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\begin{document}

\title{Differences in the success of prenatal diagnosis of birth defects
associated with singleton and multiple pregnancies: an observational
study of more than 1.9 million births in Zhejiang Province, eastern
China, during 2012--2018}



\author[1]{Shankuan Zhu}%
\author[1]{Lijin Chen}%
\author[2]{Hong Wen}%
\author[2]{Haifeng Lou}%
\author[1]{Qingcong Kang}%
\author[2]{Xinning Chen}%
\author[2]{Danqing Chen}%
\author[2]{Xiaohui Zhang}%
\affil[1]{Zhejiang University}%
\affil[2]{Zhejiang University School of Medicine Women's Hospital}%


\vspace{-1em}



  
  \date{May 26, 2024}


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\selectlanguage{english}
\begin{abstract}
Objective: To characterize differences in the prenatal diagnosis of
birth defects (BDs) associated with singleton and multiple pregnancies.
Design: An observational study conducted using data from a BDs
surveillance system. Setting: Eastern China. Population: A total of
54,572 babies with BDs, born in 90 hospitals located in 30 regions of
Zhejiang Province between 2012 and 2018. Methods: BDs were diagnosed by
obstetricians using ultra sonographic, genetic tests et al., on the
basis of the ICD 10th Revision (Q00--Q99). Main outcome measures:
Differences in incidence and characteristics of BDs associated with
singleton and multiple pregnancies. Multivariate logistic regression
models were constructed to characterize relationships between the
prenatal diagnosis of BDs and multiple pregnancies, with adjustment for
covariates. Results: Totals of 49,872 singletons and 3,324 multiple
pregnancies with BDs were analyzed. The mean incidences of BD for single
and multiple pregnancies were 26.29 and 109.99 per 1,000 births,
respectively (\selectlanguage{greek}χ\selectlanguage{english}2=7600, P\textless{}0.001). After adjustment for
covariates, BDs associated with multiple pregnancies were less likely to
be diagnosed prenatally (adjusted OR: 0.36, 95\% CI: 0.32--0.40); as
were congenital heart defects, congenital hydrocephalus, cleft lip with
cleft palate, congenital talipes equinovarus, cleft lip without cleft
palate, limb reduction defects, congenital diaphragmatic hernia, trisomy
21 syndrome, congenital malformation of the urinary system, and other
chromosomal malformation, compared with singletons with BDs.
Conclusions: Multiple pregnancy is associated with a significantly
higher risk of BD, but a significantly lower prenatal diagnosis rate.
Therefore, the healthcare of women with multiple pregnancy and their
fetuses should be strengthened.%
\end{abstract}%



\sloppy


\textbf{Introduction}

Birth defects (BDs) are identified in approximately 1 in 300 women who
undergo a routine third trimester ultrasonographic
scan\textsuperscript{1}, and the global prenatal diagnosis rates vary
from 15\% to 86\%, according to region, BD category, and the method of
diagnosis.\textsuperscript{2-5} With the rapid development of the
technology for prenatal examinations, a wide range of methods have
become available that improve the prenatal diagnosis of BDs. These
include prenatal ultrasonography, biochemical screening, invasive
techniques such as amniocentesis and chorionic villus sampling (CVS),
non-invasive prenatal testing (NIPT) using cell-free fetal DNA, and gene
diagnose, as well as autopsy.\textsuperscript{6, 7}

The prevalence of multiple birth in China and internationally has been
increasing, such that it is now between 0.9\% and 3.3\%
worldwide.\textsuperscript{8-13} This can be, at least in part,
attributed to advancing maternal age and the use of assisted
reproductive technologies (ARTs). The accurate prenatal diagnosis of BD
associated with multiple pregnancy remains challenging, but few studies
have been conducted. Club foot, Down syndrome, and trisomy 18 have been
reported to be less frequently diagnosed in twins than in singleton
fetuses,\textsuperscript{14-18} whereas Boyle \emph{et al.} showed that
multiple and singleton pregnancies were associated with comparable rates
of prenatal diagnosis.\textsuperscript{19} The methods used for prenatal
diagnosis often differ for singleton and multiple pregnancies. For
example, the ultrasonographic survey of general anatomy and
echocardiography for the identification of congenital heart disease are
recommended for twins. However, a prenatal diagnosis of aneuploidy is
commonly made on the basis of the analysis of maternal serum markers,
which is not specific for a particular fetus.\textsuperscript{18,20} In
addition, most previous studies were of small numbers of twins with
specific malformations and used specific screening methods that can be
affected by differences in technical skill level and up-to-date
knowledge.

