]^[25]. The impact of preeclampsia on offspring immune system is still being researched. The preeclamptic environment and the way that Trained Immunity (TI), which includes natural immune memory, has been linked with PE are still under investigation. Two major mechanisms have been proposed to associate the deviation from the normal immunological signature of pregnancy with future disease: the epigenetic reprogramming of the gametes following the exposure of the parent to inflammation and the uteroplacental unit through which TI is transmitted from mother to offspring [63]^[26]. Since TI and the effects of a complicated prenatal environment persist across generations, it has been suggested that TI could be causally linked to the increased risk of offspring disease following their exposure to excessive in utero inflammation associated with PE. It has been shown that PE increases the risk of both allergic and severe atopic sensitization and an increased incidence of asthma [9,64,65]^[2][27][28]. Furthermore, it has been suggested that there is an increased prevalence of neonatal sepsis in both term and preterm infants born to preeclamptic pregnancies based on inflammation and immune dysfunction associated with PE. Neonatal sepsis is the fifth leading cause of neonatal death. Shane et al. [66]^[29] define neonatal sepsis as “a systemic condition of bacterial, viral, or fungal (yeast) origin that is associated with hemodynamic changes and other clinical manifestations and results in substantial morbidity and mortality.” Various known risk factors for the development of neonatal sepsis have been described, such as a high maternal BMI, preexisting diabetes, smoking, numerous digital exams, GBS positivity, chorioamnionitis, the use of antibiotics, administration of steroids for fetal lung maturity, and cesarean delivery. A population-based cohort analysis showed that PE is an independent risk factor for the diagnosis of neonatal sepsis until the gestational age of 37 weeks [67]^[30]. This association did not persist when the analysis involved only the subgroup of individuals that delivered at term [68]^[31]. The way that preeclampsia influences the long-term susceptibility to infections of offspring is still being researched. Two main independent risk factors, which may affect susceptibility to infections, have also been proposed: gestational age at birth and cesarean section as a choice of the delivery [65,69,70]^[28][32][33]. Preeclampsia influences the development of the offspring’s immune system, either independently or due to complications that arise from the preeclamptic environment, such as iatrogenic prematurity and increased cesarean section rates [9,67]^[2][30]. Further understanding of the mechanisms by which PE affects the offspring’s immune system and predisposes a child to infections is essential to facilitate clinical interventions to reduce morbidity linked with preeclampsia.

2.4. Gastrointestinal Diseases

2.4.1. Neonatal Age

Necrotizing enterocolitis (NEC) is a pediatric gastrointestinal disease that is primarily associated with prematurity and low birth weight. The pathophysiology of NEC is multifactorial, for which prematurity, intestinal immaturity, hypoxia, formula feeding, and colonization with pathogenic bacteria are the main risk factors [71,72]^[34][35]. A prospective study showed that NEC incidence among premature infants was significantly higher in those born through preeclamptic pregnancies compared to normotensive ones. Additionally, NEC occurred significantly earlier [28]^[36] and lasted considerably longer in premature infants born to preeclamptic mothers compared to those born to normotensive mothers [53,73]^[16][37].

2.4.2. Childhood

Pediatric gastrointestinal diseases in offspring requiring hospitalization are associated with severe preeclampsia or eclampsia as independent risk factors. These diseases include esophageal morbidity, hernias, and functional colonic morbidity. It is hypothesized that within the context of an unfavorable in utero environment, fetal intestinal perfusion might be slightly reduced to preserve blood flow to other vital organs, leading to consequent ischemic bowel injury that may only be notable later in life [74]^[38]. However, this result was derived from a large population-based study, and further research based on community databases is warranted, which should focus on genetic backgrounds and environmental exposure during childhood.

2.5. Cardiovascular System

In 1993, the Barker hypothesis was developed, which proposed that maternal hypertension or placental ischemia increased the risk of hypertension, cardiovascular disease (CVD), and stroke in the affected mother’s offspring [75]^[39]. This theory is now supported both experimentally and epidemiologically [25]^[13]. A multifactorial interaction of different mechanisms including genetic background and environmental parameters [76]^[40] may explain this association.

