1 Department of Pharmacy, Women’s Hospital School of Medicine Zhejiang University, 310006 Hangzhou, Zhejiang, China
†These authors contributed equally.
Abstract
Summarize evidence across six common pregnancy complications—gestational diabetes mellitus (GDM), hypertensive disorders of pregnancy (HDP), thyroid dysfunction, intrahepatic cholestasis of pregnancy (ICP), hyperemesis gravidarum (HG), and preterm birth (PTB)—and clarify short- and long-term consequences for mothers and their children.
Adverse outcomes converge on shared pathways: abnormal placental development and perfusion, inflammatory and oxidative stress signaling, endocrine and metabolic dysregulation, and epigenetic remodeling at imprinted loci. These processes program fetal organ systems (brain, heart, lungs, kidneys) and shape lifelong disease risk.
GDM increases large-for-gestational-age birth, respiratory morbidity, and later metabolic disease. HDP drive fetal growth restriction and enduring cardiovascular and neurocognitive sequelae. Thyroid dysfunction worsens obstetric outcomes and may impair offspring neurocognition. ICP raises risks of PTB and stillbirth. HG is associated with low birth weight and small for gestational age. PTB independently predicts lifelong cardio-respiratory, endocrine, and neurodevelopmental disorders. Management spans glucose control; antihypertensive therapy and magnesium sulfate; levothyroxine or antithyroid drugs; ursodeoxycholic acid; antiemetics and nutritional support; progesterone and antenatal corticosteroids. Emerging precision strategies target angiogenic balance, inflammation, and the microbiome.
Pregnancy complications are sentinel events with intergenerational implications. Stage-appropriate screening, timely intervention, and longitudinal follow-up are essential, while multi-omics research and placental-targeted trials are needed to validate strategies that mitigate offspring risk across the life course.
Keywords
- pregnancy complications
- transgenerational health effects
- neonatal outcomes
- pregnancy management
Pregnancy complications, as a significant issue in the field of obstetrics and gynecology, have always been a subject of widespread concern in the medical community. Pregnancy complications not only affect the health of both mother and infant but also have a profound impact on the development of perinatal medicine. Although most pregnancies are considered normal medically and can be delivered safely without causing serious health problems for the child, globally up to 15%–40% of pregnancies experience a range of pregnancy and childbirth complications [1, 2, 3]. Pregnancy complications such as pre-eclampsia, preterm birth (PTB), recurrent miscarriage, and fetal growth restriction (FGR) affect more than 12% of pregnant women worldwide. These complications not only pose a threat to the health of the pregnant woman but can also have long-term effects on the development of the fetus. For example, pre-eclampsia can lead to placental dysfunction (refers to the placenta’s inability to properly perform its physiological functions during pregnancy, thereby affecting the material exchange between the mother and fetus), which in turn affects the nutritional and oxygen supply to the fetus, increasing the risk of PTB and low birth weight (LBW). Preterm infants, due to immature organ development, are more prone to respiratory distress, infections, and neurological developmental issues. Recurrent miscarriage may involve immune system abnormalities or chromosomal abnormalities, bringing significant psychological and financial burdens to families. FGR can lead to postnatal growth retardation and may even affect health in adulthood [4, 5].
This article specifically addresses 6 common complications encountered during pregnancy: gestational diabetes mellitus (GDM), hypertensive disorders of pregnancy (HDP), thyroid disorders during pregnancy, intrahepatic cholestasis of pregnancy (ICP), hyperemesis gravidarum (HG) and PTB. These conditions can significantly complicate the course of pregnancy. These diseases have complex mechanisms of action, involving multiple physiological and biochemical pathways. The development of pregnancy complications involves multiple fields including genetics, epigenetics, and metabolism, and interacts with lifestyle and environmental factors. They not only pose a threat to the health of the mother but can also have profound long-term effects on the health of the fetus. The intrauterine environment (the biological and physiological conditions within the uterus during pregnancy) has a profound impact on the developing fetus, a phenomenon known as “developmental programming”, which affects multiple systems [6]. Furthermore, the dual effects of intrauterine adverse exposures and environmental factors may increase the susceptibility of individuals to future diseases and elevate the risk of chronic illnesses later in life [7, 8]. Exposure to pregnancy complications can affect the fetus in utero through multiple pathways, including lipid metabolism, organ development, and various aspects of developmental and endocrine diseases, which may further exacerbate the vicious cycle of metabolic disorders [9, 10]. Furthermore, pregnancy complications can also indirectly affect fetal growth and development by altering placental function and maternal metabolic status. Therefore, understanding the mechanisms of these complications is crucial for developing effective prevention and treatment strategies.
Currently, there is insufficient understanding of the short-term and long-term effects of complications during pregnancy, especially those affecting the postpartum period. This article delves into the pathophysiological mechanisms of pregnancy complications, providing a deeper insight into how these diseases affect fetal health. The manuscript offers a detailed analysis of the diagnostic criteria for pregnancy complications, their impact on the fetus during pregnancy, and the long-term effects of these complications. The aim is to emphasize the importance of early diagnosis and intervention, and to provide clinicians with practical guidance to help them more effectively manage these complex health issues during pregnancy, thereby significantly improving the health outcomes for newborns.
GDM is the most common complication during pregnancy and is defined as any degree of glucose intolerance with onset or first recognition during pregnancy. The average prevalence of gestational diabetes worldwide is approximately 14% [11]. The observed variation in prevalence estimates primarily stems from heterogeneity in case-finding methodologies, application of standardized diagnostic parameters (Table 1), and differential risk profiles across study populations [12, 13]. GDM changes the maternal metabolic and uterine environment, thus increasing the risk for short- and long-term adverse outcomes for both mother and child. GDM is correlated with various adverse pregnancy outcomes, such as premature birth, cesarean delivery, and shoulder dystocia. Furthermore, offspring of GDM are more prone to obesity and face a higher likelihood of hormonal imbalances and metabolic complications [14, 15].
| Diagnostic approaches | Glucose concentration, mg/dL | ||||
| Fasting | 1-hour | 2-hour | 3-hour | ||
| One-step | All women complete a 75 g oral glucose tolerance test (OGTT) after | / | |||
| Two-step | GDM is defined as having | / | |||
| International association of diabetes and pregnancy study group (plasma)a | 92 | 180 | 153 | NA | |
| Initial screening involves a non-fasting 50 g glucose challenge test (GCT) | / | ||||
| Women screening positive on the 50 g GCT (1-hour glucose | |||||
| GDM is defined as having | |||||
| O’ Sullivan (whole blood) | 90 | 165 | 145 | 125 | |
| National diabetes data group (plasma) | 105 | 190 | 165 | 145 | |
| Carpenter and coustan (plasma)a | 95 | 180 | 155 | 140 | |
a Currently recommended criteria from the Korean Diabetes Association for the diagnosis of GDM. NA, not applicable.
