1 in 16 Babies Are Born With Birth Defects
Etiology and clinical presentation of birth defects: population based study
Marcia 50 Feldkamp
1Segmentation of Medical Genetics, Department of Pediatrics, 295 Chipeta Fashion, Suite 2S010, University of Utah School of Medicine, Salt Lake City, UT, USA,
John C Carey
iDivision of Medical Genetics, Section of Pediatrics, 295 Chipeta Way, Suite 2S010, University of Utah School of Medicine, Salt Lake City, UT, United states of america,
Janice L B Byrne
aneDivision of Medical Genetics, Department of Pediatrics, 295 Chipeta Manner, Suite 2S010, University of Utah School of Medicine, Table salt Lake City, UT, The states,
twoDivision of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Utah School of Medicine, Table salt Lake City, UT, USA
Sergey Krikov
1Division of Medical Genetics, Department of Pediatrics, 295 Chipeta Way, Suite 2S010, University of Utah School of Medicine, Salt Lake City, UT, USA,
Lorenzo D Botto
1Division of Medical Genetics, Section of Pediatrics, 295 Chipeta Way, Suite 2S010, Academy of Utah School of Medicine, Salt Lake Urban center, UT, USA,
Abstruse
Objective To assess causation and clinical presentation of major birth defects.
Design Population based case cohort.
Setting Cases of nativity defects in children born 2005-09 to resident women, ascertained through Utah's population based surveillance system. All records underwent clinical re-review.
Participants 5504 cases amidst 270 878 births (prevalence ii.03%), excluding mild isolated conditions (such equally muscular ventricular septal defects, distal hypospadias).
Main result measures The primary outcomes were the proportion of birth defects with a known etiology (chromosomal, genetic, human teratogen, twinning) or unknown etiology, by morphology (isolated, multiple, minors only), and by pathogenesis (sequence, developmental field defect, or known pattern of birth defects).
Results Definite cause was assigned in 20.2% (n=1114) of cases: chromosomal or genetic weather condition deemed for 94.four% (due north=1052), teratogens for 4.one% (n=46, mostly poorly controlled pregestational diabetes), and twinning for 1.iv% (n=16, conjoined or acardiac). The 79.8% (n=4390) remaining were classified every bit unknown etiology; of these 88.2% (n=3874) were isolated birth defects. Family history (similarly affected first degree relative) was documented in 4.eight% (northward=266). In this cohort, 92.one% (5067/5504) were live born infants (isolated and not-isolated birth defects): 75.3% (4147/5504) were classified every bit having an isolated birth defect (unknown or known etiology).
Conclusions These findings underscore the gaps in our cognition regarding the causes of birth defects. For the causes that are known, such as smoking or diabetes, assigning causation in individual cases remains challenging. Nevertheless, the ongoing touch of these exposures on fetal evolution highlights the urgency and benefits of population based preventive interventions. For the causes that are still unknown, better strategies are needed. These can include greater integration of the key elements of etiology, morphology, and pathogenesis into epidemiologic studies; greater collaboration between researchers (such as developmental biologists), clinicians (such as medical geneticists), and epidemiologists; and meliorate means to objectively measure fetal exposures (beyond maternal self reports) and closer (prenatally) to the disquisitional catamenia of organogenesis.
Introduction
Nascence defects are inborn errors of development. Broadly defined, they include any structural or functional anomaly with measureable effects on physical, intellectual, and social wellbeing.1 Birth defects represent a considerable and increasing clinical and public health challenge because of their worldwide affect on population wellness.
Major birth defects are mutual, costly, and disquisitional. Collectively, they occur in one in 33 births,2 which in 2006 translated into an estimated 7.nine million babies worldwide.3 In the Usa alone, the cost of intendance during a unmarried year (2004) was estimated at $2.6bn (£2bn, €2.4bn).4 This estimate does not account for the considerable indirect and lifelong personal and societal costs. Finally, many birth defects critically bear upon survival. In the United states, nascence defects are the leading cause of babe mortality5 and in 2013 were associated with 4778 deaths, one in every five deaths in the first year of life.
