Vital Surveillances National Perinatal Prevalence of Selected Major Birth Defects — China , 2010 − 2018

Introduction:  An  estimated  of  900,000  infants  are born  with  birth  defects  each  year  in  China  causing  a substantial disease burden. This study aimed to depict the  epidemiological  patterns  of  selected  major  birth defects  in  Chinese  perinatal  births  and  provide important baseline data for future prevention. Methods:  Data  from  the  Chinese  Birth  Defects Monitoring  Network  (CBDMN)  during  2010–2018 were used to analyze the epidemiological pattern in the prevalence  of  15  major  birth  defects  and  the  trends over time. Results:  In  the  period  of  2010–2018,  the  top  10 most  frequently-occurring  birth  defects  in  China included  congenital  heart  diseases  (CHDs), polydactyly,  cleft  lip  with  or  without  palate  (CL/P), club  foot,  syndactyly,  hydrocephalus,  hypospadias, limb  reduction  defects  (LRD),  anotia/microtia,  and anorectal  atresia/stenosis.  There  was  a  decrease  in  the prevalence  of  neural  tube  defects,  CL/P, hydrocephalus,  LRD,  gastroschisis,  and  omphalocele, but  there  were  increases  in  the  prevalence  of  CHDs, cleft  palate,  hypospadias,  club  foot,  polydactyly,  and syndactyly. The prevalence of most birth defects varied significantly  by maternal  age,  area  types  (urban/rural), and geographic regions. Conclusions  and  Implications  for  Public  Health Practice:  The  findings  indicated  that  the comprehensive prevention of birth defects should focus on  these  selected  birth  defects,  elderly  pregnant women, rural areas, and western regions. INTRODUCTION Birth  defects  (BDs)  affect  4%–8%  of  births worldwide  (1).  The  estimated  prevalence  in  China  is China CDC Weekly Chinese Center for Disease Control and Prevention CCDC Weekly / Vol. 2 / No. 37 711 5.6%,  with  approximately  900,000  infants  born  with various defects each year (2). BDs are the leading cause of  infant  mortality  in  China,  accounting  for  about 20% of deaths (2–3). Other adverse outcomes include premature  death  in  early  life,  disabilities,  impaired physical  and  mental  well-being,  negative  effects  on quality  of  life,  which  result  in  a  substantial  disease burden on families and societies (1–2,4). According to the Global Burden of Disease Study in 2017, BDs are the tenth leading cause  of  disability-adjusted life  years (DALYs) among women and ninth among men (5). As a  global  public  health  problem,  BDs  have  been  of major  concern  to  governments,  health  professionals, and the public. Although  several  genetic,  behavioral,  and environmental  risk  factors  have  been  identified,  the underlying  causes  of  most  BDs  were  unclear  (1–2). BDs surveillance played an important role in exploring possible  risks,  monitoring  dynamic  changes  in prevalence,  and  providing  evidence  for  interventions (4). With rapid socioeconomic development in China, birth  policies,  family  income,  maternal  nutrition, prenatal  care,  and  socioeconomic  and  demographic factors have varied significantly. However, reliable data on  the  prevalence  of  major  BDs  was  limited.  Using 2010–2018  data  extracted  from  the  Chinese  Birth Defects  Monitoring  Network  (CBDMN)  (4,6–8),  we aimed  to  analyze  the  epidemiological  pattern  in  the prevalence of 15 major BDs and their trends over time. METHODS CBDMN  is  a  nationwide  hospital-based  BDs surveillance network that covers 763 member hospitals in  327  counties  or  districts  in  31  provincial-level administrative  divisions  (PLADs).  