Preamble

Review and Monograph
Progress in Isolated Maternal Hypothyroxinemia during Pregnancy
WANG Yuhan, GAO Shuhong*, DENG Wenxu, TANG Yingying

Department of Gynecology and Obstetrics, Binzhou Medical University Hospital, Binzhou 256603, China

Corresponding author: GAO Shuhong, Associate chief physician; E-mail: gaoshuhongczr@126.com

[Abstract] Isolated maternal hypothyroxinemia (IMH) is a manifestation of thyroid hormone deficiency during pregnancy that may affect fetal neurodevelopment and increase the risk of miscarriage, preterm birth, and gestational diabetes. However, uncertainties remain regarding its specific mechanisms, optimal treatment protocols, and long-term effects. This article summarizes the differences in thyroid hormone levels between pregnant and non-pregnant states and provides a comprehensive analysis of the disease's etiology, impact on maternal and infant health, and treatment strategies through a review of relevant literature.

This review identifies iodine deficiency and iron deficiency as the primary causes of IMH during pregnancy, though conclusive evidence linking factors such as placental growth factor to the disease remains lacking. Currently, only the negative impact on perinatal motor and neurodevelopment is well-established; the association with adverse pregnancy events has not been definitively confirmed, and the underlying pathological mechanisms are incompletely understood. Regarding treatment, the efficacy and optimal timing of thyroid hormone replacement therapy remain controversial and require further investigation.

This review examines the current state of research on IMH, aiming to raise clinical awareness, promote early identification and intervention, and reduce adverse pregnancy outcomes.

[Key words] Isolated maternal hypothyroxinemia; Pregnancy complications; Iodine deficiency; Fetal neurodevelopment; Thyroxine

Funding: Shandong Provincial Natural Science Foundation (ZR2021MH247); Shandong Provincial Medical and Health Science and Technology Development Plan Project (2017WS363)

Citation: WANG Y H, GAO S H, DENG W X, et al. Progress in isolated maternal hypothyroxinemia during pregnancy[J]. Chinese General Practice, 2025. DOI: 10.12114/j.issn.1007-9572.2024.0710. [Epub ahead of print] [www.chinagp.net]

1. Introduction

Thyroid hormone deficiency during pregnancy primarily leads to conditions such as gestational hypothyroidism, subclinical hypothyroidism, and isolated maternal hypothyroxinemia (IMH). IMH is defined as pregnant women who are negative for thyroid autoantibodies, have normal serum thyroid-stimulating hormone (TSH) levels, but exhibit free thyroxine levels below the lower limit of the pregnancy-specific reference range [1]. The prevalence of IMH is 1–2% in iodine-sufficient populations [2]. Studies have shown that IMH may contribute to adverse pregnancy events including gestational diabetes, gestational hypertension, preterm birth, and placental abruption [3]. Particularly during early pregnancy, fetal brain development is highly dependent on thyroid hormones [4], making IMH a potential risk factor for fetal neurodevelopmental disorders [5].

Despite these potential adverse outcomes, treatment strategies for IMH remain controversial. Some researchers advocate for thyroid hormone replacement therapy, suggesting it effectively improves pregnancy outcomes [6], while others argue that evidence for levothyroxine therapy in reducing adverse pregnancy outcomes and preventing intellectual impairment in offspring is insufficient, with risks of overtreatment, making such intervention unnecessary [7]. This controversy presents challenges for clinical management.

The adverse effects of IMH on maternal and neonatal outcomes and the selection of appropriate treatment protocols remain hot topics in clinical practice and academic research. However, existing studies often rely on small-scale data with significant regional and racial differences, lacking large-scale prospective studies with broad representation. Therefore, this review aims to summarize current research findings, explore the etiology, treatment strategies, and health impacts of IMH on mothers and infants, and propose future research directions, particularly focusing on early screening, optimal treatment timing, and long-term effects of thyroid hormone replacement therapy.