The temporal trends are even more concerning. The occurrence of birth defects, with few localized exceptions (such as neural tube defects in countries that implemented folic acid fortification), has non decreased for many decades. Birth defects might indeed increase worldwide, with the alarming increase of known run a risk factors such as maternal diabetes and obesity. New threats such as the Zika epidemic are emerging. Unless progress is made in identifying and preventing the root causes of birth defects, these weather condition will continue to accept draining effects on the survival and health of individuals, families, and countries.
Progress in detecting and characterizing risk factors for birth defects has come mainly from epidemiologic studies. In fact, such studies accept produced many associations between risk factors and groups of nativity defects. Translating these associations to actual causes, however, has been difficult. Equally a first step in filling this gap, we evaluated the clinical and etiologic contour of birth defects in a well characterized population based case cohort through systematic review by clinicians, using a multidimensional assessment tool that incorporates etiology, morphology, and pathogenesis.
Methods
Written report population
The information source for this report was Utah's statewide population based public wellness surveillance organization (Utah Birth Defect Network, UBDN), housed at the Utah Department of Wellness. There is no patient involvement or contact as part of this surveillance system. The network monitors birth defects among all pregnancy outcomes (live births, stillbirths, pregnancy terminations) among Utah residents. If a termination occurred, existing medical records were ascertained and reviewed to determine eligibility. To identify potential cases, the program uses multiple reporting sources, both prenatal and postnatal. All reporting sources are mandated to regularly submit any potential diagnosis in infants aged up to 24 months and are legally protected to report if a diagnosis is made after 24 months. The detailed clinical information for each case is based on the bathetic prenatal and postnatal clinical records by trained data abstractors. The presence of a prenatal diagnosis without dissection or postnatal confirmation is not sufficient for inclusion in the system, with few exceptions, the main one being anencephaly if well described by a perinatologist. For instance, hydronephrosis based on only prenatal diagnosis was non eligible for inclusion unless it was confirmed postnatally. Some nascency defects have not ever been eligible for inclusion in the surveillance organization because it is more than challenging to place and define all cases or they are not considered a nascency defect—for example, isolated muscular ventricular septal defects, patent foramen ovale, patent ductus arteriosus, talipes equinovarus, built hip dysplasia/dislocation, congenital pulmonary airway malformation, and cryptorchidism. Cases of fetal alcohol syndrome were included only if a major birth defect was diagnosed. Further details of the system's case ascertainment and medical record brainchild have been published elsewhere.half-dozen 7
Clinical case review
A team of clinicians with training in medical genetics (LDB, JCC, JLBB) reviewed case records, including inpatient and outpatient records, laboratory reports (such as genomic microarray), diagnostic evaluations (such every bit ultrasound images and echocardiograms), operative notes, and dissection reports. In one case a case was deemed eligible, the clinician generated a list of the major and minor defects and the timing of kickoff diagnosis (prenatal or postnatal). Each defect was coded with the World Wellness Organization international classification of diseases (version nine) with British Paediatric Association extensions (ICD-9 BPA). In add-on, the clinician provided iii additional classifications for each case: known etiology (yes, no); isolated versus multiple (unrelated) birth defect versus syndromic (that is, known etiology: genetic or environmental); and whether the case was familial (aye, no). A case was considered familial if a first degree relative (parent or sib) had a concordant phenotype.