CDBMN  collects information  on  live  births,  stillbirths,  and  elective terminations  of  pregnancies  at  or  above  28  weeks  of gestation occurring in member hospitals. More than 2 million births were covered each year representing over 10%  of  live  births  in  China  (6).  All  anomalies diagnosed during the perinatal  period (from 28 weeks of  gestation  to  Day  7  after  birth)  are  required  to  be included  in  the  system  and  coded  by  health professionals  according  to  the  Tenth  Revision  of International  Classification  of  Diseases  (ICD-10). Details of data collection and quality control have been described previously (4,6–8). We  selected  15  frequently-occurring  major  BDs  in China  for  the  current  analysis,  including  neural  tube defects  (NTDs,  Q00,  Q01,  and  Q05),  hydrocephalus (Q03), anotia/microtia (Q16.0 and Q17.2), congenital heart  diseases  (CHDs,  Q20–Q26),  cleft  palate  (CP, Q35),  cleft  lip  with  or  without  palate  (CL/P, Q36–Q37),  anorectal  atresia/stenosis  (Q42), hypospadias  (Q54),  club  foot  (Q66.0),  polydactyly (Q69),  syndactyly  (Q70),  limb  reduction  defects (LRD, Q71–Q73), omphalocele (Q79.2), gastroschisis (Q79.3),  and  Down  syndrome  (Q90).  The  perinatal prevalence rate was defined as the number of cases per 10,000  live  and  still  perinatal  births  in  the  specified period. We calculated the prevalence rates by calendar year, maternal age (<20, 20–24, 25–29, 30–34, and ≥ 35  years),  infant  sex  (female  vs.  male),  maternal residence  area  type  (urban/rural),  and  geographic regions  (eastern,  central,  and  western).  The  rules  for urban/rural  and  geographic  classifications  in  the CBDMN were described previously (6–8). We used R 3.5.3 (R Development Core Team 2019) for  data  cleaning  and  analysis.  Pearson  chi-squared tests  were  used  to  examine  differences  of  prevalence between  various  groups,  and  linear  chi-squared  tests were  used  to  determine  the  time  trends.  The  95% confidence intervals (95% CI) for prevalence rates were estimated  according  to  Poisson  distribution.  The statistical significance level (α) was set at 0.05. RESULTS From 2010 to 2018, a total of 18,040,393 perinatal births were recorded, of whom 52.8% were males and 47.1% were females. Overall, 2.2% of births were born to women <20 years, and 11.3% were born to women ≥35  years.  The  newborns  whose  mothers  resided  in rural  areas  accounted  for  45.7%,  while  infants  whose mothers  lived  in  urban  areas  accounted  for  54.3%; 32.1% of  births  were  born to  women residents  of  the eastern region, while 37.2% and 30.7% of births were born  to  women  in  the  central  and  western  regions, respectively. As  shown in Table 1 and Table 2,  the  top  10 most frequently  occurring  BDs  included  CHDs, polydactyly,  CL/P,  club  foot,  syndactyly, hydrocephalus,  hypospadias,  LRD,  anotia/microtia, and  anorectal  atresia/stenosis.  The  prevalence  rates  of selected  major  BDs  varied  significantly  by  maternal age,  maternal  residence,  infant  sex,  and  geographic regions.  We  found  a  higher  prevalence  rate  in  the advanced  maternal  age  group  for  CHDs,  CP, hypospadias,  and  Down  syndrome,  whereas gastroschisis  prevalence  in  the  younger  maternal-age group (<20 years  of  old)  was  much higher.  