About 15–45% of babies born to diabetic mothers can have macrosomia, which is a 3-fold higher rate when compared to normoglycemic controls [16]. During pregnancy, fetuses of diabetic mothers often exhibit a specific characteristic of overgrowth. These newborns typically have larger circumferences of the shoulders and limbs, a diminished head-to-shoulder ratio, notably elevated body fat percentage, and augmented thickness of the skin folds on the upper extremities. There is no increase in fetal head size, yet the shoulder and abdominal circumference can undergo significant enlargement, increasing the risk of Erb’s palsy, shoulder dystocia, and brachial plexus trauma. Infants with macrosomia face a sixfold increased risk of trauma during delivery, and the likelihood of brachial plexus injury may be as high as twenty times [17]. The hyperglycemic condition of the mother triggers a series of biological cascading reactions, characterized by the excessive production of insulin in the fetus. This condition leads to enhanced glucose metabolism, which in turn stimulates the accelerated development of fat cells, ultimately causing fetal overgrowth. When the maternal glucose regulatory function is impaired and blood glucose levels rise, this metabolic excess diffuses through the placental barrier. Nevertheless, insulin derived from the mother or administered exogenously does not permeate the placenta. Consequently, when the fetus’s pancreas starts to secrete insulin independently to manage high blood sugar levels, no longer depending on glucose stimulation, this simultaneous presence of hyperinsulinemia and hyperglycemia fosters an increase in fetal fat and protein reserves, ultimately resulting in macrosomia [18]. In this population of newborns, the incidence of jaundice in macrosomia is twice that of infants born to normal mothers. Due to their higher oxygen requirements, macrosomia may increase the risk of fetal hypoxia, leading to a higher likelihood of stillbirth and asphyxia at birth [19]. Additionally, relative intrauterine hypoxia can promote the production of erythropoietin, which in turn causes polycythemia and hyperbilirubinemia [20]. When these red blood cells are broken down, an increased amount of bilirubin is produced, which raises the likelihood of neonatal jaundice [19, 21].
GDM is recognized as a significant disruptor of the intrauterine environment, predisposing offspring to metabolic dysregulation [22]. The Pima Indian cohort study demonstrated significantly elevated rates of metabolic sequelae in GDM-exposed offspring compared with their non-exposed counterparts. Longitudinal analysis of the Pima Indian cohort revealed a 2.3-fold increase in metabolic sequelae among GDM-exposed progeny versus unexposed controls. Complementary case-control data from this population demonstrated birth order effects, with post-diagnosis offspring exhibiting a 68% greater diabetes susceptibility compared to pre-diagnosis siblings, persisting after adjustment for genetic confounders [23, 24]. Pathophysiological mechanisms involve GDM-driven proinflammatory milieu characterized by placental upregulation of tumour necrosis factor-
Neonatal respiratory distress syndrome (NRDS) represents a prevalent complication among neonates born to mothers with GDM. A comprehensive systematic review and meta-analysis provides strong evidence that there is a significant positive correlation between GDM and NRDS. The pathophysiological mechanisms underlying this association are multifaceted, involving complex interactions between maternal hyperglycemia and fetal pulmonary development. Central to this phenomenon is the impairment of pulmonary maturation, where maternally derived hyperglycemia has been implicated in delayed pulmonary maturation through multiple pathways [25]. Fetal hyperglycemia may disrupt normal alveolarization processes by interfering with the synthesis and secretion of pulmonary surfactant—a critical lipoprotein complex responsible for reducing alveolar surface tension, maintaining alveolar patency, and facilitating efficient gas exchange. Surfactant deficiency may precipitate alveolar collapse, culminating in NRDS pathogenesis. Notably, the hyperglycemic intrauterine environment exerts dual detrimental effects on fetal lung development. Hyperglycemia-induced oxidative stress and inflammatory responses in fetal pulmonary tissue have been shown to disrupt cellular differentiation pathways and extracellular matrix remodeling [26]. Concurrently, GDM-associated placental insufficiency may compromise fetal oxygenation and nutrient delivery, creating a synergistic effect that exacerbates pulmonary developmental abnormalities [27]. The cumulative impact of these mechanisms significantly elevates neonatal susceptibility to respiratory failure, particularly in late preterm and early term infants.
Long-term consequences of GDM extend beyond metabolic dysregulation to encompass neurodevelopmental and reproductive health outcomes. Experimental and clinical evidence indicates that intrauterine hyperglycemia induces developmental programming alterations in fetal pancreatic
HDP, a heterogeneous group of pregnancy-specific conditions, primarily containing gestational hypertension, preeclampsia, eclampsia, pregnancy with chronic hypertension, and chronic hypertension with superimposed preeclampsia [31]. Globally, HDP affects approximately 5–10% of pregnancies, though regional disparities exist, with incidence rates ranging from 7.8% in high-income countries to 15.2% in low-resource settings [32]. Clinical diagnosis primarily relies on the presence of vasoconstriction (manifested as hypertension), increased capillary permeability (e.g., proteinuria, peripheral edema, cerebral edema, hepatic congestion, pulmonary edema), and abnormal endothelial/platelet interactions (e.g., thrombocytopenia, disseminated intravascular coagulation) among other signs and symptoms (Table 2).
| Type of HDP | Diagnosis standards |
| Gestational hypertension | Blood pressure (BP) |
| Preeclampsia | BP |
| Eclampsia | With the progression of preeclampsia, tonic-clonic seizures occur |
| Pregnancy with chronic hypertension | History of primary or secondary hypertension; BP |
| Chronic hypertension with superimposed preeclampsia | Chronic hypertension in pregnancy; Negative quantitative proteinuria before 20 weeks of pregnancy; Quantitative proteinuria |
+ positive.
Approximately 30% to 50% of patients with early-onset HDP also experience FGR growth restriction, primarily due to impaired placental development and insufficient uteroplacental blood flow [33]. In placental ischemia, an imbalance between reactive oxygen species, including superoxide anion (O2-) and hydrogen peroxide (H2O2), and antioxidants results in oxidative stress, endothelial dysfunction, and fetal malnutrition [34]. Pregnant women with HDP and FGR exhibit maladaptive cardiovascular changes, including reduced heart rate and cardiac output [35], while hypertension and placental dysfunction contribute to iatrogenic PTB (43.7% of cases), increasing neonatal mortality, morbidity, and long-term neurodevelopmental risks such as cognitive deficits, cerebral palsy (CP), and sensory impairments [36]. DNA methylation analysis of placental samples revealed placenta-specific hypomethylation at H19 imprinted maternally expressed transcript (H19)-differentially methylated region (DMR) and insulin-like growth factor 2 (IGF2)-DMR in FGR and HDP cases (incidence: 1.5%, 3/202 cases), leading to biallelic H19 expression and a significantly elevated H19/IGF2 expression ratio. This suggests that epigenetic dysregulation may contribute to the intergenerational effects of pregnancy-related complications [37]. These findings underscore that HDP-induced FGR not only compromises immediate neonatal outcomes but also predisposes offspring to chronic diseases through placental insufficiency and epigenetic dysregulation.