2.5.1. Neonatal Age– Early Childhood

The maturation of fetal myocardial cells is influenced by hormone-mediated regulation and the hemodynamic load in utero [77]^[41]. Preeclampsia is associated with increased fetal cardiac afterload due to an increase in placental vascular resistance, which promotes early asymptomatic changes to the fetal heart, through the abnormal accelerated maturation of cardiomyocytes [78,79]^[42][43]. This leads to abnormal hypertrophy and altered anatomy in the cardiac components. In preeclamptic pregnancies, the fetal heart has been reported to present an increased size (a median of 0.27 in uncomplicated pregnancies, which can be compared to 0.31 in cases of fetal growth restriction (FGR), 0.31 in cases of preeclampsia with a normally grown fetus, and 0.28 in cases of preeclampsia with FGR; p < 0.001), ventricular hypertrophy (measured wall thickness of 0.55 in uncomplicated pregnancies, which can be compared to 0.67 in cases of FGR, 0.68 in cases of preeclampsia with a normally grown fetus, and 0.66 in cases of preeclampsia with FGR; p < 0.001), and an increased myocardial performance index. This degree of fetal cardiac remodeling seems to be similar between preeclampsia and fetal growth restriction [78,80]^[42][44]. Still, gestational hypertension is independently correlated with an increase in right ventricular mass during the first three postnatal months [1]^[45], while reduced left ventricular longitudinal peak systolic strain has been observed in preterm individuals birthed by preeclamptic mothers when compared to preterm, normotensive ones. The adverse changes in left and right ventricular structure and function seem to be independent of preterm birth. In addition, it has been reported that neonates of preeclamptic mothers present coronary dilatation [81]^[46] at birth as well as higher cord blood levels of blood N-terminal pro-B-type natriuretic peptide (NT-proBNP), troponin I, homocysteine, and endothelial vascular cell adhesion molecule-1 expression, presenting early endothelial inflammation and cardiac cell damage. Muñoz-Hernandez et al. [82]^[47] have demonstrated that the levels of endothelial colony-forming cells (ECFCs) from cord blood were lower in preeclamptic pregnancies both in preterm and term groups than the normotensive controls. Distinctive postnatal microvascular remodeling was further identified by Yu [83]^[48], who observed a loss in total dermal microvascular density over the first three months of life in the offspring of hypertensive pregnancies [81]^[46]. Additionally, early-onset preeclampsia has been shown to affect osteoprotegerin concentrations at birth, thus altering the osteoprotegerin–RANKL axis involved in fetal cardiovascular “programming” [84]^[49]. These observed cytologic, anatomical, and hemodynamic changes are expressed clinically even in the first month of life. Possible candidate mechanisms with a predominantly maternal origin include endothelial impairment, angiogenic imbalance, poor angiogenesis, smooth muscle abnormalities, and subclinical metabolic disorders. Infants exposed to early-onset preeclampsia had greater reported prevalence than the late-onset group, including tetralogy of Fallot, atrioventricular septal defects, valvar dysfunction, and patent ductus arteriosus. Moreover, increased intima-media thickness of the abdominal aorta in neonates born to preeclamptic pregnancies has been reported [92]^[50]. Finally, a recent systematic review and meta-analysis by Hoodbhoy et al. on the impact of maternal preeclampsia and hyperglycemia on the cardiovascular system of the offspring [93]^[51] reported lower birth weight (MD: −0.41 kg) but increased systolic (MD: 2.2 mmHg) and diastolic blood pressure (MD: 1.41 mmHg) in children under 10 years old born to preeclamptic pregnancies compared to controls.

