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Profile and Practice of Guangxi Zhuang Birth Cohort

Liu Shun, MD.,PhD.

Director, Department of Maternal, Child and Adolescent Health

Facalty of Public Health

Guangxi Medical University

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Contents

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Background 1: The main adverse pregnancy outcomes are the most important causes of neonatal death in the worldwide

Liu L, Oza S, Hogan D, et al. The Lancet, 2016, 388(10063): 3027-3035.

http://www.who.int/news-room/fact-sheets/detail/congenital-anomalies

Global causes of under-5 mortality in 2015

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Background 2: Adverse pregnancy outcomes are the main causes of death in children (<5 years) in China

Causes of child deaths in China during 2000–2008

Rudan I, Chan K Y, Zhang J S, et al. Lancet, 2010, 376(9735):89-89.

Hao Cui, Chunhua He, Lei Miao , et al. Chinese prevention medicine, 2015, 49(2):161-165.

Proportional of cause of child death due to preterm or low birth weight in China, 1996-2013

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WEN Xiao-yan et. al. Journal of Shanghai Jiaotong University (Medical Science), 2015, 1: 29.

Background 3: Birth Defects become the main public concerns of child health in Guangxi

Map of Incidence of Birth Defects in China

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Background 4: Adverse pregnancy outcomes are attributed to the combined effects of environmental and genetic factors

Vrijheid M, et al. Int J Hyg Environ Health. 2016.

Contribution of Variance Components to Gestational Age——A Quantitative Genetic Analysis of 244,000 Swedish Births

Quality of evidence relating exposure to environmental chemicals to child health

York TP, et al. Am J Epidemiol. 2013.

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Why was Guangxi Birth Cohort Study (GBCs) set up

• The birth cohort study design represents the most powerful tool for investigating associations between prenatal environmental exposures and adverse birth outcomes.
• Guangxi is the main settlement for Zhuang people in China (18 millions). The proportion of Zhuang population is over 85% in many counties, and the population is relatively stable.
• The Zhuang nationality has unique customs and living habits.
• GBCs was set up to evaluate the effects of genetic factors and maternal environmental exposures on the main adverse pregnancy outcomes.

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Parent-child families

Inclusion criteria

• the counties with >85% of Zhuang ethnic population
• One of the spouses is Zhuang ethnic;
• The gestational weeks must less than 18;
• All the participants must be informed consent.

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Who was in GBCs

We plan to recruit 50, 000 parent-child families who live in the counties with >85% of Zhuang ethnic population

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Total of 11 hosipital in 7 eligible counties in Guangxi

Wuming

2017.7

Who was in GBCs

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Baseline information collection

• Demographic characteristics
• Pregnant history and family history
• Drugs use
• Smoking status
• Drinking status
• Physical activity and psychosocial stress

Biological samples of mothers and fathers

• In early pregnancy, two tubes of peripheral venous blood (8-10 ml) to collect the plasma, serums and cells and store in the ultra-low temperature freezer.

Data and biological samples collection, follow-ups in GBCs

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Data and biological samples collecting, follow-ups in GBCs

Umbilical cord blood

Placenta tissue

Oropharyngeal

secretion

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Profiles progress of GBCs

Baseline questionnaires

• We have recruited 23,151 pregnant women and 8,656 husbands.

Biological samples

• 24,684 peripheral venous blood from mothers and 15,967 from fathers
• 6,832 newborn cord blood
• 6,856 placenta tissues
• 6,158 Oropharyngeal secretion

Follow-ups

• 19,700 newborns with birth outcomes
• 5 preschool children (aged 4-6 years)

We have built a biobank with 20 ultra-low temperature refrigerators

Follow-up

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1.Maternal serum PFASs concertrations is associated with postpartum hemorrhage (PPH) risk

Ecotoxicology and Environmental Safety 245 (2022) 114078

BKMR model showed PPH risk increased with increasing PFASs mixture exposure

Exposure to PFHxS increased the risk of postpartum hemorrhage, while higher concentrations of PFUnA were positively correlated with the volume of postpartum hemorrhage

Per- and polyfluoroalkyl substances, PFASs

Prenatal Environmental Pollutant Exposure on Maternal and Child Health：Findings from GBCs

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2.Individual and co-exposure to PFASs increases the risk of hypertensive disorders of pregnancy (HDP)

Chemosphere, 2022, 288(Pt 1): 132468.