Additionally, depending on the presence or absence of concurrent maternal hypertensive disorders (such as preeclampsia, gestational hypertension, or chronic hypertension with superimposed preeclampsia), there are significant differences in the pathophysiological mechanisms and clinical management priorities. When early-onset FGR is accompanied by maternal hypertensive disorders, the core pathology is typically placental in origin, stemming from severe placental ischemia due to shallow implantation and inadequate spiral artery remodeling [38]. Systemic maternal vascular endothelial dysfunction and inflammatory responses further exacerbate poor placental perfusion, creating a vicious cycle. This type often progresses rapidly, with early and severe Doppler flow abnormalities (such as elevated uterine artery pulsatility index or absent/reversed end-diastolic flow in the umbilical artery), frequently accompanied by prominent maternal symptoms (e.g., hypertension, proteinuria). It is prone to iatrogenic preterm delivery and carries an extremely high risk of neonatal complications. In contrast, early-onset FGR without hypertensive disorders is also primarily caused by placental insufficiency, but the contributing factors may be more diverse, including but not limited to placental structural abnormalities (e.g., small placenta, infarctions), genetic or chromosomal anomalies, infections, antiphospholipid syndrome, severe maternal malnutrition, or chronic hypoxia. Although the degree of placental dysfunction in such cases may be milder than in those with concurrent hypertension and maternal risks are lower, the harm to the fetus remains significant and can still lead to adverse pregnancy outcomes, necessitating close monitoring and timely intervention [39].
HDP is associated with a spectrum of neurocognitive impairments across developmental stages [40]. Meta-analytic evidence indicates that offspring exposed to HDP, particularly preeclampsia, face significantly elevated risks of neurodevelopmental sequelae. Term infants (
HDP significantly impairs offspring respiratory health through placental dysfunction and systemic vascular dysregulation. HDP induces atherosclerotic changes in uterine spiral arteries, reducing placental perfusion and causing chronic fetal hypoxia, which predisposes NRDS and asphyxia [47]. Concurrently, HDP-triggered maternal inflammation and endothelial dysfunction disrupt trophoblast microvillous exchange, limiting fetal oxygen/nutrient uptake and increasing risks of LBW—a key contributor to respiratory morbidity [48, 49]. Furthermore, HDP-exposed infants exhibit elevated bronchopulmonary dysplasia (BPD) incidence due to combined prenatal and postnatal insults. Prenatally, impaired pulmonary angiogenesis and alveolarization result from FGR, oxidative stress, and inflammatory cascades [50]. Postnatally, prematurity-related interventions (mechanical ventilation, oxygen toxicity) exacerbate lung injury, particularly in early-gestation infants requiring intensive respiratory support [50, 51]. These multifactorial disruptions in lung development underscore the persistent cardiopulmonary sequelae observed in HDP offspring.
HDP, particularly preeclampsia, is closely linked to the remodeling and dysfunction of the cardiovascular system in offspring. Preeclampsia directly impairs fetal cardiac function by increasing afterload and placental vascular resistance (elevated by 1.8-fold), leading to the redistribution of left ventricular output. This condition clinically presents as cardiomegaly, ventricular hypertrophy, and dysfunction in both diastolic and systolic function [52]. Clinical observations highlight early functional abnormalities in preeclampsia-exposed offspring: preterm infants (29–35 weeks gestation) exhibit significantly higher systolic/diastolic blood pressure (BP) within the first 3 postnatal days compared to controls [53], with BP differences persisting from age 7 to 18 [54]. Maternal preeclampsia demonstrates a significant association with congenital heart disease (CHD) in offspring, exhibiting a 30% higher prevalence of severe CHD (35.0 vs. 26.9 per 10,000 births) and a 15-fold elevated risk of atrioventricular septal defects compared to normotensive pregnancies, suggesting potential shared pathogenic pathways [55]. Offspring exposed to early-onset preeclampsia had significantly higher peripheral and central systolic BP. Notably, these children also included preterm and SGA infants, which are also associated with higher BP in childhood [56]. Mechanistically, placental oxidative stress and angiogenic imbalance [soluble fms-like tyrosine kinase-1 (sFlt-1)/placental growth factor (PlGF) ratio] drive fetal cardiovascular maladaptation through hypoxia-inducible factor-1
The placenta plays a central mechanistic role in mediating these adverse developmental programming effects. Pathological changes in HDP/preeclampsia, including chronic uteroplacental insufficiency, reduced perfusion, and oxidative stress, trigger a cascade of placental dysfunction. This involves aberrant inflammation (elevated pro-inflammatory cytokines like TNF-
Numerous studies indicate that children born to mothers with preeclampsia may face risks of fetal kidney underdevelopment and abnormal function. Adverse factors within the intrauterine environment can impair the growth and development of the kidneys, resulting in renal dysfunction and hypertension in adulthood. Khalsa et al. [60] confirmed that adolescents with a history of PTB, particularly those with LBW, more frequently exhibit elevated BP and a reduced estimated glomerular filtration rate. Their study focused on evaluating the kidney function of children with extremely LBW compared to a control group at the ages of 7 and 11 years. The results indicated that children with extremely LBW had significantly smaller kidney volumes and elevated levels of cystatin C, providing evidence of early signs of kidney dysfunction that has manifested during childhood [61]. Alterations in the renin-angiotensin system have been confirmed to play a key role in cardiovascular diseases and in the programming of hypertension in offspring experiencing HDP or fetal programming due to prenatal environmental insults [62].