2. Literature Search Strategy

We conducted computerized searches of PubMed, the Chinese Medical Journal Network, and CNKI (China National Knowledge Infrastructure) databases from inception to November 2024. Search terms included "isolated maternal hypothyroxinemia during pregnancy," "gestational low T4 syndrome," "etiology," "adverse pregnancy outcomes," "treatment," "Isolated maternal hypothyroxinemia," "Hypothyroxinemia," "etiology," "adverse pregnancy outcomes," and "treatment."

Inclusion criteria: Literature addressing research progress on IMH during pregnancy, including etiology, impact on other diseases, and treatment. Exclusion criteria: Articles unrelated to the topic, poor-quality studies, unavailable full text, and unpublished literature. A total of 48 articles were ultimately included.

2.1 Increased Production and Decreased Clearance of Thyroid-Binding Globulin (TBG) Leading to Reduced Thyroid Hormone Levels

Under the influence of estrogen, TBG production begins to increase and its clearance decreases at 6–8 weeks of gestation, reaching a plateau in the second trimester at 1.5–2.5 times higher than non-pregnant levels, where it remains essentially unchanged until term [1]. As the primary thyroid hormone transport protein during pregnancy, increased TBG binds more free thyroid hormone. Additionally, the affinity of thyroxine (T4) and triiodothyronine (T3) for TBG increases by 50% in early pregnancy, reducing levels of the biologically active free thyroxine (FT4) and free triiodothyronine (FT3). This reduction in FT4 and FT3 subsequently triggers increased TSH secretion through negative feedback regulation.

2.2 Elevated Human Chorionic Gonadotropin (hCG) Levels Stimulating Thyroid Hormone Secretion

Earlier beliefs held that the placenta produced large amounts of chorionic products with thyroid-stimulating activity that promoted thyroid hormone secretion. More recent research indicates that hCG is the most likely thyroid stimulator. hCG shares structural similarity with the α-subunit of TSH and can bind to TSH receptors on thyroid follicular cells, exerting its stimulatory effect by activating intracellular messengers such as cAMP [8]. Increased hCG during pregnancy stimulates the thyroid to secrete more thyroid hormone, leading to elevated FT3 and FT4 levels, which in turn reduce TSH secretion. Studies have demonstrated a significant correlation between decreased TSH and increased hCG [9].

2.3 Fetal Dependence on Maternal Thyroid Hormones

The fetal thyroid originates from the endoderm, formed by fusion of the median primordium from the pharyngeal floor and paired lateral primordia from the fourth pharyngeal pouch. These structures begin migrating through the thyroglossal duct around gestational days 20–22, eventually reaching the anterior neck by approximately day 50. Before 16 weeks of gestation, the fetal thyroid is not fully developed and cannot produce thyroid hormones independently. The fetus relies entirely on maternal thyroid hormones, receiving T4 and small amounts of T3 across the placenta to support growth and brain development [10]. Thyroid hormones in early pregnancy are crucial not only for fetal growth and development, particularly nervous system development, but also play important regulatory roles in embryo implantation and placental development [11]. Therefore, thyroid hormone deficiency in early pregnancy may adversely affect both fetal development and maternal health. After 20 weeks, fetal dependence on maternal thyroid hormones gradually decreases, though studies indicate that term infants still derive approximately 30% of their thyroid hormones from the mother [12].

3.1 Iodine Deficiency and Excess as Potential Causes of IMH

Iodine is an essential component for thyroid hormone synthesis, and iodine deficiency is considered a significant factor in IMH development. In 2007, WHO recommended an iodine intake of 250 μg/L for pregnant women, establishing standards for iodine nutrition during pregnancy and lactation: iodine deficiency (urinary iodine concentration [UIC] <150 μg/L), adequate iodine (UIC 150–249 μg/L), more than adequate iodine (UIC 250–499 μg/L), and iodine excess (UIC ≥500 μg/L). During pregnancy, increased glomerular filtration rate enhances renal iodine clearance, while the increased fetal-maternal iodine gradient further exacerbates maternal iodine requirements [12]. When various factors lead to insufficient iodine to meet these demands, the thyroid cannot effectively synthesize adequate hormones, potentially resulting in IMH. Researchers in Saudi Arabia and Iran have experimentally confirmed this relationship [13–14]. Therefore, clinical practice should monitor iodine status and provide timely supplementation to reduce IMH incidence.