Regarding China CDC Weekly 712 CCDC Weekly / Vol. 2 / No. 37 Chinese Center for Disease Control and Prevention TA B LE 1 . P re va le nc e* (9 5% C I) of s el ec te d m aj or b irt h de fe ct s by m at er na l a ge a nd in fa nt s ex in C hi na , 2 01 0– 20 18 . Ite m M at er na l a ge a t d el iv er y (y ea rs ) In fa nt s ex To ta l <2 0 20 –2 4 25 –2 9 30 –3 4 ≥3 5 Fe m al e M al e N TD s 8. 9( 8. 0– 9. 8) 3. 9( 3. 8– 4. 2) 2. 0( 1. 9– 2. 1) 2. 1( 2. 0– 2. 3) 3. 1( 2. 9– 3. 4) 3. 1( 3. 0– 3. 2) 2. 3( 2. 3– 2. 5) 2. 7( 2. 7– 2. 8) A ne nc ep ha lu s 2. 9( 2. 4– 3. 4) 1. 0( 0. 9– 1. 1) 0. 5( 0. 4– 0. 5) 0. 5( 0. 4– 0. 6) 0. 8( 0. 7– 0. 9) 0. 8( 0. 7– 0. 9) 0. 5( 0. 5– 0. 6) 0. 7( 0. 6– 0. 7) S pi na B ifi da 4. 8( 4. 2– 5. 6) 2. 4( 2. 3– 2. 6) 1. 3( 1. 2– 1. 4) 1. 3( 1. 2– 1. 4) 1. 9( 1. 7– 2. 1) 1. 8( 1. 8– 1. 9) 1. 5( 1. 4– 1. 6) 1. 7( 1. 6– 1. 7) E nc ep ha lo ce le 1. 2( 0. 9– 1. 6) 0. 6( 0. 5– 0. 7) 0. 3( 0. 3– 0. 3) 0. 3( 0. 3– 0. 4) 0. 4( 0. 3– 0. 5) 0. 4( 0. 4– 0. 5) 0. 3( 0. 3– 0. 4) 0. 4( 0. 4– 0. 4) H yd ro ce ph al us 8. 7( 7. 8– 9. 6) 6. 2( 5. 9– 6. 4) 4. 6( 4. 4– 4. 7) 4. 7( 4. 5– 4. 9) 5. 4( 5. 1– 5. 8) 4. 6( 4. 5– 4. 8) 5. 5( 5. 4– 5. 7) 5. 1( 5. 0– 5. 2) A no tia /m ic ro tia 2. 9( 2. 4– 3. 5) 2. 7( 2. 6– 2. 9) 2. 7( 2. 6– 2. 9) 3. 0( 2. 8– 3. 1) 3. 3( 3. 0– 3. 5) 2. 4( 2. 3– 2. 5) 3. 3( 3. 2– 3. 4) 2. 9( 2. 8– 2. 9) C H D s 45 .8 (4 3. 8– 48 .0 ) 47 .7 (4 7. 0– 48 .4 ) 57 .7 (5 7. 2– 58 .2 ) 64 .4 (6 3. 6– 65 .1 ) 76 .4 (7 5. 2– 77 .6 ) 57 .8 (5 7. 3– 58 .3 ) 60 .3 (5 9. 8– 60 .8 ) 59 .2 (5 8. 9– 59 .6 ) TG A 0. 7( 0. 4– 1. 0) 0. 7( 0. 6– 0. 8) 0. 8( 0. 7– 0. 8) 0. 8( 0. 8– 0. 9) 1. 0( 0. 9– 1. 2) 0. 6( 0. 5– 0. 6) 1. 0( 1. 0– 1. 1) 0. 8( 0. 8– 0. 9) V S D 8. 0( 7. 2– 8. 9) 9. 2( 8. 9– 9. 5) 11 .3 (1 1. 1– 11 .5 ) 12 .7 (1 2. 3– 13 .0 ) 15 .9 (1 5. 3– 16 .4 ) 12 .3 (1 2. 1– 12 .5 ) 11 .1 (1 0. 9– 11 .3 ) 11 .7 (1 1. 5– 11 .8 ) A S D 29 .3 (2 7. 7– 31 .0 ) 28 .6 (2 8. 1– 29 .2 ) 36 .3 (3 5. 9– 36 .8 ) 41 .0 (4 0. 5– 41 .7 ) 48 .7 (4 7. 8– 49 .7 ) 36 .1 (3 5. 7– 36 .5 ) 38 .2 (3 7. 8– 38 .6 ) 37 .2 (3 6. 9– 37 .5 ) A V S D 1. 8( 1. 4– 2. 3) 1. 6( 1. 5– 1. 7) 1. 6( 1. 5– 1. 7) 1. 7( 1. 6– 1. 8) 2. 2( 2. 0– 2. 4) 1. 8( 1. 7– 1. 9) 1. 6( 1. 5– 1. 7) 1. 7( 1. 6– 1. 8) TO F 0. 9( 0. 6– 1. 3) 1. 3( 1. 2– 1. 4) 1. 2( 1. 1– 1. 3) 1. 4( 1. 3– 1. 5) 2. 0( 1. 8– 2. 2) 1. 2( 1. 2– 1. 3) 1. 4( 1. 4– 1. 5) 1. 3( 1. 3– 1. 4) P D A 15 .3 (1 4. 2– 16 .6 ) 15 .7 (1 5. 3– 16 .1 ) 20 .1 (1 9. 8– 20 .4 ) 22 .4 (2 2. 0– 22 .8 ) 26 .8 (2 6. 1– 27 .5 ) 19 .7 (1 9. 4– 20 .0 ) 21 .1 (2 0. 8– 21 .4 ) 20 .4 (2 0. 2– 20 .6 ) C P 2. 3( 1. 8– 2. 8) 2. 4( 2. 3– 2. 6) 2. 6( 2. 5– 2. 8) 2. 7( 2. 6– 2. 9) 2. 9( 2. 7– 3. 2) 3. 3( 3. 2– 3. 4) 2. 1( 2. 0– 2. 2) 2. 6( 2. 6– 2. 7) C L/ P 16 .5 (1 5. 3– 17 .8 ) 11 .0 (1 0. 7– 11 .4 ) 6. 8( 6. 6– 7. 0) 7. 0( 6. 7– 7. 2) 9. 3( 8. 9– 9. 7) 6. 8( 6. 6– 7. 0) 9. 4( 9. 2– 9. 6) 8. 2( 8. 1– 8. 4) C L 6. 0( 5. 2– 6. 8) 4. 3( 4. 1– 4. 6) 2. 9( 2. 8– 3. 0) 3. 0( 2. 8– 3. 1) 3. 6( 3. 4– 3. 9) 2. 8( 2. 7– 3. 0) 3. 8( 3. 7– 3. 9) 3. 3( 3. 3– 3. 4) C LP 10 .6 (9 .6 –1 1. 6) 6. 7( 6. 4– 6. 9) 4. 0( 3. 8– 4. 1) 4. 0( 3. 8– 4. 2) 5. 6( 5. 3– 6. 0) 3. 9( 3. 8– 4. 1) 5. 7( 5. 5– 5. 8) 4. 9( 4. 8– 5. 0) A no re ct al a tre si a/ st en os is 3. 2( 2. 7– 3. 8) 2. 9( 2. 7– 3. 0) 2. 5( 2. 4– 2. 7) 2. 8( 2. 7– 3. 0) 3. 7( 3. 4– 4. 0) 1. 9( 1. 8– 2. 0) 3. 5( 3. 4– 3. 7) 2. 8( 2. 8– 2. 9) H yp os pa di as § 3. 8( 3. 2– 4. 4) 4. 0( 3. 9– 4. 3) 4. 9( 4. 7– 5. 0) 5. 6( 5. 4– 5. 9) 6. 7( 6. 3– 7. 0) – 9. 6( 9. 4– 9. 8) 5. 1( 5. 0– 5. 2) C lu b fo ot 9. 4( 8. 4– 10 .4 ) 6. 5( 6. 2– 6. 8) 5. 7( 5. 5– 5. 8) 5. 5( 5. 