Thyroid disorders constitute prevalent endocrine disturbances during gestation, with epidemiological studies indicating a 4% prevalence of hypothyroidism and 2.4% incidence of hyperthyroidism in pregnant populations. The diagnosis of gestational thyroid diseases mainly relies on serum thyroid function tests. This includes, but is not limited to, the measurement of indicators such as thyroid-stimulating hormone (TSH), free triiodothyronine (FT3), and free thyroxine (FT4). When TSH levels are abnormal, combined with changes in FT4, the state of thyroid function can be preliminarily determined (Table 3) [63]. Mounting evidence highlights the dual clinical ramifications of maternal thyroid dysregulation: immediate obstetric risks (e.g., preterm delivery, preeclampsia) and enduring developmental sequelae in offspring. Mechanistically, fetal exposure to altered maternal thyroid hormone concentrations during critical periods of organogenesis (weeks 8–20 gestation) disrupts neurogenesis, cortical layering, and hypothalamic-pituitary-thyroid axis programming [51, 64]. Longitudinal cohort studies demonstrate that untreated maternal hypothyroidism correlates with a 7–10-point reduction in offspring IQ scores, while uncontrolled hyperthyroidism increases risks of intrauterine growth restriction by 3.2-fold [65, 66].
| Type of thyroid dysfunction | Definition of thyroid dysfunction | Diagnosis standards |
|---|---|---|
| Hhyperthyroidism | Group of clinical syndromes resulting from insufficient synthesis, secretion, or biological action of thyroid hormones for various reasons. | Thyroid-stimulating hormone (TSH) |
| Subclinical hyperthyroidism | Mild hypothyroidism. Elevated TSH but FT4 in the normal range. | TSH |
| Hypothyroidism | Thyroid gland synthesizes and secretes too much thyroid hormone for various reasons, resulting in a series of hypermetabolic syndromes and sympathetic excitations. | TSH |
| Subclinical hypothyroidism | Reduced serum TSH from various causes with normal FT3 and FT4 levels. | TSH |
Maternal thyroid dysfunction during pregnancy exerts profound effects on perinatal outcomes, with distinct pathophysiological mechanisms and clinical risks depending on the type of thyroid disorder. Regarding PTB and LBW, uncontrolled maternal hyperthyroidism amplifies uterine contraction frequency through
Maternal thyroid disorders during gestation exert profound effects on offspring thyroid homeostasis through distinct mechanisms involving antibody transfer, pharmacologic interference, and hormonal dysregulation. Neonatal thyrotoxicosis predominantly originates from maternal Graves’ disease, where placental transfer of TSH receptor antibodies stimulates fetal thyroid receptors, affecting 1–5% of neonates with manifestations including tachycardia, heart failure, and even craniosynostosis [69]. Furthermore, excessive use of antithyroid drugs during late pregnancy may suppress fetal thyroid function, with subsequent withdrawal leading to rebound thyrotoxicosis due to compensatory hormone hypersecretion. Conversely, neonatal hypothyroidism demonstrates strong associations with maternal thyroid status and therapeutic interventions. Untreated maternal hypothyroidism increases the risk of congenital hypothyroidism in offspring, which is attributed to insufficient placental thyroxine (T4) transport [70]. Notably, transplacental passage of maternal thyroid autoantibodies, particularly thyroid peroxidase antibodies (TPOAb), may induce immune tolerance dysregulation in offspring, predisposing them to lifelong risks of autoimmune thyroid disorders such as Hashimoto’s thyroiditis [71].
Maternal thyroid dysfunction during pregnancy exerts profound and stage-specific impacts on offspring neurodevelopment and cognitive function. During the first trimester, a critical window for fetal brain development, insufficient maternal T4 levels—particularly FT4 deficiency—are associated with a 7–10 point reduction in offspring IQ, with pronounced deficits in language acquisition and executive function [72]. Mechanistically, early gestational T4 inadequacy disrupts neuronal migration and impairs synaptic formation in the hippocampus and cerebral cortex, compromising structural brain maturation [73, 74]. In later pregnancy, maternal hyperthyroidism may perturb fetal neurodevelopment via suppression of cerebral deiodinase type 3, reducing local triiodothyronine (T3) bioavailability and impairing myelination processes critical for neural circuit integrity [75]. Conversely, persistent maternal hypothyroidism during mid-to-late gestation correlates with elevated risks of neurodevelopmental disorders in offspring, including a 1.4-fold increase in attention-deficit/hyperactivity disorder and ASD incidence, likely mediated by chronic cerebral hypothyroidism [76].
ICP, an obstetric-specific condition, is characterized by pruritus (usually localized to the palms and soles without a rash) (Table 4) during the mid-to-late gestational period and elevated serum total bile acid (TBA) levels (
| Diagnostic methods | Grade based on severity |
|---|---|
| Be alert to ICP if there is itching of the skin that cannot be explained by other causes during pregnancy (Highly recommended with strong evidence support). | Mild ICP diagnostic criteria: |
| (1) Fasting serum total bile acid (TBA) level 10–39 µmol/L or postprandial serum TBA level 19–39 µmol/L; | |
| (2) Clinical symptoms are mainly skin itching, without obvious other symptoms. | |
| (strongly recommended, high evidence level) | |
| Fasting TBA | Severe ICP diagnostic criteria: |
| (1) Pregnant women serum TBA level 4–99 µmol/L; | |
| (2) Serum bilirubin level higher than normal; | |
| (3) Accompanied by other conditions, such as multiple pregnancy, preeclampsia, recurrent ICP, has caused perinatal death due to ICP; | |
| (4) Early-onset ICP. | |
| (strongly recommended, evidence level medium) | |
| Serum transaminase can be utilized as a biochemical reference index for the diagnosis of ICP, but it is not an essential criterion for ICP diagnosis (Weak recommendation, low level of evidence). | Extremely severe ICP diagnostic criteria: |
| Pregnant women serum TBA level | |
| (strongly recommended, evidence level medium) | |
| To establish a diagnosis of ICP, abnormalities in laboratory indicators such as skin itching or elevated serum TBA levels caused by other causes must be ruled out. It is recommended to perform routine ultrasound to rule out hepatobiliary diseases in pregnant women (Highly recommended with strong evidence support). | / |
ICP is strongly associated with an elevated risk of PTB, with reported rates ranging from 11.7% to 60%, predominantly occurring between 32 and 36 weeks of gestation. While a substantial proportion of preterm deliveries result from iatrogenic interventions due to deteriorating maternal or fetal conditions, emerging evidence highlights the role of spontaneous preterm labor in ICP pathophysiology. A dose-response meta-analysis further revealed that maternal serum TBA levels
ICP is associated with an elevated risk of stillbirth, with reported rates of 0.1–0.3% beyond 37 weeks of gestation—a 3–5 fold increase compared to the general obstetric population. While the precise pathophysiological mechanisms remain incompletely elucidated, postmortem examinations of affected fetuses demonstrate acute anoxic insults without characteristic features of chronic uteroplacental insufficiency [81]. Histopathological analysis of ICP placentas reveals abrupt vascular changes, suggesting rapid-onset catastrophic events rather than progressive placental dysfunction [82]. Emerging evidence implicates BAs-induced cardiac toxicity as a critical pathway. Clinical observations document fetal arrhythmias in ICP pregnancies [83], corroborated by in vitro experiments demonstrating BAs’ dose-dependent arrhythmogenic effects on neonatal rat cardiomyocytes, including reduced contractility and disrupted electrophysiological stability [84].
