Analysis of epidemiological characteristics and associated factors of congenital hypothyroidism in Henan Province

Abstract

To investigate the epidemiological characteristics and associated risk factors of congenital hypothyroidism (CH) among newborns in Henan Province. A case-control study design was adopted. Children diagnosed with CH from January 1,2016 to December 31,2017 were selected as the cases, and healthy infants with the same sex and birth date less than 30 days old were matched in a 1:1 ratio as the control.Conditional logistic regression was performed to identify factors associated with CH. Subgroup analyses and trend tests were conducted, and restricted cubic spline models were applied to explore the potential nonlinear association between maternal age and CH risk. A total of 843 pairs of children with CH were used in the paired design case-control study.There were 387 male children and 456 female children.In all cases and control pairs, Logistic regression analysis showed that mather’s age[OR_adj(95%CI) = 1.26(1.20,1.33),aternal living in the rural [OR_adj ( 95%CI) = 1.87(1.15,3.11)], material family history of thyroid diseases[OR_adj (95%CI ) = 7.26(2.13,24.75)], exposure to formaldehyde [OR_adj(95%CI) = 3.38(1.19,9.58)], material exposure to radiation [(OR_adj (95%CI) = 7.07(3.66,21.15)], material medication intake during pregnancy[OR_adj(95%CI) = 7.59(3.25,17.72) ], Other feeding methods [OR_adj (95%CI) = 3.25(1.67,6.53) ], Progesterone intake during pregnancy [OR_adj (95%CI ) = 0.17(0.06,0.43) ], father’s age [OR_adj (95%CI) = 1.32(1.24,1.40) ]were statistically significant association with CH, all P<0.05.The results of subgroup analyses were consistent with those listed above.Restricted cubic spline analysis demonstrated a nonlinear dose-response relationship between maternal age and the risk of CH.Specifically, when maternal age exceeded 25 years, there was a positive association between maternal age and CH occurrence in both male and female newborns.Conculsion:Advanced maternal age, rural residence, family history, gestational formaldehyde exposure, radiation exposure, material medication intake during pregnancy, feeding methods, father’s age are factors associated with CH.

Supplementary Information

The online version contains supplementary material available at 10.1038/s41598-026-43133-3.

Introduction

The butterfly-shaped thyroid gland, situated below the thyroid cartilage in the neck, is a critical endocrine organ. Its secreted thyroid hormones are essential for childhood somatic growth and neurological development¹. Congenital hypothyroidism (CH) is a preventable cause of neurocognitive impairment in neonates and remains one of the most common endocrine disorders detected through newborn screening². Current research generally holds that the cause of CH is the result of the combined effects of genetics, environment, and individual factors. In terms of genetic mechanisms, gene mutations related to thyroid development (such as TSHR, PAX8, etc.) and hormone synthesis (such as TPO, DUOX2, etc.) have been confirmed to be closely associated with the onset of CH^3–5, In terms of environmental and maternal factors, existing evidence suggests that the mother’s history of thyroid disease, certain drug exposure, iodine nutritional status, and exposure to environmental endocrine disruptors during pregnancy may affect the normal development and function of the fetus’s thyroid gland.Without early detection and treatment, CH leads to irreversible intellectual disability, with severe cases progressing to lifelong dependency in adulthood, imposing substantial socioeconomic burdens on families and communities⁶. However, current studies on the associated factors of CH mostly focus on a single genetic or partial environmental factor, lacking large-scale epidemiological research targeting specific regions in China, as well as multiple dimensions such as genetics, environment, maternal and neonatal factors. Henan Province, as a populous region, it is not clear whether the epidemiological characteristics and risk factor spectrum of CH in this area are unique. Identifying these regional-specific associated factors is a prerequisite for implementing effective primary prevention.

Therefore, this study adopts a case-control study design, aiming to systematically explore the epidemiological distribution characteristics of CH in newborns in Henan Province from 2016 to 2017, and comprehensively evaluate the associations between multiple variables such as maternal factors, neonatal conditions, family history, environmental exposure history, and father factors with the occurrence of CH, in order to provide scientific basis for formulating targeted prevention and control strategies for CH in Henan Province.