3– 5. 7) 6. 3( 6. 0– 6. 7) 5. 7( 5. 6– 5. 9) 6. 1( 6. 0– 6. 3) 5. 9( 5. 8– 6. 1) P ol yd ac ty ly 23 .0 (2 1. 6– 24 .5 ) 17 .7 (1 7. 3– 18 .1 ) 17 .1 (1 6. 8– 17 .4 ) 17 .0 (1 6. 6– 17 .4 ) 18 .6 (1 8. 0– 19 .2 ) 14 .2 (1 3. 9– 14 .4 ) 20 .4 (2 0. 1– 20 .7 ) 17 .5 (1 7. 3– 17 .7 ) S yn da ct yl y 5. 9( 5. 1– 6. 7) 5. 2( 4. 9– 5. 4) 5. 6( 5. 5– 5. 8) 6. 0( 5. 8– 6. 3) 5. 7( 5. 4– 6. 1) 4. 9( 4. 7– 5. 0) 6. 3( 6. 2– 6. 5) 5. 7( 5. 5– 5. 8) LR D 4. 8( 4. 1– 5. 5) 3. 6( 3. 5– 3. 9) 3. 0( 2. 9– 3. 1) 3. 1( 3. 0– 3. 3) 4. 0( 3. 7– 4. 2) 2. 9( 2. 8– 3. 0) 3. 5( 3. 4– 3. 7) 3. 3( 3. 2– 3. 4) O m ph al oc el e † 1. 5( 1. 1– 1. 9) 0. 9( 0. 8– 1. 0) 0. 8( 0. 8– 0. 9) 1. 0( 0. 9– 1. 1) 1. 5( 1. 4– 1. 7) 1. 0( 0. 9– 1. 0) 0. 9( 0. 9– 1. 0) 1. 0( 0. 9– 1. 0) G as tro sc hi si s † 5. 3( 4. 6– 6. 1) 1. 6( 1. 5– 1. 7) 0. 5( 0. 4– 0. 5) 0. 4( 0. 3– 0. 5) 0. 6( 0. 5– 0. 7) 0. 7( 0. 7– 0. 8) 0. 8( 0. 7– 0. 9) 0. 8( 0. 8– 0. 8) D ow n sy nd ro m e 0. 6( 0. 4– 0. 9) 0. 8( 0. 7– 0. 9) 1. 0( 0. 9– 1. 1) 1. 3( 1. 2– 1. 5) 4. 7( 4. 4– 5. 0) 1. 3( 1. 2– 1. 4) 1. 6( 1. 5– 1. 7) 1. 5( 1. 4– 1. 5) A bb re vi at io ns : C I= co nf id en ce in te rv al ; N TD s= ne ur al tu be d ef ec ts ; C H D s= co ng en ita l h ea rt di se as es ; T G A =t ra ns po si tio n of g re at a rte rie s; V S D =v en tri cu la r s ep ta l d ef ec t; A S D =a tri al s ep ta l de fe ct ; A V S D =a tri ov en tri cu la r se pt al d ef ec t; TO F= te tra lo gy o f F al lo t; P D A =p at en t d uc tu s ar te rio su s; C P =c le ft pa la te ; C L/ P =c le ft lip w ith o r w ith ou t p al at e; C L= cl ef t l ip w ith ou t p al at e; C LP =c le ft lip w ith p al at e; L R D =l im b re du ct io n de fe ct s. * P er 1 0, 00 0 pe rin at al b irt hs . † E xc ep t o m ph al oc el e an d ga st ro sc hi si s, a ll se le ct ed m aj or b irt h de fe ct s va rie d si gn ifi ca nt ly b y in fa nt s ex (p <0 .0 1) ; A ll se le ct ed m aj or b irt h de fe ct s va rie d si gn ifi ca nt ly b y m at er na l a ge


INTRODUCTION
Birth defects (BDs) affect 4%-8% of births worldwide (1). The estimated prevalence in China is 5.6%, with approximately 900,000 infants born with various defects each year (2). BDs are the leading cause of infant mortality in China, accounting for about 20% of deaths (2)(3). Other adverse outcomes include premature death in early life, disabilities, impaired physical and mental well-being, negative effects on quality of life, which result in a substantial disease burden on families and societies (1)(2)4). According to the Global Burden of Disease Study in 2017, BDs are the tenth leading cause of disability-adjusted life years (DALYs) among women and ninth among men (5). As a global public health problem, BDs have been of major concern to governments, health professionals, and the public.
Although several genetic, behavioral, and environmental risk factors have been identified, the underlying causes of most BDs were unclear (1)(2). BDs surveillance played an important role in exploring possible risks, monitoring dynamic changes in prevalence, and providing evidence for interventions (4). With rapid socioeconomic development in China, birth policies, family income, maternal nutrition, prenatal care, and socioeconomic and demographic factors have varied significantly. However, reliable data on the prevalence of major BDs was limited. Using 2010-2018 data extracted from the Chinese Birth Defects Monitoring Network (CBDMN) (4,6-8), we aimed to analyze the epidemiological pattern in the prevalence of 15 major BDs and their trends over time.