In Zhejiang, a province located in eastern China, the prevalence of twin
births increased from 2.27\% in 2008 to 3.01\% in
2013.\textsuperscript{11} A provincial BD surveillance system has
existed there for over 30 years, and this provides a useful platform for
BD-related researches. In this study, we compared the prenatal diagnosis
of BDs for singleton and multiple pregnancies. We anticipate that the
findings should assist the prenatal diagnosis of BDs, especially in
women with multiple pregnancies.

\textbf{Methods}

Study design and study population

We performed an observational study using monitoring data collected as
part of the BD surveillance system of Zhejiang Province, China between
2012 and 2018. This system encompassed all births, including live birth,
early fetal loss, stillbirth, and neonatal deaths within 7 days of
birth, that involved a BD and occurred in 90 hospitals located in the 30
regions of Zhejiang Province, which covers one-third of the total number
of births in the province. A total of 54,572 births associated with a BD
were recorded in the system between 2012 and 2018. All the mothers
included in the system underwent routine antenatal health care visits at
least five to ten times during their pregnancies, in line with the
antenatal health care regulations enacted by China's Ministry of
Health.\textsuperscript{21} Questionnaire surveys regarding
socio-demographic data (including maternal age, domicile, and
education), obstetric characteristics (including maternal parity,
singleton \emph{vs} . multiple pregnancy, and prenatal diagnosis), and
birth data (including birth weight, birth outcome, and sex) were
conducted by medical staff in each of the hospitals. Quality control was
performed at the local hospital and provincial levels.

For the purposes of the present study, participants for whom data were
missing regarding whether they had a singleton or multiple pregnancy (n
= 62), period of diagnosis (prenatal or postnatal) (n = 40), the timing
of screening (in which gestational week) (n = 548), the socioeconomic
status of the mother (n = 36), maternal parity (n = 524), or infant sex
(n = 166) were excluded. Thus, ultimately, 53,196 births were included
in the analyses.

Criteria for the diagnosis of BDs and definitions of parameters

BDs were diagnosed by obstetricians using ultrasonographic, genetic,
pathologic, clinical, and laboratory tests, on the basis of the
International Statistical Classification of Diseases and Related Health
Problems, 10th Revision (Q00--Q99).\textsuperscript{22} We studied 25
types of BD, including congenital heart defects (CHDs), congenital
malformation of the urinary system, cleft lip with cleft palate, cleft
lip without cleft palate, cleft palate without cleft lip, polydactyly,
syndactyly, congenital hydrocephalus, congenital talipes equinovarus,
congenital microtia, other malformation of the external ear, trisomy 21
syndrome, other chromosomal abnormalities, hypospadias, anencephaly,
spina bifida, encephalocele, omphalocele, limb reduction defect,
congenital atresia of the rectum and anus, congenital diaphragmatic
hernia, gastroschisis, congenital esophageal atresia, conjoined twins,
and exstrophy of the urinary bladder.

We categorized mothers according to their age (\textless{}20, 20--34,
and [?]35 years); whether they lived in a urban or rural environment;
whether their educational level was primary or below, middle or high
school, or college or above; parity (0, 1, or [?]2); whether their
offspring were male, female, or of unknown sex; and whether the BD of
their child was diagnosed prenatally or postnatally.

Statistical analyses

Maternal age is presented as mean and standard deviation (SD).
Categorical data are presented as number (N) and percentage. The
incidence of BD was calculated as the number of BDs per 1,000 births.
Differences in the incidence of BD and the characteristics of the BDs
associated with singleton and multiple pregnancies were analyzed using
ANOVA with respect to maternal age and the chi-square test for
categorical variables. The chi-square test was also used to identify
differences in the prenatal diagnosis rates for BDs associated with
singleton and multiple pregnancies.

Multivariate logistic regression models were constructed to evaluate the
relationships between the prenatal diagnosis of BDs with multiple
pregnancies, after adjustment for the year of birth, maternal age group,
and maternal domicile. For the BDs that were diagnosed prenatally, we
further categorized the time of diagnosis as \textless{}28 or [?]28 weeks
of gestation, then chi-square testing was used to identify differences
in the timing of diagnosis between singleton and multiple pregnancies,
considering BDs in their entirety and specific types of BD that were
found to significantly differ in their prenatal diagnosis rate.

