Cohort Profile: The Jiangsu Birth Cohort

Abstract

The Jiangsu Birth Cohort (JBC) is a family-based prospective cohort in Jiangsu Province, China, consisting of families receiving assisted reproductive technology (ART) treatment or families with spontaneous pregnancies. The study aimed to investigate the differences between the two groups of participants regarding both short- and long-term health outcomes in women and their offspring. The cohort recruited couples who planned to receive ART treatment at ART clinics, and collected data on the ART procedures and outcomes. Spontaneously conceiving couples were recruited during early pregnancy (8–14 weeks of gestation) at obstetrics clinics. Thereafter, ART pregnancies and spontaneous pregnancies were followed throughout the whole gestation with the same protocol. After childbirth, all children were followed until up to 3 years of age. Data on health were collected through standardized and structured questionnaires and medical records, together with biospecimens from both parents and their children. The cohort thus provided a valuable resource for the research on parental and child health associated with ART pregnancies. Between April 2014 and June 2022, the JBC has recruited 7618 ART treated families and 14 996 families of spontaneous completed or ongoing pregnancies. For the families enrolled up to 30 June 2020 (5061 ART families and 12 793 spontaneous conception families), we have completed data from their entry throughout their fertility care (for ART families), pregnancy, birth and 1 year after childbirth when child health was evaluated by the health examination. Data are hosted in the China National Birth Cohort (CNBC) study group and data access may be granted via an enquiry to [[email protected]]. Following the success of the first test-tube baby in the UK in 1978, the use of assisted reproductive technology for infertility treatment has increased steadily and resulted in more than 9 million children born after assisted reproductive technology (ART) worldwide.1,2 In China, approximately 15–25% of couples suffer infertility.3 Consequently, ART has become a standard and common practice in reproductive medicine clinics, and more than 1.6% of children in China are conceived through ART.4 Meanwhile, concerns are mounting over the safety of ART and its short- and long-term health impacts on maternal and fetal wellbeing. Emerging data from some, though not all, studies suggest that compared with spontaneous pregnancies, offspring conceived through ART are prone to adverse perinatal outcomes such as preterm birth, low birthweight, small size for gestational age and perinatal death.5–7 Further, offspring conceived through ART were reported to have an elevated risk of multiple diseases such as congenital heart defect, impaired vascular function, metabolic syndromes and cancer.8–13 Whether the elevated risks are attributable to parental characteristics related to infertility or to ART procedures warrants elucidation. The China National Birth Cohort (CNBC) study is a nationalwide birth cohort study involving 12 provinces and 30 medical centres, aiming to recruit 30 000 families receiving ART and 30 000 families with spontaneous pregnancies. As the primary study centre of the CNBC, Jiangsu centre initiated the establishment of the Jiangsu Birth Cohort (JBC), which is the subset of the CNBC, since April 2014 in three cities in Jiangsu (Nanjing, Suzhou and Changzhou). It was a family-based prospective study consisting of both ART-conceiving couples and naturally conceiving couples. The overarching goals of the JBC were to systematically assess the health and wellbeing among children conceived using ART as compared with those who were conceived spontaneously, and to clarify whether the elevated risks are attributable to parental characteristics related to infertility or to ART procedures, taking into consideration ART-related parental characteristics. In addition, the cohort was designed to facilitate the conduct of state-of-the-art ‘omics’ studies by collecting maternal, paternal and child biospecimens across the pre-, peri and postnatal stages, to systematically evaluate how environmental, genetic and clinical factors may influence birth outcomes and child health. The China National Birth Cohort (CNBC) study group was responsible for the data, and access may be granted upon the proposed projects being approved by the scientific committee consisting of senior researchers in the CNBC team. The JBC study recruited both ART conceiving and spontaneously conceiving families at three major hospitals in Jiangsu, namely the Women’s Hospital Affiliated to Nanjing Medical University (Nanjing), Suzhou Hospital Affiliated to Nanjing Medical University (Suzhou) and Changzhou Maternity and Child Health Care Hospital Affiliated to Nanjing Medical University (Changzhou). Owing to the great need of family-based studies in investigating intergenerational impacts of parental factors, the JBC was designed to collect both health-related information and biospecimens from the biological parents and offspring from both the ART conceiving and spontaneously conceiving families at ART clinics and obstetrics departments, respectively. The JBC identified potential study participants among those who consulted for ART treatment at ART clinics. Eligible participants were Chinese residents of the pre-specified cities who were going to receive in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) treatment. Those who planned to conceive by sperm donation, oocyte donation or intrauterine insemination were excluded from recruitment. Upon identification, the couples were invited to participate in the JBC before their first egg retrieval cycle. On the other hand, the spontaneously conceiving couples were invited and