Materials and methods

Study population

The Newborn Screening Center of Henan Province serves as the sole government-designated institution responsible for province-wide CH screening, treatment, and follow-up under China’s national newborn screening program.We conducted a matched case-control study using Henan Provincial Newborn Screening Program data (2016–2017).Cases were CH-confirmed neonates, excluding deaths, treatment refusals, or follow-up discontinuations. The control group was matched 1:1 from individuals across 18 cities in Henan Province, based on the same gender, same birthplace, a birth date within 30 days(SMD = 0.051), normal screening results, and the absence of other congenital diseases.

Experiment and methods

Three drops of heel blood were collected from newborns 72 h after birth following adequate breastfeeding. The blood samples were spotted onto specialized filter paper cards, air-dried at ambient temperature, sealed in plastic bags, and sent within 7 days to the Henan Provincial Newborn Disease Screening Center L aboratory for analysis.Thyroid-stimulating hormone (TSH) levels in the dried blood spots were measured using time-resolved immunofluorescence assay (DEFIA). A TSH level > 9µU/mL(whole blood units) was considered indicative of a suspected positive case. Infants with suspected positive results were recalled for venous blood collection, and confirmatory diagnosis was performed using electrochemiluminescence immunoassay to measure T3, T4, FT3, FT4, and TSH levels.

Definition of study variables and covariates

The main research variables include factors related to the mother such as age, place of residence, ethnicity, medication history, exposure to formaldehyde, radiation, mode of delivery, number of pregnancies, number of births, number of fetuses, family history of thyroid diseases, feeding method, and history of progesterone use.The variables related to newborns and their fathers, including the newborn’s height, weight, gestational age, history of jaundice, history of hypoxia, and the father’s age, were used as covariates.

Maternal age: was defined as the age at delivery; Residential exposure: In this study, residential exposure was defined as continuous residence (≥ 30 days) at the registered address from the three months before conception until delivery.For the small number of participants who moved, relocation dates were collected, and a weighted average method was applied to calculate the composite exposure index; Family history of thyroid diseases: In this study, the inclusion criteria for family history were based on abnormal thyroid function (diagnosed through laboratory tests) among first-degree relatives; Formaldehyde exposure: This refers to individuals who lived in a house that had been painted or newly furnished during pregnancy, within a period of less than 3 months after the completion of the renovation, or who purchased a new car and used it for more than 3 months, or who were engaged in related industries (such as chemical, processing, manufacturing) during pregnancy and were exposed to an indoor formaldehyde concentration of ≥ 0.08 mg/m³ (the limit set by the Chinese national standard) for a duration of ≥ 3 months; Radiation exposure was defined as maternal exposure to diagnostic radiation (e.g., X-ray, CT scan, or nuclear medicine imaging) during pregnancy; Pregnancy medication: Refers to the use of drugs (antibiotics, antipyretic analgesics, hormonal drugs) through oral administration or injection during pregnancy.

Classification of congenital hypothyroidism

In this study, cases of CH were identified based on newborn screening results and subsequent clinical confirmation. Detailed etiological subtype information (e.g., thyroid dysgenesis, dyshormonogenesis, or central CH) was not consistently available in the screening database due to limitations in long-term diagnostic follow-up data. Therefore, CH cases were analyzed as a single epidemiological category. The identified risk factors should be interpreted as associations within a potentially heterogeneous CH population rather than subtype-specific effects.

Quality control

To improve data quality and reduce potential recall bias, the questionnaire was carefully developed and reviewed by a multidisciplinary expert team. Logical relationships between items were evaluated to ensure appropriate sequencing, and related questions were grouped and arranged according to chronological order or logical hierarchy. The wording of each item was refined to ensure clarity, comprehensibility, and lack of ambiguity.

Prior to the formal survey, a pilot study was conducted among a small sample of participants from the target population. Feedback regarding item comprehension and response feasibility was collected and used to revise ambiguous questions and optimize the structure and wording of the questionnaire. These procedures were implemented to enhance the accuracy and reliability of the collected information.