All analyses were carried out using STATA 13 (StataCorp, College
Station, TX, United States).

Patient and public involvement

No patients were involved in setting the research question or the
outcome measures, nor were they involved in developing plans for the
design of this study or interpretation of results.

\textbf{Results}

Differences in the incidence and characteristics of BDs between
singleton and multiple births

A total of 53,196 births between 2012 and 2018 that were associated with
BDs were included in the analysis, of which 49,872 were singletons and
3,324 were multiple births (Table 1). The mean incidence of BD for
multiple births was 109.99 per 1,000 births, which was significantly
higher than that for singleton births (26.29 per 1,000 births;
\selectlanguage{greek}χ\selectlanguage{english}\textsuperscript{2}=7600, \emph{P} \textless{}0.001). Significant
differences were also found between singleton and multiple births
associated with BDs with respect to mean maternal age, the distribution
of maternal age group, maternal domicile, maternal education, maternal
parity, and infant sex (all \emph{P} \textless{}0.05). Compared with
women who had singletons with BDs, those who had multiple pregnancies
associated with BDs were more likely to be older, live in an urban
environment, have a college-level education or above, and be
multiparous.

Differences in the prenatal diagnosis rates of BDs between singleton and
multiple pregnancies

The prenatal diagnosis rate of BDs associated with multiple pregnancies
was 14.38\%, which was significantly lower than that associated with
singletons (32.00\%; \selectlanguage{greek}χ\selectlanguage{english}\textsuperscript{2} = 452.94,\emph{P}
\textless{}0.001). A significantly lower prenatal diagnosis rate was
found not only for BDs in their entirety associated with multiple births
(\selectlanguage{greek}χ\selectlanguage{english}\textsuperscript{2} = 452.94, \emph{P} \textless{}0.001), but also for
10 types of BD (all \emph{P} \textless{}0.05) (Table 2). These were
congenital heart defects (\selectlanguage{greek}χ\selectlanguage{english}\textsuperscript{2} = 213.89,\emph{P}
\textless{}0.001), congenital hydrocephalus (\selectlanguage{greek}χ\selectlanguage{english}\textsuperscript{2} =
22.05, \emph{P} \textless{}0.001), cleft lip with cleft palate
(\selectlanguage{greek}χ\selectlanguage{english}\textsuperscript{2} = 50.23, \emph{P} \textless{}0.001), congenital
talipes equinovarus (\selectlanguage{greek}χ\selectlanguage{english}\textsuperscript{2} = 5.37,\emph{P} =0.020), cleft
lip without cleft palate (\selectlanguage{greek}χ\selectlanguage{english}\textsuperscript{2} = 18.84, \emph{P}
\textless{}0.001), limb reduction defects (\selectlanguage{greek}χ\selectlanguage{english}\textsuperscript{2} = 7.74,
\emph{P} =0.005), congenital diaphragmatic hernia (\selectlanguage{greek}χ\selectlanguage{english}\textsuperscript{2}
= 12.73, \emph{P} \textless{}0.001), trisomy 21 syndrome
(\selectlanguage{greek}χ\selectlanguage{english}\textsuperscript{2} = 28.40, \emph{P} \textless{}0.001), congenital
malformation of the urinary system (\selectlanguage{greek}χ\selectlanguage{english}\textsuperscript{2} = 29.90,
\emph{P} \textless{}0.001), and other chromosomal malformation
(\selectlanguage{greek}χ\selectlanguage{english}\textsuperscript{2} = 4.91, \emph{P} =0.027).

Relationships between the prenatal diagnosis rates for all and types of
BD and multiple pregnancies