While IMH was previously attributed solely to iodine deficiency, studies have shown that iodine excess can also cause IMH. SHI et al. [15] conducted a cross-sectional study in an iodine-sufficient region, finding that pregnant women with excessive iodine intake had a 2.85-fold increased prevalence of IMH, suggesting that iodine excess is also closely associated with IMH development. This phenomenon may be explained by the Wolff-Chaikoff effect, where high iodine states reduce thyroid hormone formation and release, potentially occurring in pregnant women with underlying thyroid disease. Therefore, iodine supplementation during pregnancy should remain within reasonable limits, as both deficiency and excess can lead to IMH and affect maternal health and fetal development.

3.2 Iron Deficiency as a Potential Cause of IMH

In clinical practice, ferritin levels serve as an important indicator of iron status in pregnant women. POP et al. [16] conducted a cross-sectional study of women at 12 weeks gestation, finding significant differences in ferritin levels between IMH and euthyroid groups. The incidence of low ferritin was 12.3% in the IMH group, significantly higher than the 4.8% in the control group, concluding that iron deficiency is an independent risk factor for IMH. The most likely mechanism by which iron deficiency affects thyroid hormones is through thyroid peroxidase (TPO), a heme-dependent enzyme whose active center contains iron and iodinates tyrosine residues in thyroglobulin to produce thyroid hormones. Therefore, iron deficiency reduces TPO activity, ultimately impairing thyroid hormone synthesis [17]. Previous animal studies have also shown that iron deficiency can interfere with thyroid deiodinase activity by reducing T4-to-T3 conversion and disrupt thyroid metabolism regulation at the central level [18]. Due to increased red blood cell mass and fetal and placental growth during pregnancy, iron requirements increase substantially, making iron deficiency anemia common and consequently leading to IMH.

3.3 Abnormal Secretion of Soluble FMS-like Tyrosine Kinase-1 and Placental Growth Factor as Potential Causes of IMH

During pregnancy, the placenta produces placental growth factor (PIGF) and soluble FMS-like tyrosine kinase 1 (sFlt-1). PIGF is a pro-angiogenic factor sharing 53% molecular homology with vascular endothelial growth factor (VEGF), while sFlt-1 is an anti-angiogenic factor that antagonizes both PIGF and VEGF. Previous animal experiments showed that after three weeks of exposure to exogenous VEGF receptor inhibitors, capillary density in multiple organs of mice decreased to varying degrees, with the most pronounced reduction (68%) observed in thyroid tissue. Thyroid capillary tissue regenerated normally two weeks after exposure cessation [19], demonstrating that thyroid capillary density can be regulated by vascular regulatory factors. Since the thyroid is a highly vascularized organ, these angiogenic factors may also affect thyroid function and cause IMH.

To further investigate the effects of PIGF and sFlt-1 on thyroid function in pregnant women, KOREVAAR et al. [20] conducted a prospective cohort study of women in early pregnancy, measuring sFlt-1, PIGF, TSH, and FT4 levels and analyzing their correlation with IMH. The study found that sFlt-1 levels were negatively correlated with FT4 but showed no significant correlation with TSH, while PIGF levels were negatively correlated with both TSH and FT4. The authors concluded that elevated sFlt-1 and PIGF are associated with IMH. Based on related animal experiments, sFlt-1 is hypothesized to primarily antagonize VEGF, inhibit thyroid angiogenesis, and directly cause decreased FT4 levels, negatively affecting thyroid function without significantly impacting TSH levels except through negative feedback regulation at very high concentrations. Although PIGF is traditionally considered a pro-angiogenic factor, its elevation in this study led to decreased FT4 and TSH levels. This phenomenon may be related to impaired hCG-mediated thyroid stimulation during pregnancy. Under normal conditions, hCG promotes FT4 synthesis, but PIGF overexpression may affect thyroid vascular perfusion and microenvironment homeostasis, reducing thyroid sensitivity to hCG and ultimately decreasing FT4 levels. Another possibility is that excessive PIGF expression during pregnancy weakens VEGF signaling, producing anti-angiogenic effects that reduce FT4 levels and negatively affect thyroid function. Since the pituitary is also a highly vascularized organ affected by changes in angiogenic factors, TSH levels may also decrease, as demonstrated in animal studies [21]. However, current research on the effects of sFlt-1 and PIGF on maternal thyroid function is limited, and the specific pathophysiological mechanisms remain unclear, necessitating further investigation.