Statistical analysis

Statistical analysis was conducted using SPSS 26.0 and Stata 14.0 software, and graphing was performed using R 3.6.2.Count data were expressed as frequencies and percentages (%),and comparisons between groups were conducted using the χ ² test; for variables related to CH onset, conditional logistic regression models were used for multiplicative interaction analysis, and addition interaction analysis was performed using EXCEL calculation tables.The significance level α = 0.05 (P < 0.05 indicated statistically significant differences), and subgroup analysis was conducted; through restricted cubic spline analysis, the dose-response relationship between maternal age and CH occurrence was explored in depth; the association between the research variables and CH was analyzed using conditional Logistic regression, with the entry standard α = 0.05 and the exclusion standard α = 0.10.The OR value and 95% confidence interval (95%) were calculated.

Ethics and regulations

All the methods of this study were in accordance with the relevant guidelines and regulations stipulated in the “Administrative Measures for Neonatal Disease Screening” (Order No. 64 of the Ministry of Health) and the “Technical Specifications for Neonatal Disease Screening” (2010 Edition) of the state.The study protocol was approved by the Ethics Committee of The Third Affiliated Hospital of Zhengzhou University (Approval No.:2024-320-01). All participants voluntarily joined the study with informed consent and provided written informed consent.

Result

Analysis of factors associated with CH

The screening cohort comprised 2,772,661 neonates (2016–2017),identifying 1,494 CH cases.After exclusions (lost to follow-up: n = 409; declined participation: n = 219; mortality: n = 24),843 cases (387 male, 456 female) were analyzed.Age-/sex-matched controls (n = 843) were randomly selected from screen-negative births.The factors associated with CH are summarized in Table 1.

Table 1.

Conditional logistic regression analysis of factors associated with neonatal congenital hypothyroidism.