METHODS
CBDMN is a nationwide hospital-based BDs surveillance network that covers 763 member hospitals in 327 counties or districts in 31 provincial-level administrative divisions (PLADs). CDBMN collects information on live births, stillbirths, and elective terminations of pregnancies at or above 28 weeks of gestation occurring in member hospitals. More than 2 million births were covered each year representing over 10% of live births in China (6). All anomalies diagnosed during the perinatal period (from 28 weeks of gestation to Day 7 after birth) are required to be included in the system and coded by health professionals according to the Tenth Revision of International Classification of Diseases (ICD-10). Details of data collection and quality control have been described previously (4,(6)(7)(8).
We used R 3.5.3 (R Development Core Team 2019) for data cleaning and analysis. Pearson chi-squared tests were used to examine differences of prevalence between various groups, and linear chi-squared tests were used to determine the time trends. The 95% confidence intervals (95% CI) for prevalence rates were estimated according to Poisson distribution. The statistical significance level (α) was set at 0.05.

RESULTS
From 2010 to 2018, a total of 18,040,393 perinatal births were recorded, of whom 52.8% were males and 47.1% were females. Overall, 2.2% of births were born to women <20 years, and 11.3% were born to women ≥35 years. The newborns whose mothers resided in rural areas accounted for 45.7%, while infants whose mothers lived in urban areas accounted for 54.3%; 32.1% of births were born to women residents of the eastern region, while 37.2% and 30.7% of births were born to women in the central and western regions, respectively.
As shown in Table 1 and Table 2, the top 10 most frequently occurring BDs included CHDs, polydactyly, CL/P, club foot, syndactyly, hydrocephalus, hypospadias, LRD, anotia/microtia, and anorectal atresia/stenosis. The prevalence rates of selected major BDs varied significantly by maternal age, maternal residence, infant sex, and geographic regions. We found a higher prevalence rate in the advanced maternal age group for CHDs, CP, hypospadias, and Down syndrome, whereas gastroschisis prevalence in the younger maternal-age group (<20 years of old) was much higher. Regarding   the prevalence by maternal age groups, a gradual Ushape was identified for NTDs, hydrocephalus, anotia/microtia, CL/P, club foot, polydactyly, syndactyly, LRD, anorectal atresia/stenosis and omphalocele. A higher prevalence in males was found for hydrocephalus, anotia/microtia, CHDs, CL/P, anorectal atresia/stenosis, club foot, polydactyly, syndactyly, LRD, and Down syndrome, while a higher prevalence for females was observed for NTDs and CP. Significant urban/rural differences in prevalence were identified for several defects. The prevalence of anotia/microtia, CHDs, CP, anorectal atresia/stenosis, hypospadias, polydactyly, syndactyly, and Down syndrome appeared higher in urban areas than in rural areas, while the prevalence of NTDs, hydrocephalus, CL/P, club foot, LRD, and gastroschisis were higher in rural areas. With respect to a geographic disparity in prevalence, the highest prevalence of CHDs, CP, anorectal atresia/stenosis, hypospadias, and syndactyly, and Down syndrome were found in the eastern region,   whereas the highest rates of NTDs, hydrocephalus, CL/P, anotia/microtia, club foot, polydactyly, LRD, omphalocele, and gastroschisis were in the western region. Figure 1 illustrated the time trends in the prevalence of selected BDs. The prevalence of NTDs, hydrocephalus, CL/P, LRD, omphalocele and gastroschisis decreased during 2010-2018. The defect with the largest decline in prevalence was gastroschisis, followed by NTDs and CL/P, with a decline of 78.8%, 77.3%, and 56.4%, respectively. The prevalence of CHDs, CP, polydactyly, syndactyly, hypospadias, and club foot increased. Compared with rates in 2010, the prevalence of CHDs, syndactyly, and polydactyly in 2018 increased by 171.4%, 60.7%, and 41.2%, respectively. Notably, the prevalence of anotia/ microtia, anorectal atresia/stenosis, and Down syndrome remained stable over time.

DISCUSSION
Using 2010-2018 CBDMN data of over 18 million births, we described the epidemiological pattern of 15 selected major BDs at the national level, with special interests in trends over time and perinatal prevalence by maternal age, maternal residence, infant sex, and geographic region. These data will help to clarify the current epidemiological distributions of the top ten most frequent congenital anomalies in the Chinese population and will help determine the disorders and populations that should be prioritized for prevention.
Compared with previous CBDMN data, the overall   prevalence of CHDs, polydactyly, syndactyly, CP and hypospadias were higher, while the rates of NTDs, hydrocephalus, LRDs, gastroschisis and Down syndrome were lower (2,4,(6)(7)(8). Similar results have been noted in several recent studies in China based on provincial or local hospital-based surveillance data (9-10). Our prevalence data on CHDs, CL/P, hydrocephalus, hypospadias, anorectal atresia/stenosis and CP, were also comparable to those from hospitalbased monitoring systems in Israel, Japan, and Spain (11). Notably, the prevalence of CHDs, CL/P, and anotia/microtia in China were higher than those in the United States and some European countries, but Down syndrome prevalence was significantly lower (11-13). The considerable variations among studies can be explained by ethnicity, socioeconomic factors, environmental exposures, lifestyle risk factors and heterogeneities of surveillance systems or study designs such as differences in inclusion and exclusion criteria, diagnostic capability, and follow-up time. A growing number of epidemiological studies reveal that greater risks or higher prevalence of certain BDs happen in younger or older women. In the current analysis, we identified an U-shaped pattern for 10 types of anomalies (NTDs, CL/P, etc., Table 1), and increased prevalence of 4 defects with maternal age (CHDs, Down syndrome, CP, and hypospadias). Maternal-age-specific prevalence patterns varied by the types of BDs, which might be partially due to the changing maternal age distribution following by the implementation of the two-child policy (9). In our study, significant urban-rural and geographic disparities were found for nearly all the selected BDs, which could be explained by differences in occupational exposures, socioeconomic levels, and healthcare among people living in different area types and regions. Similar findings have been noted in other reports, indicating considerable health inequalities in China (4,6-8,10). Therefore, BDs prevention and healthcare services in rural and western regions need to be further improved (14).