The crude and adjusted relationships between the prenatal detection
rates for all and specific types of BD were summarized as odds ratios
and \emph{P} -values. The 10 types of BD that showed significant crude
or adjusted associations are shown in Table 3. After adjustment for year
of birth, maternal age group, and maternal educational level,
significantly lower prenatal diagnosis rates for BDs associated with
multiple births remained for BDs as a whole (adjusted odds ratio
{[}OR\emph{\textsubscript{adj}} {]} = 0.36, 95\% confidence interval
{[}CI{]}: 0.32--0.40, \emph{P} \textless{}0.001), congenital heart
defects (OR\emph{\textsubscript{adj}} = 0.32, 95\% CI:
0.27--0.38,\emph{P} \textless{}0.001), congenital hydrocephalus
(OR\emph{\textsubscript{adj}} = 0.24, 95\% CI: 0.13--0.45,\emph{P}
\textless{}0.001), cleft lip with cleft palate
(OR\emph{\textsubscript{adj}} = 0.18, 95\% CI: 0.11--0.30,\emph{P}
\textless{}0.001), congenital talipes equinovarus
(OR\emph{\textsubscript{adj}} = 0.50, 95\% CI: 0.27--0.92,\emph{P}
=0.025), cleft lip without cleft palate (OR\emph{\textsubscript{adj}} =
0.27, 95\% CI: 0.14--0.50,\emph{P} \textless{}0.001), limb reduction
defects (OR\emph{\textsubscript{adj}} , = 0.33 95\% CI:
0.16--0.68,\emph{P} =0.003), congenital diaphragmatic hernia
(OR\emph{\textsubscript{adj}} = 0.18, 95\% CI: 0.06--0.58,\emph{P}
=0.004), trisomy 21 syndrome (OR\emph{\textsubscript{adj}} = 0.09, 95\%
CI: 0.04--0.23, \emph{P} \textless{}0.001), congenital malformation of
the urinary system (OR\emph{\textsubscript{adj}} = 0.30, 95\% CI:
0.19--0.47, \emph{P} \textless{}0.001), and other chromosomal
malformation (OR\emph{\textsubscript{adj}} = 0.22, 95\% CI:
0.06--0.86,\emph{P} =0.030).

Differences in the timing of the prenatal diagnosis of BDs associated
with singleton and multiple births

Table 4 shows the timing of the prenatal diagnosis of BDs associated
with singleton and multiple births. For BDs as a whole that were
associated with multiple pregnancies, 70.08\% of BDs were diagnosed
before 28 weeks of gestation, which was significantly lower than the
74.82\% diagnosis rate for BDs associated with singletons
(\selectlanguage{greek}χ\selectlanguage{english}\textsuperscript{2} = 5.51, \emph{P} =0.019). The significantly lower
rate of early diagnosis of BDs associated with multiple pregnancy was
also found for cleft lip with cleft palate (\selectlanguage{greek}χ\selectlanguage{english}\textsuperscript{2} =
7.75,\emph{P} =0.005), trisomy 21 syndrome (\selectlanguage{greek}χ\selectlanguage{english}\textsuperscript{2} =
5.46,\emph{P} =0.020), and congenital malformation of the urinary system
(\selectlanguage{greek}χ\selectlanguage{english}\textsuperscript{2} = 10.07, \emph{P} =0.002).

Techniques used to diagnose BDs

Table 5 shows the techniques that were used to diagnose BDs. For BDs as
a whole, 73.45\% were diagnosed using ultrasonography, 30.02\% were
diagnosed using clinical tests, and 4.86\% were diagnosed using
chromosomal testing. Ultrasonography was the technique that was most
commonly used for the identification of congenital heart defects
(93.00\%), congenital hydrocephalus (94.11\%), cleft lip with cleft
palate (86.50\%), cleft lip without cleft palate (72.54\%), limb
reduction defects (70.93\%), congenital diaphragmatic hernia (85.93\%),
and congenital malformation of the urinary system (93.32\%). Clinical
testing was the technique that was most commonly used for congenital
talipes equinovarus (56.04\%), and chromosomal testing was the technique
that was most commonly used to diagnose trisomy 21 syndrome (85.06\%)
and other chromosomal malformations (79.88\%).

\textbf{Discussion}

Main findings

Although the findings made to date regarding the incidence of BDs
associated with multiple and singleton pregnancies have been
inconsistent, most studies have shown that multiple pregnancies are
associated with a higher risk of BD than singletons.\textsuperscript{23,
24} However, univariate analysis alone was performed in the previous
studies, and they did not categorize the BDs and had small sample sizes.
In contrast, we studied multiple types of BD and the study had a large
sample size of more than 1.9 million births, which should have
facilitated the drawing of reliable conclusions. We found that multiple
pregnancy is associated with a significantly higher risk of and a lower
prenatal diagnosis rate for BDs than singleton pregnancy.