The proposed dual-pathway model encompasses two distinct mechanisms: BAs-mediated vasoconstriction of placental chorionic vessels inducing acute anoxia [85], synergistically interacting with direct cardiotoxic effects that trigger lethal ventricular arrhythmias through myocardial potassium channel inhibition [86]. Notably, fetal myocardial dysfunction severity correlates strongly with maternal serum TBA concentrations, with significant myocardial deformation observed exclusively in severe ICP cases (TBA
MSAF complicates 10–44% of ICP cases, representing a 2–3 fold increased risk compared to non-ICP pregnancies [88]. While the pathophysiology remains partially defined, 2 predominant hypotheses emerge: (1) traditional fetal hypoxic stress triggering defecation reflex, and (2) direct BAs-mediated stimulation of fetal colonic motility. Experimental models provide compelling evidence for BAs-specific mechanisms. In ex vivo rabbit colonic strips, cholic acid exposure (50–200 µmol/L) induced dose-dependent increases in smooth muscle contraction amplitude [89]. These findings challenge the conventional hypoxia paradigm and suggest BAs toxicity alone may suffice to induce meconium passage.
A prospective multicenter cohort study (N = 504) of gestational age-matched pregnancies (ICP = 77, controls = 427) demonstrated that ICP confers significant neonatal respiratory morbidity, with adjusted analyses revealing a 2.1-fold increased risk of NRDS and a 0.2% incremental NRDS probability per 1 µmol/L rise in maternal serum BAs after controlling for prematurity and delivery mode [90].
HG, a severe pregnancy complication characterized by intractable nausea, vomiting (
| Type of diagnostic methods | Diagnostic criterion | |
| Fairweather criteria (1968) | More than 3 episodes of vomiting a day | |
| Weight loss | ||
| Ketonemia | ||
| Electrolyte imbalance | ||
| Volume depletion | ||
| Onset usually at 4–8 weeks of pregnancy | ||
| Windsor definition (2021) | Compulsory features | |
| At least one of nausea and vomiting is severe | ||
| Incapability of normal drinking or eating substantially impacts on daily living activities Initiation of symptoms in early pregnancy (Early pregnancy was defined as before a gestational age of 16 weeks) | ||
| Contributory features | ||
| Symptoms of dehydration | ||
The impact of HG on offspring birth outcomes has been substantiated by multiple prospective studies and mechanistic investigations. A recent meta-analysis demonstrated that HG significantly elevates the risk of LBW and SGA incidence, primarily attributed to placental dysfunction caused by chronic maternal nutritional deficiencies and metabolic disturbances [93]. Pathological studies of placental tissue have revealed that under hyperglycemic conditions during pregnancy, common variations in genes encoding placental proteins [namely growth differentiation factor 15 (GDF15) and insulin-like growth factor binding protein 7 (IGFBP7)] and hormone receptors [namely GDNF family receptor alpha like (GFRAL) and progesterone receptor (PGR)] are involved, along with decreased levels of placental angiogenic factors such as PlGF. These changes directly restrict the fetus’s access to nutrients and oxygen [94].
The association between HG and neurodevelopmental/behavioral abnormalities in offspring has emerged as a critical focus of research, with recent evidence uncovering a multifactorial pathogenic network. A Dutch birth cohort study demonstrated that prenatal HG exposure elevates the risk of ASD in offspring by 1.6-fold, exhibiting a dose-dependent relationship with the duration of ketosis during early gestation [95]. Mechanistically, maternal thiamine (vitamin B1) deficiency induced by HG disrupts mitochondrial function in the fetal hippocampus and prefrontal cortex, impairing neuronal synaptic plasticity via suppression of alpha-ketoglutarate dehydrogenase activity and subsequent reduction in acetyl-CoA production [96]. Furthermore, elevated human chorionic gonadotropin (hCG) levels associated with HG may dysregulate fetal cortical T4 homeostasis by hyperactivating maternal thyroid hormone receptor-beta, triggering microglial activation and neuroinflammation [97, 98, 99]. Researchers from the United States and Denmark have noted that children exposed to HG in utero show signs of reduced cortical area and volume in the brain. Additionally, they found an association between abnormal neurodevelopment and a decrease in brain size. Furthermore, fetal head growth in HG patients is positively correlated with maternal weight gain in the second trimester, indicating that malnutrition related to HG in the first half of pregnancy may affect the growth and development of the fetal brain, explaining the increased risk of neurodevelopmental delays in childhood [100, 101].
Additional research has revealed a possible connection between HG experienced by mothers during pregnancy and an increased risk of respiratory diseases in their children during early childhood [102]. The study revealed a dual risk of HG: on one hand, it may cause intrauterine damage, affecting the normal development of the fetus’s lungs; on the other hand, HG may lead to malnutrition in pregnant women, which hinders the normal growth of the fetus and consequently restricts the growth and development of the fetal lungs. This includes reduced lung capacity, fewer branching airways, fewer alveoli, and reduced blood vessel formation [103]. In addition, malnutrition during pregnancy may indirectly affect the development of the fetal lungs due to deficiencies in key micronutrients such as vitamin A, vitamin C, and vitamin D. Hormones involved in metabolic regulation play a crucial role in the development of the lungs during pregnancy, and impaired function of these hormones can also lead to incomplete lung development. Mechanistically, HG-induced maternal micronutrient deficiencies—particularly vitamins A and D—disrupt fetal lung branching morphogenesis and alveolarization.