Consistent with previous studies in China, an increasing prevalence for CHDs, CP, polydactyly, syndactyly, and hypospadias during 2010-2018 was found (2,9-10). Indeed, the increased overall CHD prevalence can be largely attributed to substantial increases in several mild lesions (i.e. small ventricular septal defect, atrial septal defect, and patent ductus arteriosus, etc.). Improvements in diagnostic capabilities, disease screening, and the widespread use of echocardiography can lead to the earlier identification of mild lesions or asymptomatic CHD subtypes and lead to a higher detection rate of CHDs in the perinatal period (9-10,12-13). Changes in environmental exposures like exogenous estrogenic endocrine disruptors have been reported to be associated with increased hypospadias prevalence (10,13), but the exact reasons for increased prevalence of CP, polydactyly, and syndactyly were unclear. The decreasing prevalence of NTDs, hydrocephalus, LRD, and gastroschisis might reflect the combined effect of strengthened primary and secondary prevention (i.e. the National Folic Acid Supplementation Program and prenatal screening and diagnosis for structural malformations and Down syndrome) in China (2,(9)(10). Given the high prevalence of these defects, we believe further etiological studies are needed, and postnatal care, surgical correction, rehabilitation, and social support should be strengthened.
This study was subject to some limitations. The calculation of perinatal prevalence rate in the current analysis excluded cases <28 weeks of gestation. The rates mainly reflected the effect of combinations of risk factors and primary and secondary preventions and could not be simply explained as an indicator of disease risk. Hospital-based CBDMN data may introduce referral bias, but the impact could be minimal because of the high hospital delivery rate in China (≥99.9%) (15). Since the follow-up time period was relatively short (28 weeks of gestation to Day 7 after birth), CBDMN had limited ability to obtain reliable data on congenital metabolic diseases, functional abnormalities, and outcomes in the infancy period. However, considering the large sample size and wide geographic coverage, this data can well represent the epidemiological characteristics of most structural malformations in China. In summary, we presented the prevalence patterns of 15 major BDs during 2010-2018, mainly focusing on the time trends and the prevalence of the top ten most frequently occurring structural malformations by maternal and infant characteristics. These findings will contribute to health policy making and future BDs prevention by providing important baseline references.
Acknowledgements: We thank all the colleagues from local institutions for participating in the data collection.
Conflicts of interest: The authors declare no competing interests. Birth defects, including congenital structural or functional abnormalities, remained a main cause of death among infants and represented a significant clinical and public health challenge (1). Periconceptional folic acid supplementation has been shown to effectively reduce the risk of pregnancies complicated with neural tube defects (NTDs) (2) and limb reduction (3). The prevalence of NTDs have decreased from 118.9/10,000 births to 31.5/10,000 in northern China from 2000 to 2014 and pre-perinatal (<28 gestational weeks) NTDs accounted for 60% of all NTDs (4).The trends of other birth defects among this population and the correlation with the folic-acid supplement program and population policy change had not been reported. This study aimed to examine the trends of selected structural birth defects (Supplementary Table S1, available in http://weekly. chinacdc.cn/) in 5 counties in Shanxi Province during 2000-2019 based on a population-based birth-defect surveillance system. The results showed that the prevalence of selected structural birth defects in the study area decreased significantly from 182.8/10,000 to 119.3/10,000 during the past two decades.
Data from a population-based birth-defect surveillance system that covered 5 counties (Pingding, Xiyang, Taigu, Zezhou, and Shouyang) in Shanxi Province from 2000 to 2019 were analyzed in this study (Supplemental Figure S1, available in http:// weekly.chinacdc.cn/). Details of the birth defects surveillance system were described in our previous publication (4). Briefly, the system was established in the early 2000s, and more than 20,000 births were covered each year. All pregnant women residing in the study area for more than 1 year were monitored. All livebirths or stillbirths of 28 or more complete gestational weeks and pregnancy terminations at any gestational age following the prenatal diagnosis of birth defects were included. The surveillance data covered more than 95% of live births and data quality was ensured. Information on the diagnostic criteria of birth defects (coded according to International Statistical Classification of Diseases and Related Health Problems, 10 th revision), sex, gestational weeks, birth outcome and maternal residence was collected. The study protocol was reviewed and approved by the Institutional Review Board of Peking University.