Strengths and limitations

The present study had several limitations. First, owing to limited
information regarding the use of ARTs in the database, we could not
adjust the data for the effect of ARTs. Several previous studies have
shown that the incidence of malformations is higher in multiple
pregnancies that are achieved using \emph{in vitro} fertilization or
intracytoplasmic sperm injection than in singletons. Second, most of the
BDs associated with multiple pregnancies were isolated fetal
abnormalities, because multiple abnormalities may lead to stillbirth or
abortion.\textsuperscript{25} Because the database does not contain
information regarding spontaneous abortion, artificial abortion, or
stillbirth, this may have skewed the analysis of the BD data. Thus, the
high incidence of BDs associated with multiple pregnancies may have been
at least in part determined by selection bias, because clinicians are
more careful with respect to twin pregnancies and may therefore have
conducted more diagnostic tests to check for fetal defects. These
limitations should be addressed in the design of future studies.

Interpretation

Mastroiacovo and Li previously analyzed the incidence of BDs, and found
that it is significantly higher in twins than in
singletons.\textsuperscript{26} In the present study, we also found that
the incidence of BD associated with multiple pregnancies is more than
four times higher than that associated with singletons. The previous
study also showed higher incidences of a number of types of BD, such as
CHD, congenital hydrocephalus, and cleft lip with or without cleft
palate. Table 1 also shows that mothers of children with BDs that were
derived from multiple pregnancies were more likely to be older, to live
in an urban environment, to have a college education or above, and to be
multiparous, than mothers who gave birth to singletons. This may be
explained by the use of ARTs. Although we could not collect information
regarding the use of ARTs in the present study, previous studies have
shown that the age of women who are using ARTs in China is increasing,
and that children born as a result of the use of some ARTs are at higher
risk of BD than those that result from natural
conception.\textsuperscript{27, 28}

There was also a significantly lower prenatal diagnosis rate for BDs
that were associated with multiple pregnancies than for those that were
associated with singletons, and this applied to 10 specific types of BD.
Eight of these were structural malformations that are normally
identified in the second or third trimester. Shielding of one fetus by
another in multiple pregnancies might account for this lower prenatal
diagnosis rate. The study by Razavi \emph{et al} . yielded consistent
results, because they found that the accuracies of the prenatal
diagnosis of congenital clubfoot in fetuses that were singletons or part
of multiple pregnancies were 68.8\% and 35\%, respectively.

With regard to chromosomal malformations, the accuracy of screening was
also lower for multiple pregnancies, despite the government of Zhejiang
Province providing free serological tests as part of prenatal healthcare
during the first or second trimester. At present, nuchal translucency
thickness (NT) in combination with NIPT is the most effective
non-invasive method of screening for Down syndrome in multiple
pregnancies,\textsuperscript{29} but this must be performed by
physicians experienced in maternal and fetal care. Invasive prenatal
methods of screening for chromosomal malformations in multiple
pregnancies, which include CVS or amniocentesis, should also be
performed by an experienced physician, because of the difficulty and
risks associated.

There are few centers in Zhejiang Province where prenatal diagnosis can
be performed for multiple pregnancies, but the Prenatal Diagnosis
division of the China Ultrasound Association has generated standards for
the prenatal ultrasonographic diagnosis of six types of BD and trained
ultrasonographers for this purpose. This probably explains why there
were no significant differences in the prenatal diagnosis rates of spina
bifida, encephalocele, anencephaly, gastroschisis, or omphalocele
between singletons and multiple pregnancies. However, owing to the
limitations of the available methods of screening, the prenatal
diagnosis rates for anal atresia, microtia, and esophageal atresia are
extremely low: these defects can only be diagnosed using non-specific
signs, with or without magnetic resonance imaging
(MRI).\textsuperscript{30,} \textsuperscript{31} Consequently, there
were no significant differences in the prenatal detection rates for
these three defects between singleton and multiple pregnancies. Given
the greater technical challenge in prenatally diagnosing BDs in multiple
pregnancies, we suggest that women with multiple pregnancies should be
cared for from as early a date as possible in institutions in which the
staff are capable of performing accurate prenatal diagnosis in women
with multiple pregnancies. In addition, physicians should be more
cautious when discussing prenatal diagnoses for women with multiple
pregnancies and choose the most accurate non-invasive prenatal screening
methods to avoid misdiagnoses. Finally, multiple methods of screening
should be used for multiple pregnancies, such as ultrasonography, MRI,
and genetic testing, as described for a combination of neurological and
cardiac defects\textsuperscript{32} to improve the prenatal diagnosis
rate for BDs.