recruited from obstetrics departments when they established health record profiles during early pregnancy (8–14 weeks of gestation). Eligible couples were Chinese residents who planned to have routine antenatal clinical examinations in the same hospital. Obstetricians or professional health workers explained the objectives, procedures, potential benefits and confidentialities of the study to all eligible families. Informed written consent was obtained from those who agreed to participate. The JBC provided each family with a membership card and a unique family ID for further follow-up. The participants could withdraw from the cohort at any time. The study was approved by the ethics committees of Nanjing Medical University and the participating hospitals. Between April 2014 and June 2022, 11 330 eligible ART conceiving families and 28 306 eligible spontaneously conceiving families were identified. We invited 1000 ART conceiving families and 2000 spontaneously conceiving families annually, based on a convenience sampling method. As a result, 7618 ART and 14 996 spontaneously conceiving families agreed to participate. The participation rates were 95.2% for ART conceiving families and 93.7% for spontaneously conceiving families. Among recruited families, the mean age of ART couples was greater than that of spontaneously conceiving couples (women: 31.1 ± 4.3 years for ART vs 28.7 ± 3.8 years for spontaneous, P <0.001; men: 32.5 ± 5.2 years for ART vs 30.1 ± 4.5 years for spontaneous conception, P <0.001). Most of the participants were urban residents and had an education level of more than 12 years (Table 1). Baseline characteristics of couples enrolled in the Jiangsu Birth Cohorta ART, assisted reproductive technology; BMI, body mass index; SD, standard deviation Figures are number (%) or mean ± SD. For the families enrolled up to 30 June 2020 (5061 ART families and 12 793 spontaneous conception families), we have completed data from their entry throughout their fertility care (for ART families), pregnancy, birth and at 1 year after childbirth when 1-year-old health examination was performed (Figure 1). Among the ART participants, 90 did not undergo oocyte retrieval, 407 had retrieval but not a transplanted embryo. A total of 4564 couples completed 7154 embryo transplant cycles (IVF or ICSI), among which three were excluded due to loss to follow-up, 2475 ended in implantation failure and 725 pregnancies were only chemically detected by a beta human chorionic gonadotropin (β-hCG) blood test but not clinically visualised on ultrasound (biochemical pregnancy loss) (Figure 1). Among the remaining 3951 ultrasound-confirmed pregnancies, 79 ended in ectopic loss, 555 ended in miscarriage, 45 ended in induced abortion, 12 ended in stillbirth and 3260 successful pregnancies resulted in 3980 live births (Figure 1). Among the 12 793 spontaneous conception families enrolled at early pregnancy (8–14 weeks of gestation), 147 were excluded due to loss to follow-up or withdrawal (Figure 1). The remaining 12 647 families reported pregnancy outcomes, among which 12 410 pregnancies resulted in 12 500 live-born infants, 106 ended in miscarriage, 103 in induced abortion and 27 in stillbirth (Figure 1). Flow chart of the Jiangsu Birth Cohort. aThe follow-up status was reported for 5061 ART families and 12 793 spontaneous conception families enrolled before 30 June 2020. ART, assisted reproductive technology; IVF, in-vitro fertilization; ICSI, intracytoplasmic sperm injection; PL, pregnancy loss Detailed newborn characteristics were shown in Table 2. Among all the live-birth pregnancies, ART conceiving pregnancies have higher incidence of preterm birth than spontaneously conceiving pregnancies (18.1% vs 4.2%). Among the 3980 ART conceiving and 12 500 spontaneously conceiving live births, ART conceiving live births were more likely to have low birthweight (18.1% vs 2.9%). Newborn characteristics of the Jiangsu Birth Cohorta ART, assisted reproductive technology; SD, standard deviation. Figures are number (%) or mean ± SD. The JBC had seven neonatal deaths and three child deaths among the 3980 ART-conceived live births, and six neonatal deaths and six child deaths among the 12 500 spontaneously conceiving live births. The postnatal follow-up for the families enrolled up to 30 June 2020 has been completed, with 3238 ART conceived and 9964 spontaneously conceived infants being assessed by telephone at 42 days after birth; 3237 ART conceived and 8993 spontaneously conceived infants were assessed by telephone at 6 months after birth. One year after birth, 3318 ART conceived infants and 9026 naturally conceived infants visited the child health care clinic for health examination, with follow-up rate reaching 83.6% in ART conceived infants and 72.3% in spontaneously conceived infants (Figure 1). We compared the characteristics of families enrolled in the present study with the general population, using data obtained from the National Maternal Near Miss Surveillance System (NMNMSS) of Jiangsu province, which to some extent could represent the general population of Jiangsu province,14 and from the ART clinics of the three above-mentioned hospitals in Jiangsu, with women in the NMNMSS database between 2014 and 2019. Spontaneously conceiving women included in the JBC study had a similar mean age but a higher level of education. There was no significant difference in neonatal sex, whereas the incidences of preterm birth (gestational age <37 weeks), low birthweight (birthweight <2500 g) and macrosomia (birthweight ≥4000 g) in the JBC study were lower as compared with the NMNMSS database (Supplementary Table S1, available as Supplementary data at IJE online). When compared with the overall couples who received treatments between 2015 and 2022 in ART clinics of the