The prevalence at birth of birth defects by year/period, by type, and by gestational week's group was compared using chi-squared tests. Perinatal prevalence (cases of 28 or more gestational weeks) and pre-perinatal prevalence (cases before 28 gestational weeks) were calculated, and 5 periods of time were demarcated according to population policy and public strategy. Two-tailed p≤0.05 was considered statistically significant. All statistical analyses were performed using the SPSS package (version 18.0, SPSS Inc., Chicago, IL, USA).
From 2000 to 2019, a total of 293,573 births were covered and 4,748 infants with 5,845 cases of structural birth defects (an infant may have multiple birth defects) were recorded in the system.
Perinatal structural birth defects decreased from 83.9% of all birth defects in 2000 to 59.9% in 2019 ( Figure 1A) (Pearson chi-squared tests: 62.958, p<0.05) and the perinatal prevalence decreased dramatically from a peak of 139.6/10,000 births in 2003 to 74.7/10,000 in 2019 ( Figure 1B). Prevalence of nervous system defects was the highest and decreased from 169/10,000 births to 35/10,000 in the past two decades. Musculoskeletal system defects remained the second most common birth defect and fluctuated between 29/10,000 to 39/10,000. Cleft lip with or without cleft palate ranked third and decreased from 27/10,000 to 17/10,000 during 2000-2019 (Table 1, Figure 2A).

DISCUSSION
A population-based birth-defect surveillance system showed that the prevalence of selected structural birth defects in the 5 counties in Shanxi Province decreased significantly from 182.8/10,000 to 119.3/10,000 in the past two decades. After introduction of the massive folic acid supplementation program in 2009, both the perinatal and prenatal prevalences decreased significantly, especially for congenital abnormalities of the nervous system.
During the study period, premarital physical checkups were changed from mandatory to voluntary in 2003, and a nationwide folic acid supplementation program was initiated in 2009. Corresponding with the reduction in the number of premarital check-ups, the prevalence of birth defects before 28 weeks increased significantly in 2000-2003 compared to 2004-2008. After the change in policy, fewer women went to have a checkup and the opportunity for prophylaxis against birth defects was lost (5). Strengthening pre-pregnancy checkups and birth defect screening are important in preventing birth defects. To raise folic acid supplementation and to reduce the high prevalence of NTDs in rural areas of the country, the Ministry of Health of China (currently known as the National Health Commission) initiated a nationwide folic acid supplementation program in 2009 (6). The program provides folic acid supplements to all women who have a rural household registration (also known as hukou ) and who plan to become pregnant. Our study showed that the prevalence of selected birth defects in 2009-2019 was significantly lower than that in 2000-2008, especially NTDs and cleft lip with/without cleft palate, which may be partly due to folic acid supplementation.
Our study found that the prevalence of defects of the nervous system in this area was still high as evidenced by the prevalence of 35/10,000 in 2019, which was significantly higher than national average level (7). Specifically, the prevalence of anencephaly in this study was found to be as high as 9/10,000 live births in 2016-2019 and 0.19/10,000 in Sichuan, China in 2010-2018. The prevalence of spina bifida was 15/10,000 in 2016 to 2019 in this study compared to 0.84/10,000 in Sichuan, China. The study conducted in Sichuan only captured perinatal pregnancies (more than 28 weeks), which may have contributed to lower prevalences as compared to this study (7). The folic acid supplementation rate increased significantly after 2009. However, most women began taking folic acid supplements after pregnancy, which was too late for the prevention of NTDs (6). Therefore, to improve the compliance of periconceptional folic acid supplementation, starting supplementation before the last menstrual period and supplementing for enough time are crucial for utilizing the maximum potential of the supplementation program. Fortifying staple foods with folic acid and improving health education on early prenatal check-up should be considered to further reduce birth defects risk in the population.
The current study did not find that the change in population policy had an effect on the epidemiology of birth defects. There were 3 major waves of adjustment on population policy during 2000 and 2019. Compared with the transition of "one child" to "twochild" policy from 2011 to 2013, the prevalence of birth defects did not change significantly during the universal two-child policy started in 2016. So far, we did not observe the influence of population policy on the risk of birth defects in the population. Studies revealed longer interpregnancy interval (IPI>60 months) increased the risk of having an infant with a  birth defect (8). Advanced maternal age (AMA) increased the risk of aneuploidy, while AMA was associated with an overall decreased risk for major anomalies in the absence of aneuploidy (9). As more than 80% of subjects were from rural areas in the current study, age of childbearing was comparably young and the policy effect may not have been significant. Following the enactment of the universal two-child policy, the proportion of women with AMA increased, and the risk of birth defects deserves more study in the future. The rank of birth defects in this population was different from a study conducted in Sichuan, a southern province in China, that showed congenital   heart disease being the most prevalent birth defect (7). In our study, although the total prevalence of birth defects and the prevalence of several subtypes of birth defects decreased with time, congenital abnormalities of the nervous system, such as NTDs, was still the most prevalent birth defects, followed by defects of the musculoskeletal system, cleft lip and cleft palate, other system defects, and eye anomalies. The improvement of detection methods and changes in the diagnostic standard may have contributed to the increasing prevalence of congenital heart disease. The different patterns due to varying nutritional status, including but not limited to folate, among northern and southern China needs further study in the future. This study was subject to some limitations. Due to the small selection area of a five mostly rural counties in Shanxi Province, the results were not generalizable to the province at large or to the country. The changes in policy may have affected different regions of the country differently and may have differing effects on urban populations. SUPPLEMENTARY TABLE S1. Classification (ICD-10 code) of selected types of birth defects in the surveillance system.