3.4 Other Factors

Beyond the aforementioned influences, other factors may contribute to IMH. Some studies suggest IMH is associated with maternal characteristics, with results showing that age ≥35 years, non-local residence, multiparity, and pre-pregnancy overweight or obesity are all correlated with IMH. Therefore, clinical practice should pay special attention to maternal age, place of origin, parity, and pre-pregnancy BMI, carefully monitoring these women for IMH. Air pollution may also disrupt maternal thyroid function and cause IMH. Research has shown that for every 10 μg/m³ increase in NO₂ exposure during early pregnancy and PM2.5 exposure during mid-pregnancy, FT4 levels decreased by 0.61% and 0.73%, respectively [22]. Previous animal and human epidemiological studies have demonstrated associations between maternal air pollution exposure during pregnancy and neurodevelopmental deficits in children, possibly related to IMH development. Additionally, vitamin D deficiency, insulin resistance, and dyslipidemia have been implicated in IMH among women of childbearing age [23]. Since treatment measures for IMH remain undefined, clinicians should address these risk factors by supplementing vitamin D promptly, controlling diet, preventing gestational diabetes and dyslipidemia, and managing body weight to prevent IMH at its source.

4.1.1 IMH Affects Fetal Brain Development and May Impact Offspring Cognitive Function

Thyroid hormones play a critical role in fetal brain development. Before the fetal thyroid matures, the fetus depends entirely on maternal thyroid hormones. Maternal T4 and small amounts of T3 are transferred across the placenta to support fetal growth and brain development [10]. Thyroid hormones in early pregnancy are essential not only for fetal growth and development, particularly nervous system development, but also for embryo implantation and placental development [11]. Therefore, maternal thyroid hormone deficiency in early pregnancy may adversely affect both fetal development and maternal health. After 20 weeks, fetal dependence on maternal thyroid hormones gradually decreases, though term infants still derive approximately 30% of their thyroid hormones from the mother [12].

Thyroid hormones are crucial for fetal brain development. Before the fetal thyroid is fully functional, the fetus relies completely on maternal thyroid hormones. Inadequate maternal thyroxine levels may suppress fetal brain development, affecting intelligence, motor skills, social abilities, and language development. Studies have linked IMH to neurodevelopmental problems in offspring, including intellectual disability, delayed speech and language development, and motor coordination disorders [24–25], as well as increased risks of autism spectrum disorder and attention deficit hyperactivity disorder [26]. Animal studies have yielded similar conclusions, with offspring of IMH rats showing significantly increased risks of anxiety, impaired social ability, and repetitive stereotyped behaviors after 40 days [27]. Furthermore, the impact of IMH on offspring diminishes with increasing gestational age, with research indicating that the effect on fetal brain development depends on the timing of FT4 deficiency [24].