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3. Maternal PFASs exposure is associated with gestational anemia

Chemosphere, 2022, 309(Pt 2): 136798.

PFDA and PFNA were associated with increased risk

WQS regression indicated a negative association between PFASs mixture exposure during second-trimester and anemia risk

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4.Prenatal exposure to higher levels of PFASs mixture is associated with preterm birth (PTB)

Chemosphere, 2022, 307(Pt 1): 135741

PFOS, PFHpA, PFBS, PFSA were positively associated with PTB risk

BKMR showed a positive overall association between the PFASs mixture and PTB

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Restricted cubic spline (RCS) models assessing dose-response relationships

• Analysis using restricted cubic spline models revealed non-linear, inverted U-shaped relationships of PFDoA and PFBS with LBW risk after covariate adjustment. Conversely, exposures to PFOS, PFOA, and PFHpA exhibited significant positive dose-response relationships with LBW risk.

5. PFASs exposure are associated with Low Birth Weight (LBW)

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• Co-exposure to 9 PFASs increased LBW risk
• Single exposures to PFOS, PFOA, PFBS associated with increased LBW risk
• No significant interactions found among the 9 PFASs

BKMR model confirmed association between mixture and LBW

5. PFASs exposure are associated with Low Birth Weight (LBW)

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Bisphenols，BPs

1.Prenatal BPs exposure may increase the risk of gestational anemia

Environmental Research, 2022, 207(112625).

Individual exposure analysis

• High BPA associated with decreased Hb in first trimester.
• Middle BPB associated with decreased Hb in second trimester.
• Middle and high TBBPA associated with higher anemia risk in third trimester.
• High BPF associated with decreased Hb in mothers carrying male fetuses in third trimester

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Environmental Research, 2022, 207(112625)

Mixed-effect analysis

The results from both PCA and Qgcomp demonstrated negative associations with Hb levels, which were more pronounced in mothers carrying a male fetus

1.Prenatal BPs exposure may increase the risk of gestational anemia:

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2.Prenatal exposure to BPs was negatively associated with birth weight

Chemosphere 252 (2020) 126422

Prenatal exposure to BPA, BPF, and TBBPA was negatively associated with birth weight, and BPF, and TBBPA was more pronounced on male infants

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Chemosphere 252 (2020) 126422

Higher TBBPA associated with decreased birth length in males

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3.Prenatal exposure to bisphenols may increase PTB risk

Ecotoxicol Environ Saf, 2021, 228: 112960

Individual exposure analysis

• BPF expsoure was positive assocatied with PTB risk, which was more pronounced in male
• BPA exposure was positive associated with PTB riks only in female

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Ecotoxicol Environ Saf, 2021, 228: 112960

RCS analysis showed BPB, BPS, and TBBPA were inversed U shap with PTB risk

PCA analysis showed combined effect of BPs on PTB risk

Qgcomp analysis showed BPs mixed-exposure was associated with increased PTB risk (BPF, BPS, BPA are main contributors)

3.Prenatal exposure to bisphenol mixture may increase PTB risk

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4.BPs and Gestational Diabetes Mellitus (GDM) risk

Environ Sci Pollut Res Int . 2023 Feb;30(10):25170-25180

BPS showed a positive effect on GDM risk, while BPA and TBBPA showed negative effects.

Exposure to the mixture of five bisphenols was negatively associated with GDM risk.

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5.Association with telomere length (TL) modified by maternal age

Environ Sci Pollut Res Int . 2023 Feb;30(10):25013-25023

• Positive association between cord serum TBBPA and relative TL in infants of younger mothers (<28 years).

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• Negative association between cord serum BPS and relative TL in infants of older mothers (≥28 years).