Multidimensional etiologic classification
To systematically capture the clinical presentation and etiology in the written report accomplice nosotros developed and implemented a multidimensional classification with three axes: etiology (known, unknown), morphology (isolated, multiple majors, minors only), and pathogenesis (sequence, developmental field, or pattern). Table 1 summarizes the organisation and definitions. Briefly:
Table 1
Classification groups and definitions for etiologic nomenclature of all cases of birth defects in Utah, 2005-09
| Group | Definition |
|---|---|
| Etiology | |
| Known | Anomaly of chromosome number (trisomy 21) or construction (del 22q); single gene status (such as Noonan syndrome); anomaly of gene expression (methylation-related Beckwith-Wiedemann syndrome); established human teratogen (such every bit pregestational diabetes, valproic acid); specific twinning abnormality (such equally acardiac or conjoined twin) |
| Unknown | No identifiable cause could definitively exist established and documented |
| Morphology | |
| Isolated | Single major malformation, with or without a not-objective minor defect. Notation: a sequence (see beneath for definition) if isolated is considered an isolated defect, as in the case spina bifida with clubfoot and hydrocephalus |
| Multiple | Ii or more than unrelated major malformations |
| Minor* | Select, distinctive, and objective structural defect that is not clinically or surgically pregnant |
| None | No major or distinctive minor defects were detected. Case might still exist eligible in the presence of an eligible chromosomal anomaly (such as child with trisomy 21, without a major defect, or i of the selected pocket-size defects in the list of objective minors). |
| Pathogenesis | |
| Sequence† | Pattern of related malformations that occur every bit a consequence of a single primary malformation. Examples include spina bifida with hydrocephalus and clubfoot (spina bifida sequence, with spina bifida every bit the primary malformation). A sequence can occur as an isolated defect (spina bifida sequence) or equally multiple defect (such as spina bifida sequence and cleft lip) |
| Developmental field defect‡ | Pattern of malformations resulting from the aberrant development of an embryonic unit (developmental field) that develops as a single unit of measurement in early embryogenesis (such equally during blastogenesis). Etiology of developmental field defects is typically heterogeneous. An example is the DiGeorge anomaly, related to abnormal development and fate of populations of neural crest cells, leading to multiple structural anomalies and potentially caused by unlike genetic abnormalities (such as deletion 22q11) or ecology factors (such equally retinoic acid) |
| Blueprint§ | Non-random occurrence or pattern of multiple malformations without a known cause. Examples include the VATER/VACTERL recurrent and variable blueprint of anomalies. |
-
Known etiology was assigned based on specific and bourgeois criteria and could be either genetic, environmental (teratogenic), or due to twinning:
-
Genetic—cases were classified as having a known genetic etiology if there was documentation of abnormal chromosomal number (trisomy) or structure (insertion, deletion) or a single factor condition (such equally Noonan syndrome)
-
Ecology—this required documentation of exposure to a recognized human teratogen8 (for instance, medication, such every bit valproic acid, or pregestational diabetes with abnormal hemoglobin A1c concentration during the periconceptional period or early pregnancy). Among mothers noted to have diabetes (pregestational or gestational), nosotros reviewed their timing of diagnosis before or during pregnancy, medication use for control of blood sugar, and if listed, the hemoglobin A1c testing date and concentration. Women listed as having gestational diabetes with a diagnosis in the kickoff trimester were reclassified as having pregestational diabetes if their hemoglobin A1c was >five.6. To assign diabetes as a cause, the mother had to have evidence of poorly controlled pregestational diabetes and an infant with selected birth defects that, based on the published literature, were indicative of diabetic embryopathyix 10 11: heterotaxy, holoprosencephaly, multiple vertebral defects, bilateral renal defects, or caudal dysgenesis. Conversely, pregestational diabetes in cases of isolated defects such as anencephaly or a built heart defect, or a major with modest defect was not considered as a known cause for those particular infants
-
Twinning—abnormalities in twinning included either acardiac or conjoined twins.