Variables	ALL				Male				Female
	OR及95%CI	P	ORadj及95%CI	P	OR及95%CI	P	ORadj及95%CI	P	OR及95%CI	P	ORadj及95%CI	P
Ethnicity
Han ethnicity	1.00		1.00		1.00		1.00		1.00		1.00
Ethnic minorities	1.08(0.49,2.37)	0.842	0.91(0.79,1.04)	0.169	1.50(0.53,4.21)	0.442	0.38(0.60,2.39)	0.301	0.67(0.19,2.36)	0.530	0.76(0.10,5.84)	0.791
Residential Area
Urban	1.00		1.00		1.00		1.00		1.00		1.00
Rural	2.31(1.83,2.92)	<0.001	1.87(1.15,3.11)	0.013	1.93(1.39,2.67)	<0.001	1.92(0.79,4.70)	0.152	2.75(1.98,3.83)	<0.001	1.73(0.86,3.49)	0.124
Neonatal length	0.90(0.84,0.96)	0.070	0.90(0.79,1.04)	0.169	0.92(0.83,1.01)	0.082	0.84(0.67,1.05)	0.116	0.88(0.79,0.99)	0.320	0.96(0.77,1.19)	0.716
Birth weight	1.03(0.86,1.23)	0.778	0.82(0.55,1.22)	0.333	1.28(0.98,1.66)	0.069	0.77(0.40,1.46)	0.419	0.82(0.68,1.07)	0.143	0.70(0.39,1.27)	0.241
Gestational age	1.09(1.01,1.17)	0.026	1.21(1.05,1.40)	0.100	1.08(0.97,1.22)	1.171	1.67(1.24,2.25)	0.001	1.09(0.99,1.12)	0.081	1.12(0.94,1.33)	0.221
History of Neonatal Hypoxia
No History	1.00		1.00		1.00		1.00		1.00		1.00
History	3.10(1.52,6.32)	0.002	4.27(0.94,9.33)	0.060	3.20(1.17,8.74)	0.023	2.67(1.01,13.65)	0.049	3.00(1.09,8.25)	0.033	4.35(0.58,32.49)	0.152
History of Neonatal Jaundice
No History	1.00		1.00		1.00		1.00		1.00		1.00
History	3.83(2.77,5.29)	<0.001	3.45(2.12,5.92)	<0.001	3.59(2.24,5.76)	<0.001	5.23(2.17,12.59)	<0.001	4.04(2.59,6.14)	<0.001	4.18(2.05,8.54)	<0.001
Maternal Age (years)	1.28(1.23,1.33)	<0.001	1.26(1.20,1.33)	<0.001	1.31(1.23,1.39)	<0.001	1.38(1.25,1.53)	<0.001	1.26(1.20,1.32)	<0.001	1.28(1.19,1.36)	<0.001
Maternal Education Level
College or higher	1.00		1.00		1.00		1.00		1.00		1.00
Below college	3.22(2.53,4.13)	<0.001	5.27(3.13,8.88)	<0.001	3.16(2.19,4.58)	<0.001	2.65(0.74,9.54)	0.137	3.23(2.34,4.56)	<0.001	9.32(4.94,17.41)	<0.001
Mode of Delivery
Vaginal delivery	1.00		1.00		1.00		1.00		1.00		1.00
Cesarean delivery	1.37(1.12,1.66)	<0.001	1.36(0.95,1.95)	0.093	1.42(1.06,1.91)	0.019	2.02(1.07,3.82)	0.031	1.32(1.02,1.72)	0.039	1.16(0.71,1.89)	0.549
Fetal Number
Singleton	1.00		1.00		1.00		1.00		1.00		1.00
Multiple gestation	2.22(1.01,4.88)	0.047	1.86(0.37,9.37)	0.450	2.00(0.60,6.64)	0.258	1.75(0.03,10.27)	0.788	2.4(0.85,6.82)	0.100	1.56(0.24,10.88)	0.673
Birth Order
First-born	1.00		1.00		1.00		1.00		1.00		1.00
Later-born	1.62(1.32,1.99)	<0.001	0.69(0.32,1.50)	0.347	1.81(1.34,2.46)	<0.001	0.81(2.24,2.68)	0.723	1.48(1.12,1.94)	0.005	0.51(0.30,0.86)	0.012
Parity
Primiparous	1.00		1.00		1.00		1.00		1.00		1.00
Multiparous	1.61(1.32,1.97)	<0.001	0.82(0.39,1.74)	0.603	1.81(1.35,2.43)	<0.001	0.82(0.26,2.56)	0.733	1.46(1.12,1.94)	0.006	0.75(0.24,2.23)	0.613
Feeding Method
Breastfeeding	1.00		1.00		1.00		1.00		1.00		1.00
Non-breastfeeding	3.55(2.24,5.36)	<0.001	3.25(1.67,6.53)	0.001	3.53(2.06,6.05)	<0.001	7.66(2.50,23.49)	<0.001	3.58(1.89,6.80)	<0.001	2.35(0.86,6.78)	0.113
Medication During Pregnancy
No medication	1.00		1.00		1.00		1.00		1.00		1.00
Medication use	8.91(4.78,16.62)	<0.001	7.59(3.25,17.72)	<0.001	6.74(3.06,14.85)	<0.001	3.32(1.01,10.89)	0.048	8.75(4.61,27.28)	<0.001	9.86(5.95,33.74)	<0.001
Family History
Negative	1.00		1.00		1.00		1.00		1.00		1.00
Positive	11.60(4.64,28.92)	<0.001	7.26(2.13,24.75)	0.002	7.00(3.67,18.69)	<0.001	6.26(2.16,16.04)	0.011	7.75(2.74,19.96)		4.84(1.19,16.77)	0.028
Radiation Exposure
No radiation exposure	1.00		1.00		1.00		1.00		1.00		1.00
Radiation exposure	8.00(3.16,20.23)	<0.001	7.07(3.66,21.15)	<0.001	9.50(2.21,20.79)	0.002	5.63(0.80,15.57)	0.082	7.00(2.09,23.47)	0.002	6.77(2.79,21.59)	<0.001
Formaldehyde Exposure
No formaldehyde exposure	1.00		1.00		1.00		1.00		1.00		1.00
Formaldehyde exposure	7.71(3.51,16.94)	<0.001	3.38(1.19,9.58)	0.022	6.25(2.16,17.96)	0.001	0.69(0.14,3.43)	0.647	9.67(2.95,31.33)	<0.001	9.99(2.24,32.99)	0.005
Progesterone Use
No progesterone	1.00		1.00		1.00		1.00		1.00		1.00
Progesterone use	0.13(0.68,0.24)	<0.001	0.17(0.06,0.43)	<0.001	0.12(0.04,0.33)	<0.001	0.27(0.06,1.19)	0.083	0.14(0.06,0.30)	<0.001	0.12(0.04,0.37)	<0.001
Paternal age (years)	1.20(1.16,1.23)	<0.001	1.32(1.24,1.40)	<0.001	1.24(1.18,1.30)	<0.001	1.50(1.32,1.70)	<0.001	1.16(1.12,1.21)	<0.001	1.27(1.18,1.37)	<0.001
Paternal Education Level
College or higher	1.00		1.00		1.00		1.00		1.00		1.00
Below college	3.06(2.39,3.91)	<0.001	1.08(0.47,2.45)	0.863	3.06(2.10,4.37)	<0.001	3.17(0.88,11.39)	0.077	3.27(2.34,4.56)	<0.001	0.60(0.19,1.92)	0.387