Of all the BDs diagnosed prenatally, the proportion diagnosed before 28
weeks of gestation was significantly lower in multiple pregnancies than
in singleton pregnancies, and the same finding was also made for cleft
lip with cleft palate, trisomy 21 syndrome, and congenital malformation
of the urinary system. Congenital urinary system malformations, such as
hydronephrosis, duplication of the kidney, or genital abnormalities,
normally become apparent during the second or third trimester and are
identified during the third trimester.\textsuperscript{33} However,
orofacial cleft may be difficult to confirm in multiple pregnancy
because of the fetal position. Therefore, women with multiple
pregnancies should be informed of the limitations of prenatal
ultrasonographic screening for structural malformations of the fetus
during the first and second trimesters, and should be made aware of the
importance of screening for structural malformations during the third
trimester, even if such screening was negative during the first. With
respect to euploidy, a previous study found no significant difference in
the incidence of trisomy 21 between singletons and multiple
births.\textsuperscript{34} We speculate that the limitations of NIPT,
the lack of experienced personnel in many centers, sampling error,
and/or cross-contamination of samples collected during invasive prenatal
diagnostic procedures may be responsible for delays in diagnoses.

The high incidence of structural malformations associated with multiple
pregnancies can be explained not only by of the larger number of
fetuses, but also by the existence of specific complications associated
with multiple births, especially in monochorionic twins. With the
development of ultrasonographic methods of examination and the
increasing availability of various diagnostic techniques, increasing
numbers of reports have been published regarding BDs in association with
multiple pregnancies. Table 5 shows that the methods used for the
prenatal diagnosis of defects in multiple pregnancies mainly comprise
ultrasonography, clinical history or physical examination, genetic
testing, and biochemical testing. We found that the prenatal
ultrasonographic diagnosis rates for CHD and hydrocephalus were very
high, and indeed, in recent years, the methods of prenatal diagnosis,
such as ultrasonography, serum biochemical screening, CVS, and
amniocentesis, have improved substantially. More recently, great
advances have been made in NT, NIPT, and ultrasonographic screening for
structural defects in early pregnancy. The improvements in these
techniques, accompanied by improvements in prenatal healthcare, account
for the declining incidences of BDs and chromosomal anomalies. However,
we should also be aware that the prenatal diagnosis of structural
malformations is more difficult in multiple pregnancies, because one
fetus may obscure another. Therefore, obstetricians should inform
pregnant women that the prenatal diagnosis of defects is not always
highly accurate, especially in multiple pregnancies.

\textbf{Conclusion}

Multiple pregnancy is associated with a significantly higher risk of BD
and a significantly lower prenatal diagnosis rate for BDs than singleton
pregnancies. Therefore, more effort should be put into the prenatal
healthcare of women with multiple pregnancies.

\textbf{Disclosure of interests}

The authors have declared that no competing interests exist.

\textbf{Contribution to authorship}

XZ and LC contributed to the design. LC conducted data analysis. LC, HW
and HL drafted the first version of the manuscript. XZ and SZ supervised
this work. XC, QC, DC, SZ and XZ reviewed and edited the manuscript. All
authors contributed to the content and critical revision of the
manuscript and agreed to submit the manuscript for publication.

\textbf{Details of ethics approval}

This study was approved by the Ethics Committee of the Women's Hospital,
Zhejiang University School of Medicine (number: 2018KY036).

\textbf{Funding}

This work was supported by grants from the Cyrus Tang Foundation
{[}419600-11102{]}, the China Medical Board (CMB) Collaborating Program
{[}12-108 and 15-216{]}, and the National Key Research and Development
Plan {[}2018YFC1002700 and 2018YFC1002702{]}. SZ is funded by the Cyrus
Tang Foundation (http://www. tangfoundation.org/), CMB Collaborating
Program (\emph{https://chinamedicalboard.org/}), and Hsun K.Chou Fund of
Zhejiang University Education Foundation {[}419600-11107{]}. XZ works on
a project that is supported by the National Key Research and Development
Plan. The funders had no role in the study design, data collection and
analysis, decision to publish, or preparation of the manuscript.

\textbf{Acknowledgements}

We would like to thank all the obstetricians, pediatricians, and
participants involved in the BD surveillance system for their generous
help during the data gathering process.

\textbf{Data sharing}

The data cannot be shared publicly because we are obligated to protect
the privacy of participants within the BD surveillance system of
Zhejiang Province, China. Data are available from the Chronic Disease
Research Institute, School of Public Health, and Women's Hospital,
Zhejiang University School of Medicine (zjfb@zju.edu.cn) for researchers
who meet the criteria for access to confidential data.

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