2.5.2. Adolescence–Early Adulthood

In preeclampsia, vasculotoxic factors that enter the placenta provoke excessive hypoxic pulmonary hypertension and may lead to a premature cardiovascular deficiency through the permanent impairment of the systemic and pulmonary circulation [94]^[52]. In a metanalysis of eighteen studies by Davis et al. [95]^[53] examining traditional cardiovascular risk factors in children and adolescents exposed to preeclampsia, in utero exposure to preeclampsia was associated with a 2.39 mmHg higher systolic and a 1.35 mmHg higher diastolic blood pressure and an increased Body Mass Index (BMI) by 0.62 kg/m² during childhood and early adulthood. The findings were independent of gender and birth weight. The documented elevation in systolic blood pressure was related to an increase of 8% in mortality via ischemic heart disease and 12% from stroke [25]^[13]. Additionally, a 2.5-fold higher risk of scores above the 75th centile of global lifetime risk (QRISK) was observed in young adults exposed in utero to preeclampsia [96]^[54]. A causative link between in utero exposure to preeclampsia and metabolic adverse effects has also been studied. According to a recent population-based study, the incidence of obesity was higher in the preeclampsia-affected offspring (odds ratio = 1.34) during early childhood even though the incidence of low birth weight (LBW) was higher [97]^[55]. A recent meta-analysis studying offspring BMI during peripubertal life reported a higher risk of obesity (odds ratio 2.12 [1.70, 2.66]; p < 0.00001) and increased waist circumference (MD 1.37 cm [0.67, 2.06]; p = 0.0001) in the preeclamptic compared to non-preeclamptic group. However, offspring BMI was inversely associated with maternal age in both groups [23]^[11]. Studies have also described increased adiposity and expression of obesity-related genes as well as increased placental leptin synthesis and leptin concentration in the cord-blood of offspring prematurely born to preeclamptic mothers [94,98,99]^[52][56][57]. Moreover, the aforementioned concentric heart remodeling with the hypertrophic ventricles and the reduced left ventricular end-diastolic volume has been observed in adolescents born preterm to preeclamptic mothers [100]^[58]. Although prematurity is linked to higher blood pressure in childhood and young adulthood, the endothelial dysfunction observed in the offspring of preeclamptic mothers is unique. Furthermore, siblings of these individuals, born at term from uncomplicated pregnancies, have not presented any of the aforementioned cardiovascular defects, suggesting an effect related to preeclampsia rather than a shared genetic background [101]^[59]. 

2.6. Renal System

Renal function impairment represents another significant aspect when analyzing the cardiovascular risks in preeclamptic offspring. Human nephrogenesis occurs mostly in the third trimester when the incidence of preeclampsia is more common, thus having a negative impact on the fetal kidney development [107,108]^[60][61]. Preeclampsia may coexist with FGR and be associated with prematurity, further reducing nephron quantities, decreasing the renal filtration rate, promoting glomerular hypertrophy, and reducing renal vasodilation [109]^[62]. The decreased number of nephrons also seems to be independently related to placental dysfunction associated with preeclampsia. The hemodynamic changes and prenatal hypoxia observed in preeclampsia induce molecular, pathophysiological, and histological alterations, which negatively impact fetal renal function and renal vascular tension. Additionally, maternal endothelial dysfunction caused by placental hypoxia leads to an imbalance in maternal vasoactive elements, including increased concentrations of vasoconstrictors (such as thromboxane A2, endothelin, and phenylephrine) and decreased concentrations of vasodilators (such as prostacyclin and nitric oxide) [110,111,112]^[63][64][65]. This imbalance of vasoactive compounds may lead to reduced vascular relaxation and injury of the endothelium of renal interlobar arteries in fetal kidneys. It has also been suggested that the decrease in the level of vasodilatory nitric oxide in preeclampsia cannot counterbalance the increased sympathetic tone in fetal renal vessels, which is partially induced by the increased sensitivity of the fetus to adenosine, leading to a vasoconstrictive effect [26,27,28]^[14][36][66]. Finally, early-onset preeclampsia has been associated with an altered renin–angiotensin–aldosterone system in the offspring that persists into adolescence. More specifically, aldosterone levels were found to be elevated in adolescent males born preterm due to preeclampsia. This increase may predispose the offspring of preeclamptic mothers to developing hypertension [89,113]^[67][68].