three above-mentioned hospitals, the ART couples included in the JBC study showed similar mean age and maternal body mass index (BMI), but were more likely to have a higher level of education (Supplementary Table S2, available as Supplementary data at IJE online). Once enrolled, the ART couples were followed through the whole fertility treatment procedure including oocyte pick-up (ART Visit 1), embryo transplantation (ART Visit 2), blood β-hCG test (ART Visit 3) and ultrasound scan to confirm pregnancy status (ART Visit 4) (Figure 2). The ART couples were asked to complete standardized and structured questionnaires and they donated biological samples including blood, urine, follicular fluid, sperm and seminal plasma with the follow-up. The clinical data were collected from medical records (Figure 2). Women who showed negative pregnancy results, biochemical pregnancy or early abortion usually entered next embryo transfer cycle or egg retrieval cycle, which were followed afterwards (Figure 2). The recruitment and follow-up in the Jiangsu Birth Cohort. IVF, in-vitro fertilization; ICSI, intracytoplasmic sperm injection; GW, gestational week Spontaneously conceiving couples were recruited during early pregnancy (8–14 weeks of gestation) at obstetrics clinics. Baseline information and blood and urine specimens were collected from both the biological mother and father. The clinical data were collected from medical records (Figure 2). Thereafter, all ART and spontaneous pregnancy couples were followed with the same protocol. They were seen at another two antenatal care visits, once during mid-pregnancy (Antenatal Visit 1: 22–26 weeks of gestation), and again during late pregnancy (Antenatal Visit 2: 30–34 weeks of gestation). During these visits, questionnaire surveys were conducted and blood and urine samples from women were collected. Detailed clinical data including physical examination, clinical tests and pregnancy complications (i.e. gestational diabetes mellitus, hypertensive disorder complicating pregnancy) were extracted from medical records (Figure 2). During parturition (Delivery Visit), pregnancy complications and birth outcomes (i.e. premature delivery, birthweight and birth defects) were collected from medical records. Infants were examined as newborns at obstetrics clinics and their anthropometric parameters were measured (Figure 2). During the postnatal period, mothers were interviewed by telephone approximately 42 days after birth (Postnatal Visit 1) and 6 months after birth (Postnatal Visit 2) to complete a structured questionnaire collecting data on infants’ feeding patterns, sleep patterns and diseases. When children reached the ages of 1 year (Postnatal Visit 3) and 3 years (Postnatal Visit 4), they would be invited along with their mothers to visit the child health care department at the hospital where they were born. The hospitals would offer physical examinations, anthropometric measurement and neurodevelopment assessments (Figure 2). Once enrolled, women and their partner were asked to complete the standardized and structured questionnaires by face-to-face interview covering their demographic and socioeconomic data, lifestyle and behavioural traits (i.e. smoking, alcohol consumption and physical activity), occupational exposure, reproductive history and disease and medication history (Table 3). All couples were asked to complete a self-administered Food Frequency Questionnaire (FFQ) to access their habitual dietary habits during the past 1 month. The 20-item Centre for Epidemiologic Studies Depression Scale (CES-D), 10-item Perceived Stress Scale (PSS-10) and a 20-item Self-rating Anxiety Scale (SAS) captured their mental health status.15–17 The Pittsburgh Sleep Quality Scale was used to evaluate maternal sleep quality (Table 3).18 During antenatal visits (one during 22–26 weeks of gestation, and one during 30–34 weeks of gestation) information on the mother’s lifestyle, behavioural traits, health and diseases and medication during pregnancy was collected at the two visits (Table 3). Summary of collected data from the questionnaires and medical records and collected biological samples during baseline, antenatal and postanal follow up. A, ART-conceived; S, spontaneous-conceived; ART, assisted reproductive technology; BSID-III, Bayley Scales of Infant Development, 3rd Edition; GDS, Gesell Development Scale. For ART couples, the core clinical data were collected from medical records at ART clinics, including a multiple hormone examination for women before ART procedure, a semen quality examination for men, detailed infertility diagnosis, embryo type, embryo score and detailed protocol of ART treatment (Supplementary Table S3, available as Supplementary data at IJE online). After the pregnancy, clinical data were available for ART-treated and spontaneously conceiving women, such as complete blood count, urinalysis, blood biochemical examination, obstetric complications, prescribed medication and adverse pregnancy outcomes (for example miscarriage and stillbirth) (Table 3; and Supplementary Table S4, available as Supplementary data at IJE online). After delivery, the birth outcomes with detailed obstetric data (i.e. birthweight, birth defects, delivery mode) were extracted from medical records (Table 3). All couples’ peripheral blood and urine samples were collected at enrolment. Follicular fluid, sperm and seminal plasma were collected from ART-treated couples on the day of oocyte pick-up. During mid and late pregnancy, peripheral blood was collected repeatedly from women. The amniotic fluid, cord blood, meconium and placental tissue were also collected at delivery (Table 3). The urine samples were stored at −20 °C and other biospecimens stored at −80 °C, before being retrieved and thawed for assays. All cohort