PTB, clinically defined as delivery occurring between 24+0 and 36+6 weeks of gestation [World Health Organization (WHO) criteria], imposes a significant global health burden with profound interregional disparities. However, defining PTB solely by gestational age fails to reflect the highly heterogeneous pathophysiological mechanisms underlying this condition. Modern clinical practice emphasizes etiology-based classification, which is critical for understanding risks and guiding tailored prevention and treatment strategies (Table 6). Global estimates indicate an incidence of 10.6% of live births, translating to approximately 15 million cases annually, of which over 80% occur in low- and middle-income countries (LMICs) where limited healthcare access exacerbates outcomes [104, 105]. It is a common and serious complication during pregnancy, posing a major threat to the newborn’s quality of survival and long-term health, and is the leading cause of perinatal death.
| Type of phenotype | Pathophysiological mechanisms | Diagnostic markers |
| Infectious/Inflammatory | 1. Microbial invasion (chorioamnionitis, deciduitis or systemic infection) | 1. Maternal C-reactive protein (CRP)/interleukin (IL)-6 ↑ |
| 2. Sterile inflammation (e.g., alarmin-mediated) | 2. Positive amniotic fluid culture | |
| 3. Placental histopathology: chorioamnionitis | ||
| Vascular/Ischemic | 1. Placental insufficiency | 1. Uterine artery Doppler abnormalities |
| 2. Maternal vascular disorders (e.g., preeclampsia) | 2. Increased soluble fms-like tyrosine kinase-1 (sFlt-1)/placental growth factor (PlGF) ratio | |
| 3. Thrombophilia | 3. Placental infarction pathology | |
| 4. Placental abruption | ||
| Endocrine/Stress | 1. Premature activation of hypothalamic-pituitary-adrenal (HPA) axis | 1. Elevated maternal salivary cortisol |
| 2. Maternal physiological/psychological stress | 2. Dynamic cervical shortening (without contractions) | |
| Cervical insufficiency | 1. Structural/functional cervical defects | 1. Transvaginal ultrasound: cervical length |
| 2. History of second-trimester miscarriage | ||
| Iatrogenic/Indicated | 1. Medically indicated delivery for maternal/fetal compromise | 1. Maternal indications: severe preeclampsia/heart failure |
| 2. Fetal indications: Fetal growth restriction (FGR)/abnormal fetal heart rate |
PTB, particularly occurring before 32 weeks of gestation, poses significant risks of lifelong neurological deficits by disrupting normal brain development through multiple pathways. Cohort studies demonstrate stronger correlations between smaller gestational ages and adverse outcomes: Infants born before 28 weeks have a 30%–40% probability of developing severe disabilities (compared to 5%–8% in full-term controls), including CP, intellectual disability, and ASDs [106, 107, 108]. This dramatically increases the risk of neurodevelopmental impairments, with negative effects persisting throughout childhood and into adulthood, forming the characteristic “premature neurodevelopmental phenotypic spectrum”. The core mechanisms underlying these long-term impacts involve forced interruptions during critical brain development phases (mid-to-late gestation) and exposure to adverse uterine conditions (such as inflammation, hypoxia-ischemia, nutritional stress, and abnormal sensory stimulation). These factors lead to white matter damage [particularly periventricular leukomalacia (PVL)], gray matter developmental abnormalities, and impaired construction of complex neural networks [109, 110]. The manifestations are multidimensional functional impairments: In motor domains, CP risk increases dramatically (extremely preterm infants face 20–40 times higher risks than full-term infants), with developmental coordination disorder becoming more prevalent [111]. Cognitive domains exhibit an age-of-birth gradient effect, marked by declining average IQ levels, particularly pronounced executive dysfunction, attention deficits, slowed processing speed, and learning difficulties, significantly increasing special education needs [112]. Behavioral and mental health aspects show that PTB is one of the strongest environmental risk factors for attention deficit/hyperactivity disorder (ADHD) (with 2–5 times increased risk, predominantly in attention deficit variants), substantially elevating ASD prevalence (extremely preterm infants face 4–10 times higher risks than full-term infants), while also raising risks for anxiety, depression, social-emotional difficulties, and behavioral regulation disorders [113]. Sensory function domains demonstrate markedly elevated incidence rates of sensorineural hearing loss, retinopathy of prematurity (ROP), refractive errors, strabismus, cortical visual impairment (CVI), and sensory processing disorder (SPD, characterized by abnormal sensory regulation) [114, 115].
PTB, particularly very preterm (
PTB imposes profound and persistent burdens on respiratory health by disrupting critical developmental processes. Infants born before 37 weeks of gestation exhibit structural lung immaturity, characterized by impaired alveolar septation, deficient pulmonary surfactant synthesis, and dysregulated angiogenesis due to aberrant VEGF signaling. These defects can acutely manifest as respiratory distress syndrome, and more than 60% of newborns born before 28 weeks of gestation are affected by atelectasis due to insufficient surfactant [121]. Iatrogenic interventions—including mechanical ventilation-induced volutrauma and oxygen toxicity—further drive nuclear factor kappa-light-chain-enhancer of activated B cells (NF-
PTB confers enduring endocrine dysfunction through disruption of hypothalamic-pituitary axis maturation and metabolic programming [123]. Epidemiological studies consistently demonstrate that individuals born preterm exhibit an elevated risk of developing endocrine disorders across the life course. Notably, systematic reviews and meta-analyses reveal a 1.5- to 3-fold increased incidence of insulin resistance, type 2 diabetes mellitus (T2DM), and metabolic syndrome in adulthood compared to term-born counterparts [124, 125]. This predisposition is mechanistically linked to developmental programming alterations in hypothalamic-pituitary-adrenal (HPA) axis function and pancreatic
Pregnancy complications—including GDM, HDP, ICP, HG, PTB and thyroid dysfunction—are pivotal determinants of global maternal morbidity (affecting 15–20% of pregnancies) and offspring health trajectories, with intergenerational consequences spanning cardiometabolic, neurodevelopmental, and epigenetic domains [103, 126]. Robust evidence from the developmental origins of health and disease (DOHaD) consortium demonstrates that unmanaged GDM increases offspring obesity risk by 3-fold, while HDP elevates childhood hypertension incidence by 40% (Table 7) [127, 128]. Thus, optimizing antenatal care transcends clinical obligation, emerging as a public health imperative to disrupt cycles of transgenerational disease transmission.