-
-
Morphology: a case with a single major birth defect (with or without a small-scale birth defect) was considered isolated. This definition includes isolated sequences. Infants without a major birth defect were included if they had a chromosomal anomaly (such as trisomy 21 with no reported major nativity defect, normal echocardiogram, and none of the selected list of objective minor defects) or eligible genetic condition (such as skeletal dysplasia). Only a selected listing of minor defects was classified and analyzed; these were selected considering they tin be considered as objective findings with express variation in reporting and nomenclature (table 1 ). This listing included mainly discontinuous traits such as preauricular tags or single umbilical artery, rather than continuous traits such equally hypertelorism, which crave careful measurements and chart based decision criteria
-
Pathogenesis: three groups were created and divers by machinery based on embryology, non ICD-9 BPA codes (sequence, developmental field defect, or known blueprint of nascence defects, table 1 ). An example of a "known pattern" is the VATER/VACTERL association. This association was operationally defined as the presence of three or more VACTERL defects (vertebral defects, anal atresia, cardiac anomaly, esophageal atresia or tracheoesophageal (TE) fistula, renal malformation, radial limb malformation) with at least i being either esophageal atresia/TE fistula or anal atresia.12 To farther promote consistency, the aforementioned clinical geneticist (JCC) reviewed and classified all cases of potential VACTERL association
Implementation of multidimensional classification
For this study, the clinicians together adult a systematic process for the re-review of all cases. In general, each example was reviewed by one clinician, and the accuracy of the classification was farther enhanced by assigning certain phenotypes to the clinician with the greatest expertise in that specialty. We re-reviewed the complete population based resident cohort for five consecutive birth years (1 January 2005 to 31 December 2009). We elected to assess this 5 year birth cohort because some genetic tests tin be ordered well afterward infancy, changing the classification status. Instance classification can as well change equally knowledge progresses. For example, cases of CHARGE association (coloboma, heart defect, choanal atresia, growth/developmental retardation, genital and ear abnormalities) were changed from "multiple congenital anomaly" to "syndrome/genetic" afterwards mutations in the CHD7 cistron were established as a cause in 2004xiii—in this situation, cases that met the established clinical criteria for CHARGE (with or without CHD7 mutation testing) were reclassified as "genetic." The classification was supported by an Access database module that captured both the classifications and comments from the clinical reviewers.
The cohort included 6547 confirmed cases. We excluded 834 cases of isolated birth defect: twin related (n=ii); pelviectasis or hydronephrosis without evidence of obstruction (n=47); small (<4 mm) secundum atrial septal defects (n=200); and distal (kickoff degree) or megameatus type hypospadias (northward=585). Nosotros also excluded spontaneous abortions occurring at <20 weeks' gestation (north=209). After exclusions, the terminal written report cohort included 5504 cases.
Statistical analyses were washed with SAS Enterprise Guide version vi.1 software (SAS Plant, Cary, NC, 2013).
Patient involvement
No patients were involved in setting the research question or the event measures, nor were they involved in the design and implementation of the study. In that location are no plans to involve patients in the dissemination of results.
Results
The population based study cohort included 5504 infants with major nascency defects among 270 878 full births (alive births and stillbirths), giving a prevalence of 2.03%. In this cohort, 92.one% (5067/5504) of cases (isolated and non-isolated) occurred in liveborn infants: 75.iii% (4147/5504) had an isolated defect (unknown and known etiology combined) (tabular array 2, fig 1 ). A positive family history (having a similarly affected commencement degree relative) was documented in 4.8% cases overall (266/5504). Compared with the underlying birth accomplice (births in Utah, 2005-09), the affected cohort included more boys (57.7%, P<0.001), fifty-fifty after we excluded cases known to be sexual practice express anomalies (such as hypospadias, 47,XXY/XYY/XXX, 45,Ten).