Summary
What is already known about this topic? Improving their utilization of health examination is important for improving the health of menopausal and older women.

What is added by this report?
Only 32.3% and 29.7% of women had been screened for cervical cancer and breast cancer, respectively. The overall utilization rate of health examination for menopausal and older women is low. The health examination services for menopausal and older women were utilized less in the western regions and in rural areas than in the eastern and central regions and in urban areas.
What are the implications for public health practice?
The imbalance of development is an important factor affecting the utilization of health examination for menopausal and older women. It is necessary to take effective measures to improve the level of service utilization in the western region and rural areas, in order to narrow the gap in health between different regions.
With the extension of human life expectancy and the intensification of the aging of the population, the number of menopausal and older women in China has increased sharply. According to the sixth census in 2010, the number of women aged 40−65 years old in China has reached 220 million (1). Menopause is a special period in a woman's life. With the gradual decline of ovarian function and the decline of hormone levels, menopausal women are prone to cardiovascular disease, diabetes, osteoporosis and other chronic diseases, which will affect their health and quality of life (2). Health examination is not only an important part of health care for menopausal and older women, but also an important means of detecting a variety of age related diseases in the early stages (3). In order to provide a scientific basis for targeted health care for older women and to promote the health of older women, a cross-sectional survey involving 5,049 women aged 50-70 years was conducted across eastern, central and western China. The main result of this study showed that the utilization rate of health examination for older women is low. The imbalance of development is an important factor affecting the utilization of health examination for menopausal and older women. The study was a cross-sectional survey in Jiangsu and Shandong, Hunan and Anhui, and Shaanxi and Sichuan provinces, which were selected to represent the three socio-economic regions of China: Eastern, Central and Western China. In each province one urban and one rural area was selected as investigation sites.
Face-to-face interview questionnaires were completed by 5,049 women aged 50-70 years in the 6 provinces.
The average age of the respondents was 58.94±6.195 years. The main occupation of the cohort was farming, accounting for 55.2%, followed by retirees, accounting for 17.1%. Most of the participants (55.0%) had only primary school education or were illiterate, followed by those who had junior and senior high school education, accounting for 42.0%. The monthly income of the family was low -less than RMB 3,000 Yuan for 52.9%, followed by RMB 3,000-4,999 Yuan for 27.1%. The majority (89.9%) of the women were postmenopausal (Table 1).

DISCUSSION
The overall utilization rate of health examination by older women was low. Breast and cervical cancer screening and regular physical examination are one of the important elements of health care for menopausal and older women. However, this study found that the utilization of health examination services by menopausal and older women was low. Only 32.5% of women had received a regular physical examination within one year, which was lower than the overall result of the Fifth National Health Service Survey (43.3%) (4). Only 27.8% of women reported having been screened for both breast and cervical cancer in the past, and 32.3% and 29.7% of women had been screened for cervical cancer or breast cancer, respectively. The breast and cervical cancer screening rates were slightly higher than the results of the national sample survey in 2013 (22.5% and 26.7%, respectively) (5). However, the screening rate for breast (16.4%) and cervical cancer (15.2%) within one year were lower than those of the Fifth National Health Service Survey (26.5% and 24.3%, respectively) (4).
The village committee and community workers should play a greater role in organizing health examination to increase the participation rate. This study showed that a few (only 27.5%) menopausal and older women took the initiative to obtain health examination services. Many studies have shown that the lack of awareness was a major obstacle for women to participate in the examination. Women with older age, low education level, underemployment, low family income and lack of health insurance are less likely to take the initiative to seek a health examination (6)(7). In this study, the most common reasons for not having a regular physical examination were the lack of organization, and feeling it was unnecessary or being unwilling. It reminds us that in order to enhance the service utilization of menopausal and older women and improve the participation rate, it is critical to encourage the village committee and community workers to play a role in organizing health examination, to carry out targeted health education for different groups of women.
The imbalance of regional economic development is an important factor affecting the utilization of services for menopausal and older women. Many studies have shown that the imbalance of regional economic development is an important factor restricting the utilization of services by menopausal and older women (5,8). The results of this study showed that menopausal and older women in the western region and in rural areas were less likely to utilize the health examination services than those in the eastern and central regions and in urban areas. This pattern may be related to the health awareness, education level, economic conditions of women and level of development of the health system (7). Therefore, we need to take effective measures to effectively improve the level of service utilization in the western region and rural areas, in order to narrow the gap in health between different age groups of women. There were some limitations in this study. Firstly, self-reported information might be subjected to biases. Secondly, the study used convenience sampling, and data were collected in 12 counties/districts in 6 provinces, so the results might not be representative of the regional and national levels.