| Type of disease | Management strategies | Pharmacotherapy key | Critical considerations |
| GDM | 1. Lifestyle modification: Medical nutrition therapy + 30 min/day moderate exercise. | 1. Insulin: Aspart/Detemir (dose adjusted to glucose levels). | 1. Avoid hypoglycemia/ketoacidosis. |
| 2. Glycemic control: Insulin (1st-line) or metformin (2nd-line). | 2. Oral agents: Metformin (limited safety data in pregnancy). | 2. Postpartum OGTT at 6–12 weeks. | |
| 3. Fetal surveillance: Growth ultrasound + amniotic fluid assessment. | 3. Long-term type 2 diabetes mellitus (T2DM) risk counseling. | ||
| HDP | 1. BP control: Target | 1. Antihypertensives: Labetalol (1st-line), nifedipine, hydralazine. | 1. Monitor for hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome [platelets |
| 2. Eclampsia prophylaxis: Magnesium sulfate (for severe hypertension). | 2. MgSO4: 4–6 g IV loading dose, then 1–2 g/h (monitor reflexes/urine output). | 2. Postpartum BP monitoring for 6 weeks. | |
| 3. Delivery timing: Based on gestational age and severity. | |||
| Thyroid disease in pregnancy | 1. Hypothyroidism: Levothyroxine (LT4) adjusted to trimester-specific TSH targets [Trimester 1 (T1): | 1. Hypothyroidism: LT4 dose ↑ by 25–30% at conception. | 1. Monitor for fetal thyroid dysfunction (hyperthyroidism overtreatment). |
| 2. Hyperthyroidism: Propylthiouracil (PTU) (1st-line in T1) or methimazole (T2 onward), aiming for FT4 at upper-normal range. | 2. Hyperthyroidism: PTU (50–150 mg/day) or methimazole (5–15 mg/day); avoid overtreatment. | 2. Postpartum thyroiditis screening [if particularly thyroid peroxidase antibodies (TPOAb)+]. | |
| ICP | 1. Symptom relief: Ursodeoxycholic acid (UDCA, 10–15 mg/kg/day). | 1. UDCA: First-line. | 1. BAs |
| 2. Fetal surveillance: Daily fetal movement + cardiotocography (CTG). | 2. S-Adenosyl methionine (SAMe): Adjunctive therapy. | 2. Avoid estrogen-containing medications. | |
| 3. Delivery: Recommended at 34–36 weeks if bile acids (BAs) | 3. Vitamin K: Prophylaxis if coagulopathy. | ||
| HG | 1. Rehydration: IV fluids with thiamine + electrolyte correction. | 1. First-line: Pyridoxine + doxylamine. | 1. Exclude thyroid dysfunction/gastrointestinal (GI) disorders. |
| 2. Antiemetics: Pyridoxine (10–25 mg q8h) + doxylamine (12.5 mg q8h); ondansetron (refractory cases). | 2. Second-line: Ondansetron. | 2. Psychological support (high anxiety/depression risk). | |
| 3. Nutrition: Enteral/parenteral support if severe. | 3. Refractory cases: Methylprednisolone (short-term). | ||
| PTB | 1. Prevention: Vaginal progesterone if corpus luteum (CL) | 1. Tocolytics: Nifedipine (1st-line); indomethacin ( | 1. Avoid |
| 2. Promote fetal lung maturation: Antenatal corticosteroids (ACS) | 2. ACS: Betamethasone 12 mg intramuscular (IM) × 2. | 2. Complete ACS | |
| 3. Neuroprotection and infection prophylaxis | 3. Neuroprot: MgSO4 ( | 3. Delayed cord clamping |
GDM is strongly associated with maternal metabolic dysfunction, including obesity [body mass index (BMI)
HDP arise from a combination of maternal vascular susceptibility (pre-existing hypertension, diabetes, or autoimmune diseases), placental dysfunction (defective spiral artery remodeling, elevated anti-angiogenic factors like sFlt-1) [131], and genetic predisposition [angiotensinogen (AGT), Fms-related tyrosine kinase 1 (FLT1) polymorphisms] [132]. Demographic factors, multifetal gestation, and lifestyle factors (high-sodium diet, vitamin D deficiency) further amplify risks. A history of prior HDP or placental insufficiency (e.g., FGR) significantly increases recurrence likelihood.
Gestational Thyroid Dysfunction (hypothyroidism or hyperthyroidism) is influenced by autoimmune disorders (e.g., Hashimoto’s thyroiditis, Graves’ disease), iodine imbalance (deficiency or excess), and genetic susceptibility [TSH receptor (TSHR), thyroglobulin (TG) gene variants] [69]. Advanced maternal age, obesity, and prior thyroid disease are significant risks.
ICP is linked to hormonal dysregulation (elevated estrogen/progesterone), genetic mutations [ABCB4, ATP-binding cassette subfamily B member 11 (ABCB11) bile transporter genes], and environmental triggers (low selenium levels) [133]. Multiparity, advanced maternal age, and geographic factors are notable risks. A history of ICP in prior pregnancies or gallbladder disease also elevates susceptibility.
HG is driven by hormonal hyperstimulation, particularly elevated hCG and TSH, often exacerbated by thyroid dysfunction. Genetic variants (GDF15, IGFBP7) affecting nausea pathways, young maternal age, primigravidity, obesity, and psychosocial stress are key contributors [94]. A history of motion sickness or prior HG further predisposes to severe symptoms.
PTB is strongly associated with maternal biological vulnerability, including cervical insufficiency (e.g., short cervical length
Recent advances in GDM management focus on precision therapeutics and technological integration to optimize maternal-fetal outcomes. Emerging microbiome-targeted interventions, exemplified by Lactobacillus and Bifidobacterium probiotic supplementation combined with dietary modulation, demonstrate enhanced insulin sensitivity [138, 139]. Pharmacological innovation includes ultra-long-acting insulin analogs such as degludec, which, when paired with rapid-acting aspart, reduce hypoglycemia risk through stabilized glycemic profiles and minimized peak-trough fluctuations [140]. Additionally, anti-inflammatory strategies targeting IL-6 signaling and omega-3 fatty acid supplementation show promise in trials, addressing subclinical inflammation implicated in placental insulin resistance [141, 142]. These multimodal approaches underscore a paradigm shift toward individualized, pathophysiology-driven therapies, though long-term efficacy and safety warrant further validation in diverse cohorts.
In the pharmacological management of HDP, labetalol and nifedipine sustained-release tablets remain the first-line antihypertensive agents. However, methyldopa is newly recommended as a safer alternative for pregnant women with coexisting FGR. For patients with moderate-to-severe preeclampsia, magnesium sulfate must be administered during the antenatal period and within 24 hours postpartum to prevent eclamptic seizures, regardless of the presence of neurological symptoms. Concurrently, the guidelines have clarified adjustments to contraindicated medications: angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor blockers (ARBs) are strictly prohibited (due to their teratogenic risk), and diuretics are restricted to cases complicated by pulmonary edema or heart failure. However, the current management model for HDP is gradually shifting from traditional therapies to novel treatment approaches targeting placental dysfunction and inflammatory pathways. Leading advancements include anti-angiogenic therapies and sFlt-1 apheresis (e.g., Apharesis), which reduces circulating sFlt-1 and prolongs gestation by 7–10 days in trials [143]. Immunomodulatory strategies show promise: complement inhibitors (e.g., eculizumab) mitigate refractory cases associated with complement overactivation [144], and pravastatin reduces the risk of early-onset preeclampsia by upregulating PlGF and suppressing sFlt-1 [145]. While these innovations highlight a shift toward precision medicine, rigorous evaluation of fetal safety and long-term efficacy remains essential. Future directions emphasize multi-omics integration and placental-targeted drug delivery to optimize outcomes.