Tabular array 2
Number of cases of nativity defects, per centum, and prevalence (per 1000 births) stratified by morphology (isolated and not-isolated) and pregnancy consequence in Utah, 2005-09
| Morphology | Pregnancy outcome | Full | |
|---|---|---|---|
| Live birth | Fetal loss | ||
| Isolated | |||
| No of infants | 4147 | 204 | 4351 |
| % total | 75.iii% | 3.7% | 79% |
| Prevalence/thou | 15.3 | 0.8 | xvi.1 |
| Non-isolated * | |||
| No of infants | 920 | 233 | 1153 |
| % total | 16.7% | 4.two% | 21% |
| Prevalence/1000 | 3.4 | 0.9 | 4.three |
| Total | |||
| No of infants | 5067 | 437 | 5504 |
| % total | 92% | 7.9% | 100% |
| Prevalence/thousand | eighteen.7 | 1.half-dozen | twenty.3 |
*Non-isolated: cases with ≥ii majors, minors only, and no major or pocket-sized malformations.
Fig ane Known and unknown etiology of birth defects
Unknown etiology
Overall, 79.eight% of cases (n=4390) were classified as unknown etiology (tabular array iii ), 3.6% were known to be familial (isolated iii.vii%; multiple 2.7%). Boys were over-represented in both isolated (59.5%, P<0.001) and multiple (55.four%, P=0.02) instance groups.
Table 3
Etiologic classification of birth defects stratified past morphology and pregnancy outcome in Utah, 2005-09. Figures are numbers (percentage)
| Morphology | Total (n=5504) | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| None | Isolated | ≥two majors | Minors simply* | |||||||||
| Live birth (north=66, 1.2%) | Fetal loss† (n=43, 0.8%) | Live birth (n=4147, 75.three%) | Fetal loss† (n=204, iii.7%) | Alive birth (n=749, xiii.half dozen%) | Fetal loss† (n=137, 2.ix%) | Live birth (n=105, 1.ix%) | Fetal loss† (northward=53, i.0%) | |||||
| Known etiology | ||||||||||||
| No (%) full | 66 (5.9) | 43 (3.nine) | 407 (36.5) | 70 (6.3) | 287 (25.8) | 83 (vii.five) | 105 (9.4) | 53 (4.8) | 1114 (20.two) | |||
| Chromosomal abnormality | 58 | 43 | 285 | 52 | 183 | 67 | 103 | 53 | 844 | |||
| Number | 41 | 41 | 216 | 47 | 103 | 63 | 92 | 53 | 656 | |||
| Structure | 17 | 2 | 69 | 5 | 80 | 4 | 11 | — | 188 | |||
| Genetic | viii | — | 106 | 5 | 80 | 7 | ii | — | 208 | |||
| Expression | — | — | iii | — | iv | — | — | — | seven | |||
| Single gene | 8 | — | 103 | v | 76 | 7 | two | — | 201 | |||
| Teratogen | — | — | 15 | i | 23 | 7 | — | — | 46 | |||
| Diabetes | — | — | 8 | — | 18 | 7 | — | — | 33 | |||
| Infections | — | — | 5 | 1 | 3 | — | — | — | 9 | |||
| Medications | — | — | two | — | 2 | — | — | — | 4 | |||
| Twinning | — | — | 1 | 12 | 1 | ii | — | — | 16 | |||
| Acardiac | — | — | — | 8 | — | — | — | — | viii | |||
| Conjoined | — | — | 1 | 4 | 1 | two | — | — | 8 | |||
| Unknown etiology | ||||||||||||
| No (%) total | — | — | 3740 (85.2) | 134 (iii.1) | 462 (x.5) | 54 (i.2) | — | — | 4390 (79.eight) | |||
Among the unknown etiology instance grouping, 344 (7.8% of 4390) were further classified as a sequence (due north=242, 70.3%), a developmental field defect (northward=71, 20.6%), or a known pattern (n=31, ix.0%) (table 4 ). Isolated defects accounted for near cases classified as a sequence (n=187, 77.3%) or developmental field defect (north=fifty, 70.4%), whereas cases classified as a design were more probable to have multiple birth defects (due north=30, 96.8%). Eighteen of 20 infants with birth defects consistent with VATER/VACTERL clan (known blueprint) were classified as unknown etiology.