Birth order: refers to the sequence of the child among all live births to the mother, and is not related to the sequence within a multiple pregnancy.

Interaction Analysis

A statistically significant interaction was observed between maternal age and progesterone use history (P = 0.049), indicating effect modification.No additive or multiplicative interactions were detected between other studied variables (all P > 0.05).Detailed results are presented in Table 2.

Table 2.

Interaction effects between maternal age and other risk factors.

Variables	Multiplicative Interaction		Additive Interaction
	OR(95%CI)	P	RERI(95%CI)	AP(95%CI)	SI(95%CI)
Maternal Age (years)	3.79(3.05ཞ4.07)	<0.001
Medication DuringPregnancy	15.47(5.92ཞ40.39)	<0.001
Age* Medication	0.48(0.13ཞ1.71)	0.245	9.60(-17.90ཞ37.08)	0.34(-0.41ཞ1.10)	1.56(0.46ཞ5.22)
Maternal Age (years)	3.65(2.97ཞ4.50)	<0.001
Radiation Exposure	9.09(2.54ཞ32.57)	<0.001
Age* Radiation	0.99(0.14ཞ6.57)	0.965	20.07(-27.12ཞ67.26)	0.63(-0.01ཞ1.27)	2.87(0.46ཞ17.86)
Maternal Age (years)	3.62(2.94ཞ4.48)	<0.001
Formaldehyde Exposure	6.89(2.47ཞ4.50)	<0.001
Age* Formaldehyde	1.23(0.26ཞ5.58)	0.256	21.11(15.63ཞ57.86)	0.69(0.26ཞ1.12)	3.48(0.80ཞ15.05)
Maternal Age (years)	1.27(1.22ཞ1.32)	<0.001
Progesterone Use	<0.001(0ཞ0.16)	0.016
Age* Progesterone	1.34(1.00ཞ1.80)	0.049	26.60(-36.40ཞ89.60)	0.55(0.17ཞ1.27)	2.30(0.43ཞ12.21)

RERI: Relative Excess Risk due to Interaction;AP:Attributable Proportion;SI:Synergy Index.

Subgroup analysis

We conducted stratified analyses by neonatal residence, history of jaundice, history of hypoxia, birth weight, and paternal education level to assess the association between family history of thyroid disorders and CH risk, Forest plot (Fig. 1) summarizes subgroup-specific ORs and 95% CIs, demonstrating consistent positive associations between family history and CH risk.

Fig. 1.

Subgroup analysis of the association between family history of thyroid disorders and neonatal CH risk.