2.7. Endocrine System

Although endocrine diseases in childhood are relatively uncommon, obesity in children and adolescents has developed into a significant public health problem, mainly due to its high prevalence and the association with other comorbidities. It seems that preeclampsia considerably increases the offspring’s risk of long-term endocrine morbidity and, specifically, obesity. The rates of hospital admissions due to endocrine morbidity and obesity for the offspring of preeclamptic pregnancies [98]^[56] have been found to be higher compared to controls (0.7% vs. 0.4%; p < 0.001 and 0.2% vs. 0.4% p < 0.001, respectively), showing a linear correlation with the severity of preeclampsia (0.7% in mild vs. 1.4% in severe preeclampsia, p = 0.002). Endocrine morbidity was still significantly increased even after controlling for confounders (OR 1.433 95% CI 1.115–1.841 p = 0.005) [98]^[56]. The increased obesity prevalence in PE offspring has also been reported in a recent meta-analysis (RR 1.45, 95% confident interval [CI] 1.19–1.78) that further showed that PE offspring were associated with higher mean arterial, systolic, and diastolic blood pressure in puberty. The authors concluded that PE might be associated with central obesity, hypertension, and type 2 diabetes mellitus in offspring later in life [107]^[60]. Compared to unexposed girls, higher DHEAS concentrations were found in girls exposed to mild and moderate preeclampsia, while lower concentrations were found in a group exposed to severe preeclampsia. The differences in DHEAS concentrations according to the degree of severity of preeclampsia had an impact on the timing of adrenarche, which was probably due to a different androgenic influence. Τhe severe preeclamptic group with lower DHEAS concentrations entered adrenarche relatively late, while earlier menarche and pubarche before thelarche [117]^[69] were observed in female offspring exposed to non-severe preeclampsia with a possible increased risk of PCOS and hyperinsulinemia during adulthood [118]^[70]. Concerning boys born to severe preeclamptic pregnancies, DHEAS levels were also decreased compared to a control group but did not differ between the mild, moderate, and unexposed groups [117]^[69]. Furthermore, boys exposed to mild and moderate preeclampsia also presented increased testicular volume and elevated concentrations of IGF-I, indicating a higher risk of metabolic disorders later in life [118]^[70]. Moreover, concerning the long-term reproductive consequences of in utero exposure to hypertensive disorders, these also seem to depend on the gender of the offspring. The timing of pubertal development in male offspring does not seem to be affected by maternal preeclampsia. On the contrary, a recent study proposed a mild acceleration in pubertal timing in the daughters of preeclamptic mothers, while in the daughters of hypertensive mothers, some pubertal milestones seemed to occur earlier than in the daughters of normotensive mothers [119]^[71]. Although preeclampsia has been associated with earlier menarche [120^[72][73],121], some studies found no impact of preeclampsia on the onset of pubertal timing [117,122]^[69][74]. In summary, it has been suggested that prenatal exposure to preeclampsia may induce changes in the endocrine system of the offspring, affecting obesity prevalence, adrenal activity, salt sensitivity, androgen balance, and pubertal development.

2.8. Respiratory System

2.8.1. Neonatal Life

In preeclamptic offspring, the imbalance of angiogenic and inflammatory factors may dysregulate their pulmonary vascular and alveolar development. Studies on extremely premature (23–28 weeks) [125]^[75], premature (30–34+6 weeks) [126]^[76], and very-low-birthweight infants [127]^[77] have reported an increased risk of severe neonatal respiratory distress syndrome (RDS) (≥30% supplemental oxygen on day 1) [128]^[78]. Furthermore, the incidence of neonatal pneumonia, RDS, and lower Apgar scores was found to be higher in the preterm and full-term offspring of pregnancies complicated by gestational hypertensive disorders, for which there was a positive correlation between the severity of maternal hypertension and neonatal respiratory morbidity. Whether in utero exposure to preeclampsia is associated with bronchopulmonary dysplasia (BPD) in preterm infants less than 32 weeks remains controversial. 

2.8.2. Childhood

The preeclampsia-mediated effects on systemic and pulmonary circulation seem to be permanent according to a study assessing pulmonary artery pressure and flow-mediated dilation of the branchial artery in children born to preeclamptic women [95]^[53]. More specifically, pulmonary artery pressure was 30% higher and flow-mediated dilation was 30% reduced in the offspring of preeclamptic women, while both changes were attributed to augmented oxidative stress related to preeclampsia. Furthermore, the effect of preeclampsia on the relationship between maternal and offspring asthma has been investigated. According to a recent clinical trial [131]^[79] comparing the offspring of asthmatic mothers, the risk of asthma was 50% greater for children born to preeclamptic mothers compared to the offspring of normotensive mothers with asthma (adjusted hazard ratio, 2.68; 95% CI: 1.30–5.61). These results support the interaction between already-existing obstetric factors and in utero fetal immune dysregulation because of preeclampsia, making it an independent risk factor for the respiratory morbidity of the offspring [132]^[80]. In summary, in utero exposure to preeclampsia may be associated with severe neonatal RDS in addition to asthma and elevated pulmonary artery pressure later in life.