Table iv
Pathogenesis of 344 cases of birth defects with unknown etiology, stratified by morphology and pregnancy effect in Utah, 2005-09. Figures are numbers (percentage)
| Morphology | Full | |||||
|---|---|---|---|---|---|---|
| Isolated | ≥ 2 majors | |||||
| Alive birth | Fetal loss* | Live birth | Fetal loss* | |||
| Sequence (north=242, 70.iii%) | ||||||
| Spina bifida, hydrocephalus, clubbed foot | 46 | 5 | 14 | — | 65 (26.9) | |
| Renal† | 13 | 16 | iv | 1 | 34 (xiv.0) | |
| Arthrogryposis | 15 | two | 10 | 4 | 31 (12.eight) | |
| Pierre Robin | 21 | - | 8 | — | 29 (12.0) | |
| Amniotic ring | xi | 8 | 1 | — | twenty (8.three) | |
| Urethral obstruction‡ | 10 | 4 | 1 | 2 | 17 (vii.0) | |
| Limb-trunk wall with/without amniotic ring | 2 | 11 | — | two | 15 (6.2) | |
| Gastroschisis with atresia§ | 11 | one | 1 | — | thirteen (v.iv) | |
| Urethral obstruction with renal¶ | 4 | 2 | 5 | — | 11 (4.five) | |
| Poland bibelot | 2 | — | 1 | — | 3 (one.2) | |
| Sturge-Weber | 3 | — | - | — | 3 (1.2) | |
| Frontonasal malformation | — | — | 1 | — | ane (0.iv) | |
| Full | 138 (57.0) | 49 (twenty.2) | 46 (19.0) | ix (iii.7) | 242 | |
| Developmental field defect (n=71, 20.6%) | ||||||
| Laterality | 27 | 1 | 8 | one | 37 (52.i) | |
| Holoprosencepahly | 10 | 2 | 5 | 4 | 21 (29.6) | |
| Septo-optic dysplasia | 2 | — | 2 | — | four (five.vi) | |
| Urorectal septum defect | 3 | — | i | — | 4 (5.6) | |
| Pentalogy of Cantrell | two | — | — | — | 2 (two.eight) | |
| Sirenomelia | two | — | — | — | 2 (2.viii) | |
| Cloacal exstrophy | 1 | — | — | — | ane (1.4) | |
| Total | 47 (66.2) | 3 (4.2) | xvi (22.five) | v (7.0) | 71 | |
| Pattern (n=31, 9.0%) | ||||||
| VATER/VACTERL | — | — | 16 | 2 | eighteen (58.1) | |
| Goldenhar/OAV | 1 | — | 8 | 1 | ten (32.3) | |
| Caudal dysgenesis | — | — | 3 | — | three (9.viii) | |
| Total | ane (three.two) | 0 | 27 (87.one) | 3 (9.6) | 31 | |
Known etiology
A fifth (20.two%, north=1114) of cases were assigned a known etiology (table three ). Equally shown in figure 2 , 90.4% of the cases with a known etiology were represented by the three common trisomies (21, 18, xiii), Turner syndrome, structural chromosomal abnormalities, and single gene disorders.
Fig ii Number and cumulative per centum of cases of birth defects with a known etiology, Utah 2005-09. TBSS=tract based spatial statistics
For the known etiology instance group, 57 (v.1% of 1114) were farther classified as a sequence (due north=35, 61.4%), a developmental field defect (northward=xiii, 22.8%), or a known pattern (n=10, 17.five%) (data not shown). Of the remaining two cases with VATER/VACTERL clan (known pattern), 1 case occurred with pregestational diabetes (teratogen) and another with partial trisomy (7q11.21 duplication) (chromosomal-structure).