Restricted cubic spline analysis

Adjusted for gestational weeks, family history of thyroid disorders, residential area, medication use during pregnancy, exposure history, progesterone use history, and paternal age, this study examined the association between maternal age and neonatal CH, This study found that Maternal age is an independent risk factor for CH, After adjusting for multiple confounding variables (such as medication use during pregnancy, exposure history, and family history); the risk remains significantly elevated with increasing maternal age; Age 25 appears to be a turning point, after which the risk of CH begins to rise, with a marked increase observed beyond age 29; The increasing risk trend is consistent across both male and female newborns, with no significant sex-specific interaction observed; The results are presented in Figs. 2 and 3, and Fig. 4, respectively.

Fig. 2.

Restricted cubic spline plot of maternal age and CH in the total population.

Fig. 3.

Restricted cubic spline plot of maternal age and CH in male offspring.

Fig. 4.

Restricted cubic spline plot of maternal age and CH in female offspring.

Discussion

Based on the analysis of 843 case-control pairs from Henan Province, our study demonstrates that CH is significantly associated with multiple factors. These include a family history of thyroid disease, advanced parental age, specific environmental exposures (e.g., formaldehyde, radiation, certain medications), a history of maternal progesterone use during pregnancy, perinatal conditions (such as neonatal jaundice, hypoxia, and non-breastfeeding), as well as a rural living environment. These findings are largely consistent with existing literature^3,4.

Studies have shown that the incidence of CH in newborns born to mothers over 20 years of age is 59.2 per 100,000 live births, and increases slightly to 59.6 per 100,000 among those born to mothers over 30 years of age—both higher than the incidence observed in younger mothers⁷,In early pregnancy, all thyroid hormones required by the fetus are derived from the mother.As maternal age increases, thyroid function tends to decline, resulting in reduced hormone secretion.Meanwhile, pregnancy imposes an increased demand for thyroid hormones.This mismatch may impair fetal thyroid development during the embryonic stage, thereby increasing the risk of CH after birth^8,9.This study revealed a non-linear dose–response relationship between maternal age and the risk of CH.When maternal age exceeded 25 years, the incidence of CH in both male and female newborns may be increased with advancing maternal age.These findings underscore the need for heightened attention to advanced maternal age, and highlight the importance of strengthening CH screening and early intervention during both the prenatal and postnatal periods.The genetic contribution to the development of CH in newborns has been increasingly recognized.On one hand, the molecular mechanisms by which thyroid hormones regulate neurodevelopment may involve various receptors in the brainstem.During pregnancy, any genetic mutations that affect the synthesis of thyroid hormones or the function of their receptors may impair fetal thyroid function and contribute to the onset of CH in newborns¹⁰,On the other hand, the effects of thyroid hormones on brain development may be associated with decreased expression of genes such as G-proteins, Krev-1,OSP, DOC-2, and TRP-.In newborns with a family history of thyroid disorders, mutations at various loci during gene expression may lead to abnormal transcription or function of these genes, thereby increasing the risk of CH^11–14.,This study also found that newborns with a family history of thyroid disease had a significantly higher risk of developing CH compared to those without such a history.Subgroup analysis further indicated that prevention efforts in families with a thyroid disease history should particularly focus on populations residing in rural areas, as well as those with a history of perinatal hypoxia, neonatal jaundice, or abnormal birth weight. This study also found an association between preterm birth and the occurrence of CH.Since the hypothalamic-pituitary-thyroid axis in neonates matures gradually after 26 weeks of gestation, preterm infants may develop CH due to the incomplete maturation of this axis¹⁵.Multifactorial association analysis revealed that maternal medication use, exposure to formaldehyde, and radiation during pregnancy were all linked to the occurrence of neonatal CH.Research indicates that fetal thyroid development primarily occurs between 12 and 26 weeks of gestation; exposure to these factors during this critical period may result in delayed thyroid development in the fetus. This study identified a significant inverse association between maternal progesterone use during pregnancy and the risk of CH in offspring. However, this observational finding requires cautious interpretation. The association may be influenced by prescription bias and unmeasured confounding. For instance, progesterone is typically prescribed to women with specific clinical conditions, such as threatened miscarriage, assisted reproductive technology, or other pregnancy complications. These women often receive more intensive prenatal monitoring and management.This enhanced clinical surveillance itself, potentially combined with other incompletely controlled clinical factors, might partly explain the observed reduction in CH risk among their offspring.In other words, progesterone use could serve as an indicator of systematic medical intervention within this specific patient population, rather than being the direct cause of the risk reduction.