The management of thyroid dysfunction during pregnancy has advanced beyond conventional approaches, such as levothyroxine (LT4) for hypothyroidism and propylthiouracil (PTU) for hyperthyroidism. Recent innovative studies have focused on optimizing hormone delivery systems, modulating autoantibody activity, and developing personalized nutritional regimens. Evidence confirms that thyroid hormone analogs, including nanoformulated LT4 [(e.g., Tirosint-solution (SOL)], enhance bioavailability while reducing interpatient dosage variability compared to conventional formulations [146]. TSH receptor monoclonal antibodies (such as K1-70) are currently in Phase I clinical trials and may potentially block maternal TSH receptor autoantibodies to protect thyroid function in fetuses with Graves’ disease [147].
Current management of ICP primarily involves ursodeoxycholic acid (UDCA) to reduce BAs toxicity, often combined with cholestyramine for pruritus relief. Recent advances aim to address BAs dysregulation and genetic underpinnings: novel BAs modulators, such as the Farnesoid X receptor (FXR) agonist obeticholic acid, can inhibit BAs synthesis. Research findings indicate that oral BAs preparations can improve fetal BAs metabolism [148]. Gut microbiota-targeted therapies, including fecal microbiota transplantation, reshape BAs-metabolizing bacteria (e.g., Bacteroides), lowering serum BAs in preclinical models [149].
Current management of HG relies on conventional approaches, including antiemetics (e.g., ondansetron), corticosteroids, intravenous hydration, and nutritional support. Recent advances have introduced targeted therapies addressing underlying molecular and neuroendocrine mechanisms. Neurokinin-1 receptor antagonists such as aprepitant suppress central vomiting reflexes, showing efficacy in refractory HG cases. Additionally, gut microbiota modulation via probiotic formulations may attenuate vomiting frequency through gut-brain axis regulation, though requiring validation in large-scale trials [150].
Recent advances in PTB prevention and management emphasize targeted molecular interventions and precision risk stratification to mitigate neonatal morbidity. In monitoring technology, the innovative application of electrophysiological sensing platforms tracks real-time electrophysiological activities and intracellular calcium transients, enabling dynamic monitoring of uterine cellular behavior during inflammation-associated PTB [151]. This facilitates investigation into mechanisms of inflammation-driven PTB and further development of targeted therapies. Emerging anti-inflammatory strategies—such as the use of a small peptide, HSJ633, which antagonizes the IL-6 receptor to block IL-6 signaling—inhibit the inflammation cascade associated with PTB and mitigate adverse neonatal outcomes [152]. Novel microbiome-based interventions include vaginal microbiota transplantation from Lactobacillus-dominant donors, reducing PTB recurrence in bacterial vaginosis [153, 154]. Despite these advances, clinical translation confronts persistent barriers: real-time electrophysiological monitoring techniques are prohibitively costly for routine screening, and novel anti-inflammatory agents lack robust human safety data.
Gestational metabolic and endocrine disorders, including GDM, HDP, ICP, HG, and thyroid dysfunction, exhibit intricate pathophysiological crosstalk mediated by shared mechanisms such as inflammatory activation, oxidative stress, placental dysfunction, and hormonal dysregulation. Insulin resistance in GDM activates NF-
Placental dysfunction serves as a central hub for crosstalk. HIF-1
Hormonal interplay further links these disorders: HG-associated hyperemesis elevates hCG, which cross-reacts with TSH receptors to induce transient gestational thyrotoxicosis, while malnutrition from severe vomiting disrupts thyroid hormone synthesis [163]. GDM-driven hyperinsulinemia suppresses thyroid peroxidase activity via phosphoinositide 3-kinase (PI3K)/v-akt murine thymoma viral oncogene homolog (Akt) signaling, increasing subclinical hypothyroidism risk [164]. Adipokine imbalances (e.g., elevated leptin/adiponectin ratios) in GDM and HDP perturb TSH secretion through hypothalamic-pituitary-thyroid axis dysregulation [165].
In conclusion, our review discussed that pregnancy complications function not only indicate perinatal risks but may also exert transgenerational impacts on offspring lifespan health through mechanisms including epigenetic regulation, placental dysfunction, and maternal-fetal metabolic interactions. However, these mechanisms remain incompletely elucidated, such as the interactive mechanisms underlying comorbid pregnancy complications. Meanwhile, tracking of offspring long-term outcomes predominantly terminates at adolescence, lacking life-course multi-omics longitudinal data. Future research is expected to provide further insights into both the independent pathogenesis of pregnancy complications and their cross-talking interaction mechanisms. This mechanistic clarity will catalyze the development of precision screening modalities and targeted therapeutic strategies. However, while current clinical guidelines provide frameworks for complication management, interventions capable of reducing or blocking offspring impacts remain unvalidated—to improve the long-term health effects on offspring of pregnancy complications globally, these areas still require in-depth research.
In the future, by focusing on genetic and epigenetic regulatory networks, we will systematically investigate the genetic susceptibility genes and the critical roles of epigenetic modifications (e.g., DNA methylation and non-coding RNAs) in pregnancy complications, aiming to elucidate their biological basis in mediating transgenerational health effects on maternal and offspring outcomes. Building on this foundation, we will delve into metabolic interaction mechanisms, employing multidimensional approaches to unravel the molecular linkages between gestational metabolic dysregulation (such as bile acid imbalance and insulin resistance) and these complications, with a particular emphasis on the dynamic metabolic crosstalk at the placental-maternal-fetal interface, thereby establishing a robust theoretical foundation for targeted interventions. Furthermore, through the integration of multi-omics technologies (metabolomics, proteomics, and microbiome analysis), we will identify early-stage specific biomarkers reflecting pathological progression, develop high-sensitivity and high-specificity screening models for pregnancy complications, and drive the transformation of clinical diagnostic paradigms from a “symptom-driven” to a “prevention-oriented” framework.
GDM, gestational diabetes mellitus; HDP, hypertensive disorders of pregnancy; ICP, intrahepatic cholestasis of pregnancy; HG, hyperemesis gravidarum; PTB, preterm birth; FGR, fetal growth restriction; LBW, low birth weight; OGTT, oral glucose tolerance test; GCT, glucose challenge test; TNF-
JL, SC and YY drafted and revised the manuscript. JL, SC and YY made substantial contributions to data acquisition and analysis and critically reviewed the important intellectual content. The table was conducted by JL. YY contributed to preparing draft and editorial revisions. All authors read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.
Not applicable.
Not applicable.
This study was supported by the Huadong Medicine Joint Funds of the Zhejiang Provincial Natural Science Foundation of China under Grant No. LHDMZ23H190002.
The authors declare no conflict of interest.
References
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