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6.Maternal bisphenol exposure affected thyroid hormone levels during pregnancy

Environ Sci Pollut Res Int . 2022 Dec;29(58):87170-87183

First trimester

Middle level of BPA positive associated with FT3

BPF positive associated with TSH

BPB negative associated with T4, FT4

Middle level of BPS negative assocaited with T3

Middle level of TBBPA negative associated with T3

exhibited spicific with trimester and exposure

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Environ Sci Pollut Res Int . 2022 Dec;29(58):87170-87183

RCS models showed non-linear (inversed U-shaped) relationships between BPA and FT3, and BPS and FT4

BKMR model showed no mixed-effect of BPs exposure on FT3

6.Maternal bisphenol exposure affected thyroid hormone levels during pregnancy

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1.Alkylphenols as a risk factor for preterm birth

Environ Sci Pollut Res Int. 2022 Jul;29(35):52954-52963

Table 4 Relationship between exposure levels of nonylphenols and octylphenol and preterm birth

RCS showed NP and 4TOP were inverse U-shaped assocaited with PTB risk

Alkylphenols

nonylphenol (NP), 4-nonylphenol (4-N-NP), 4-tert-octylphenol (4-T-OP), and 4-n-octylphenol (4-N-OP)

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2. Relationship between prenatal alkylphenol exposure and preschool children's IQ

Single and mixed exposure to 4 alkylphenols in maternal and cord serum was associated with a decreasing trend in preschool children's IQ scores

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Phthalates and Fetal Growth Restriction (FGR)

Environ Sci Pollut Res Int . 2022 Aug;29(38):57318-57329

Phthalates，PAEs

Single phthalate substance exposure and FGR risk

• Single-phthalate models showing BBP, DEHP, DMP significantly positively associated with FGR risk.
• WQS model weights identified BBP, DEP, DMP, DEHP, DBP, MBP as high-weight contributors.
• BKMR model showed positive joint effect of seven phthalates on FGR risk

Mixed phthalate substance exposure and FGR risk

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1.Associations between prenatal multiple plasma metal exposure and newborn telomere length

Metals

Environ Pollut. 2022 Dec 15:315:120451

• The GLMs revealed the inverse association between plasma arsenic and barium concentrations and newborn TL
• The joint effect analysis using BKMR showed metals was negatively associated with newborn TL.

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2.Association between maternal metal exposure during early pregnancy and intelligence in children aged 3-6 years

Environ Res. 2024 Nov 15:261:119685.

• ICP-MS was employed to detect 17 metals, including 7 essential metals (Mn, Fe, Co, Ni, Cu, Zn, Mo) and 10 non-essential metals (As, Rb, Sr, Cd, Sb, Cs, Ba, W, Pb, U)
• The GLM analysis revealed that U and Sb had a significant adverse effect on child IQ scores

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2.Association between maternal metal exposure during early pregnancy and intelligence in children aged 3-6 years

Environ Res. 2024 Nov 15:261:119685.

• BKMR modeling indicated that overall IQ scores decreased as concentrations of non-essential metals mixtures increased after adjusting for essential metal mixtures, consistent with findings from the WQS (β [95% CI], -8.463 [-14.449, -2.476], p = 0.007) and Qgcomp models (-7.003 [-12.928, -1.078], p = 0.022). Among the non-essential metals, U had the highest negative weight at 37.96%, followed by Pb (23.35%) and Sb (16.91%).

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• Household fuel type: Sci Total Environ . 2022
• Aflatoxin B1 (AFB1): Toxins (Basel) . 2021 ; Environ Sci Pollut Res Int . 2022
• Phytoestrogens: Environ Sci Pollut Res Int. 2023
• Neonicotinoids: Environ Res. 2025; Environ Pollut. 2025; Chemosphere. 2023; Ecotoxicol Environ Saf. 2024

Other environmental exposures

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Summary

• Established a parent-child birth cohort including nearly 60,000 individuals.
• Collected over 100,000 biospecimens (venous blood, cord blood, placenta, etc.).
• Established multiple prediction models for adverse birth outcomes/pregnancy risks.
• Development and application of methods for quantifying serum levels of multiple environmental pollutants to assess their associations with adverse birth outcomes

Outlook

• Enhance follow-up procedures and broaden research on the associations between diverse environmental exposures and adverse pregnancy outcomes.
• Strengthen data mining and biospecimen analysis to identify susceptible subpopulations, mediating effects, and combined mixture effects of exposures.
• Intensify omics-based research to elucidate the molecular mechanisms underlying the health effects of environmental pollutants.
• Foster collaboration and exchange with domestic and international birth cohort studies to promote resource and data sharing.

Summary and Outlook

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Thank You For Your Attention！

Acknowledgments

• Pro. Qiu xiaoqiang
• Pro. Zeng xiaoyun
• Pro. Yu hongping
• Pro. Huang dongping
• Pro. Wu junduan

Welcome to China

Welcome to GXMU

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Welcome to GX, GXMU