Although our multivariate models adjusted for several known potential confounders, residual confounding cannot be entirely ruled out due to the complexity of clinical indications and specific prescription practices. Future prospective cohort studies, collecting detailed information on the indications, dosage, and duration of progesterone use earlier in pregnancy and employing stricter designs to control for confounding, are warranted. Furthermore, basic experimental research is needed to explore the potential molecular mechanisms by which progesterone might influence fetal thyroid development. Such investigations are essential to ultimately determine whether a true causal protective relationship exists.

This study has several limitations. First, information regarding newborns and their parents was collected retrospectively through telephone interviews conducted several years after birth, which may have introduced recall bias or reporting bias. Second, as a case–control study, the present analysis can identify associations between potential risk factors and the occurrence of CH but cannot establish causal relationships. Third, the subgroup analyses were conducted based on patterns observed in the primary results and were not fully pre-specified. Therefore, these analyses should be considered exploratory and interpreted with caution. Further large-scale prospective cohort studies with pre-defined hypotheses are needed to establish temporal relationships and clarify the potential causal pathways underlying the identified associations.

In summary, the findings of this study indicate that advanced maternal age, rural residence, exposure to formaldehyde and radiation during pregnancy, history of medication use, as well as neonatal jaundice and hypoxia, are all factors that increase the risk of CH, As the present study is a case-control investigation, the findings primarily demonstrate associations between factors and cannot directly infer causality. Future research should aim to establish large-scale, prospective birth cohorts, recruiting participants early in pregnancy or even before conception. Such studies should prospectively and systematically collect detailed exposure information—such as specific indications and dosage for progesterone use, biomonitoring data for environmental exposures—and implement more rigorous control and measurement of potential confounders. This type of design will be more effective in clarifying the potential causal relationships between prenatal exposures and CH risk, thereby providing higher-grade evidence for the primary prevention of CH.

Supplementary Information

Below is the link to the electronic supplementary material.

Author contributions

Sincerely, First Author: Chunwei LuoSecond Author: Suna LiuThird Author: Shubo Lv (Corresponding Author).

Funding

This work was supported by Zhengzhou Science and Technology Bureau(Project Number: 2024YLZDJH002).

Data availability

The datasets generated and/or analyzed during the current study cannot be publicly accessed, but upon the reasonable request of the corresponding author, they can be obtained from the corresponding author.

Declarations

Competing interests

The authors declare no competing interests.

Ethics statement

Due to concerns regarding patient privacy, we do not have the authority to disclose certain data. All authors have agreed not to share the data publicly. Thank you for your understanding. All methods in this study were carried out in accordance with relevant guidelines and regulations, and were approved by the Medical Ethics Committee of the Third Affiliated Hospital of Zhengzhou University (Ethical Review Number: 2024-320-01).

Informed consent

Informed consent was obtained from all human participants (including donors of tissue samples) involved in this study. Prior to their participation, all individuals were fully informed about the study’s purpose, procedures, potential risks and benefits, and data confidentiality measures. All participants voluntarily provided written informed consent. The study protocol was approved by the Ethics Committee of The Third Affiliated Hospital of Zhengzhou University (Approval No.:2024-320-01 ).

Guardian’s informed consent

The inclusion of all minor participants (including minor donors of tissue samples) in this study strictly adhered to ethical guidelines for the protection of vulnerable populations. Informed consent was obtained from the parents and/or legal guardians of all minor participants. Prior to consent, guardians were provided with comprehensive information regarding the study’s purpose, procedures, anticipated benefits, potential risks, confidentiality measures, and the right to withdraw at any time. All parents and/or legal guardians provided written informed consent on behalf of the minors. The study protocol was approved by the Ethics Committee of The Third Affiliated Hospital of Zhengzhou University (Approval No.:2024-320-01 ).