children were offered free child health examinations from infancy to early childhood, as scheduled. Approximately 42 days after delivery, mothers received telephone requests to complete questionnaires that covered a broad range of items about their children including anthropometric parameters, breastfeeding, dietary and supplements intake, behaviour traits and sleep quality, diseases, injuries and medication usage (Table 3). Six months after delivery, mothers were followed one more time via telephone. Then cohort children were invited to visit the child health care clinic at ages 1 and 3 years along with their mothers. During each clinic visit, physical examination, clinical examinations and blood test were conducted (Table 3). Trained health professionals examined and evaluated children’s neurodevelopment using standardized tools (Gesell Development Scale, GDS; Bayley Scales of Infant and Toddler Development, Version-III, Bayley-III) at the ages of 1 and 3 years (Table 3).19,20 The children’s fingertip blood and feces samples were collected at their 1-year and 3-year clinic visits (Table 3). All data collection and management were based on the Cloud Cohort System for the JBC a designed for the has three participants questionnaire and quality and questionnaire All follow-up data was performed in time. For data only have access to the The has unique designed for the questionnaire for example to items and to during data The data that the standardized were and the JBC study has assessed the differences in health and wellbeing between children born after ART those born after spontaneous pregnancies. We first compared the incidence of total birth both major and defects) between ART children and naturally conceived and that ART an increased risk for birth in offspring vs that for of the risk of birth the of further the safety of ART including the number of embryo In a study of ART and naturally conceived we reported that the children conceived via ART more than their who were born after spontaneous Further, we have associated the of with the increased risk of congenital heart disease in data, we in both parents and offspring. data showed that infants born after ART had than spontaneously conceived of parental and other study that the was attributable to the transfer of In the the and the of the in ART we and in ART which was by ART Following up these for 6 months after their births, we further the of on In studies of children’s neurodevelopment evaluated by the Gesell Development Scale or we reported a between antenatal and an increased risk of infants being in at 1 year of information when the benefits and potential risks of maternal antenatal In addition, we identified to and maternal dietary and maternal as factors for neurodevelopment at 1-year-old follow-up. study has the family-based study both ART-treated pregnancies and spontaneous pregnancies, and the of maternal and child health between ART conceiving and spontaneously conceiving and the of of pregnancy outcomes and child health. the JBC and repeatedly health information as as biospecimens from parents and which into in early the of the for (i.e. and in to blood and urine placental and cord blood are also collected. Follicular fluid, sperm and seminal plasma samples are collected from the ART The collected biospecimens are a resource for studies on and for of and the of data on health and biospecimens collected with a unique to evaluate the early environmental, behaviour and status factors and of the cohort the that families with spontaneous conception are enrolled during early pregnancy than adverse pregnancy outcomes in early pregnancy, early miscarriage, are not in the The of adverse pregnancy outcomes among ART-treated women has been and cohort is established with the to assess health and wellbeing in children born after conception We the that couples are included in the spontaneous conception as the and time to conception were not among It of the risk of adverse health outcomes in children born after ART, is when with those born to spontaneously conceiving families. In addition, families participating in the JBC were from urban and on from higher socioeconomic the ART families. The JBC a of throughout pregnancy and but risk of of data due to be in some couples, but not those who are in reproductive be more likely to potential such as family mothers were of status in the which likely resulted in the of ART is data are available to with projects that the and overall of the through a and a completed of the to [[email protected]]. information be on the study or through to [[email protected]]. regarding data be to [[email protected]]. of University of for and of University of of National of Health Hospital Affiliated to University of of of National University of study of and Nanjing Medical and Hospital Affiliated to Nanjing Medical Suzhou Hospital Affiliated to Nanjing Medical Changzhou Maternity and Child Health Hospital Affiliated to Nanjing Medical The study was approved by the ethics committees of Nanjing Medical University of the Supplementary data are available at IJE and conceived of the study and were in of overall and and designed the and conducted the data and and the protocol. and performed data quality and and the data and the and obtained for the establishment of the All the of the to be cohort is by the China National Development the National of China and the for of the National of China We in of and of Chinese of in of Chinese of in of Chinese of in University in Maternity and Hospital of China of in Centre for Hospital Affiliated to for the birth cohort at the and with the and of the We in the of for and scientific The is to the participants in the to of the group of the China National Birth Cohort.

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