Current understanding of IMH's impact on fetal brain development relies primarily on animal studies. IMH impairs fetal brain development and affects brain morphology [25], potentially through three mechanisms. First, thyroid hormones regulate specific gene expression. Animal experiments have shown that thyroid hormones control expression of key genes in rodent brains, likely through T3 and T4 conversion and action in the brain. After T4 enters the brain via transporters and is converted to T3, T3 acts through nuclear receptors to control genes involved in myelination, cell differentiation, and signal transduction. Reduced FT4 may affect this gene expression cascade, leading to fetal brain developmental disorders. Second, thyroid hormones regulate embryonic neuronal cell migration, proliferation, and differentiation, which ultimately contribute to cortical formation. Reduced FT4 leads to decreased cortical thickness and impaired cortical maturation. Third, IMH causes delayed neuronal growth by interfering with related protein expression. Animal studies support epidemiological findings and suggest that the severity of FT4 deficiency is critical for determining the type and severity of neurological deficits. When IMH occurs in early pregnancy, offspring exhibit problems with visual attention, visual processing, and gross motor skills; if IMH occurs later in pregnancy, offspring may show slowed reaction times and fine motor deficits [24].

4.1.2 IMH Affects Perinatal Body Weight

The effect of IMH on fetal birth weight remains controversial. WEI et al. [28] included 19,770 pregnant women in a retrospective study comparing pregnancy outcomes between IMH patients and euthyroid controls, finding that the incidence of macrosomia was significantly higher in the IMH group, particularly among women with pre-pregnancy obesity, suggesting that early IMH may provide warning information for macrosomia risk. DU et al. [29] reached similar conclusions in a prospective study.

A Japanese study including 4,164 pregnant women found that IMH increased the risk of small-for-gestational-age infants but showed no significant association with large-for-gestational-age or low birth weight infants [30]. In contrast, LI et al. [31] conducted a study of 7,051 pregnant women in southern China showing that IMH was only associated with increased risk of large-for-gestational-age infants. A meta-analysis revealed that IMH was associated with both macrosomia and small-for-gestational-age infants but not with large-for-gestational-age infants. Currently, multiple studies suggest associations between IMH and fetal weight and birth weight, but findings are inconsistent, and no studies have definitively established the precise mechanisms by which IMH affects perinatal weight.

4.2.1 IMH May Increase Preterm Birth Risk

YANG et al. [32] investigated the relationship between IMH and preterm birth and its subtypes in a large prospective study of 41,911 pregnant women, concluding that IMH significantly increased preterm birth risk compared to euthyroid women. The association was primarily with spontaneous preterm birth with intact membranes, not with preterm premature rupture of membranes or medically indicated preterm birth. The study also found that IMH's effect on preterm birth was related to fetal sex, with more pronounced effects observed in women carrying female fetuses.

The increased preterm birth risk in IMH patients is hypothesized to relate to elevated vasopressin levels and increased oxidative stress. The sex-related correlation may be due to sex-specific intrauterine metabolic changes in IMH patients, as the intrauterine environment plays a critical role in spontaneous preterm birth. A previous meta-analysis examining the relationship between thyroid dysfunction and preterm birth reached similar conclusions, finding that IMH was significantly associated with increased risks of preterm and very preterm birth [33]. Numerous studies have suggested an association between IMH and preterm birth [34], but further research is needed to elucidate the underlying pathophysiological mechanisms and optimize clinical strategies to reduce adverse pregnancy events.

4.2.2 IMH May Increase Gestational Diabetes Risk

The relationship between IMH and gestational diabetes remains unclear. XIE et al. [35] conducted a prospective analysis of 1,903 pregnant women, comparing gestational diabetes incidence, thyroid function, and mid-pregnancy glucose metabolism indicators between IMH and euthyroid groups, concluding that FT4 levels had no significant effect on gestational diabetes incidence but influenced some mid-pregnancy glucose metabolism parameters. In contrast, GONG [36] identified IMH as a risk factor for gestational diabetes. Due to inconsistent findings across studies, CAROL et al. [37] conducted a comprehensive meta-analysis summarizing heterogeneity in previous research, ultimately concluding that IMH is significantly associated with gestational diabetes development. Unfortunately, this analysis only examined the correlation without exploring why IMH increases gestational diabetes risk. Some studies suggest FT4 levels may affect insulin requirements [38], but direct evidence for a causal relationship between IMH and gestational diabetes is lacking, necessitating mechanistic studies to clarify the biological link.

4.2.3 IMH May Increase Hypertensive Disorders of Pregnancy

WANG et al. [39] included 52,027 pregnant women to investigate the relationship between IMH and preeclampsia, finding that IMH significantly increased preeclampsia risk compared to euthyroid women. Although multiple observational studies have evaluated the association between IMH and gestational hypertension, varying examination methods and IMH definitions have yielded inconsistent results. TOLOZA et al. [40] addressed this through a meta-analysis of 1,530 published studies, ultimately including 19 cohorts comprising 46,528 pregnant women, concluding that only subclinical hypothyroidism was associated with preeclampsia risk, while IMH showed no significant correlation with gestational hypertension or preeclampsia.

4.2.4 IMH May Increase Other Adverse Pregnancy Events

Comparing pregnancy outcomes between IMH patients and euthyroid controls, researchers have found that IMH also increases the incidence of placenta previa, placental abruption, premature rupture of membranes, fetal distress, and cesarean delivery rates [3, 41–42]. Additionally, using questionnaires to assess maternal cognitive function, researchers have shown that IMH not only affects fetal neurodevelopment but also significantly impacts maternal cognitive function, with IMH patients showing significantly higher cognitive dysfunction scores throughout pregnancy, increasing between 12–24 weeks and decreasing by pregnancy's end [43]. While research on pregnancy outcomes in IMH patients has increased, not all studies agree that IMH affects maternal and neonatal outcomes, with some finding no increased risk of adverse maternal or perinatal complications [44].

5. Treatment Measures

Significant progress has been made in understanding IMH regarding its etiology, impact on mothers and infants, and treatment selection. The associations between iodine deficiency, iron deficiency, and IMH have been validated clinically and supported by pathological mechanisms, though evidence linking placental growth factors and maternal characteristics to IMH remains inconclusive. Future research should focus on how these factors increase IMH risk and explore the combined effects of genetic, immune, and environmental factors to provide new theoretical foundations for early prevention and individualized treatment strategies.

Regarding effects on maternal and infant health, only the negative impact on fetal brain development is currently well-established. The effects on other pregnancy outcomes require further investigation, and the underlying pathological mechanisms remain incompletely understood—representing a major research challenge. Future large-scale, multicenter prospective cohort studies should evaluate causal relationships between IMH and various maternal-neonatal outcomes while investigating potential biological mechanisms to further explain these associations.

The key unresolved question regarding levothyroxine treatment for IMH is whether correcting IMH with levothyroxine provides substantive benefits for promoting offspring brain development, improving cognitive function, and reducing adverse pregnancy outcomes. Unfortunately, existing studies have yielded inconsistent conclusions with insufficient power. Considering that thyroid hormone receptor genes begin expressing as early as gestational week 8 [47], many intervention studies have initiated levothyroxine treatment after this critical period. Future research should target IMH patients before 8 weeks gestation to verify whether early levothyroxine supplementation improves maternal and neonatal outcomes.

However, treating IMH patients before 8 weeks gestation demands higher diagnostic capabilities. Future studies should integrate more sophisticated genomic, metabolomic, and molecular marker technologies to facilitate early IMH diagnosis and promote etiology-based treatment. Furthermore, IMH involves not only obstetrics and gynecology but also endocrinology, pediatrics, neurology, and other specialties. Therefore, enhanced interdisciplinary collaboration and establishment of robust multidisciplinary cooperative models are needed to drive development of individualized treatment strategies and provide more precise therapeutic approaches for patients.

Author contributions: WANG Yuhan was responsible for conceptualization, design, and manuscript writing; DENG Wenxu and TANG Yingying collected and organized research materials; WANG Yuhan revised the manuscript, performed quality control, and took overall responsibility; GAO Shuhong provided supervision.

Conflict of interest: The authors declare no conflicts of interest.

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Received: December 16, 2024; Revised: April 13, 2025
Edited by: JIA Mengmeng