Discussion
In this 5 twelvemonth population based nativity defect case cohort, systematic clinical review identified known etiology in just ane in five—specific etiology could not exist conclusively assigned in most (79.viii%) cases. We considered the etiology known if in that location was conclusive evidence of ane of four factors: chromosomal abnormalities (structure or number), genetic conditions, twinning, or an established human teratogen. Methods to determine if an environmental exposure is a human teratogen were recently reviewed and applied to the nativity defects associated with the Zika virus.14
Based on current science, our study revises and updates the historical findings from two well known hospital based studies of infants with nascency defects.15 16 The overall conclusion remains that a specific crusade cannot yet be determined for nigh birth defects, underscoring the current gaps in knowledge and the claiming of primary prevention.
Comparison with other studies
We focused on major nascence defects (excluding some mutual defects), for a prevalence of ii%. If nosotros extrapolate from this bourgeois estimate, nosotros estimate that each year a minimum of 78 000 infants are born in the The states with a serious birth defect. In 63 000, in that location would be no identifiable etiology. These figures are intended as minimum estimates. With different criteria for inclusion, investigators have reported a prevalence of 2.24% amongst infants with a birth defect diagnosed earlier discharge from the maternity ward or earlier the age of 5 days at Boston Hospital for Womensixteen and 5.5%17 from the Texas Birth Defects Monitoring Programme.
Our guess of a known etiology in just over twenty% is conservative. As genetic technology advances and more discoveries made on the genetic causes of nativity defects, the proportion with a known crusade volition increase. For instance, estimates of the genetic contribution to congenital centre disease (the about common birth defect) has increased, based on contempo data suggesting that copy number variants and de novo mutations together could business relationship for 15% of all cases.xviii 19 20 As well, for some well known chance factors, attribution of an exposure to a birth defect in an individual example remains challenging. The epidemiologic metric of owing fraction (that is, the proportion of nativity defects owing to the exposure when cause is known) is applicable to populations, not individual cases. In this study, it was non possible to determine if a woman'south history of smoking directly resulted in her baby's oral facial cleft every bit the modest odds ratio of nearly ane.iii predicts that many children practice non have an oral cleft because of that exposure. For pregestational diabetes, yet, nosotros used data on the estimates and attributable fraction of 70% for isolated and xc% for multiple defectsx to select certain birth defects equally related to diabetes.
Decision of etiology is critically important to focus research efforts for reduction of run a risk or prevention of occurrence (such as preconception folic acrid supplementation and neural tube defects). Few studies have tried to directly assess the proportion of birth defects with or without a known etiology. Higurashi and colleagues re-examined infants each month for the outset year to identify those with malformation syndromes not diagnosed at birth simply did not mention the proportion without a known etiology.21 Two hospital based cohorts used different methods (such every bit inclusion criteria and diagnosis within days later birth) to generate estimates of those infants without a known etiology.15 16 Nelson and Holmes estimated 43.2% of their infants with birth defects born in a single hospital did not have a known etiology.16 Infants were included if they received a diagnosis on or before the fifth day of life. Notably, cases considered to be familial (14.v%) or "multifactorial" (23%) were considered to be of known etiology; nevertheless, definitions were non provided and the inclusion especially of the "multifactorial" conditions is debatable. In dissimilarity, in our report, we defined familial cases only as infants with an afflicted first degree relative (4.8% overall, three.6% unknown etiology). Moreover, because of the difficulty in defining and proving multifactorial inheritance, we did non accept such a category. Of notation, if we add the cases classified by Nelson and Holmes16 as multifactorial inheritance (23%) and familial (14.5%) to those that they classified originally as unknown (43.ii%), the total adds to 80.7%, similar to our finding.
The causes of birth defects currently without known etiology are probably circuitous and could include interactions between the genetic profiles of parents and embryo and the environmental milieu during preconception and early gestation. For some nativity defects, some progress has been made over the past decades, such as the contribution of microdeletions (such every bit deletion 22q11 in cases of heart defects and scissure palate22 23 24 25) and novel single gene mutations (such equally CHD7 mutations in Charge syndromethirteen). While these genetic causes are relatively straightforward, nevertheless, it is probable that further inquiry volition discover more complex networks accounting for genetic and environmental contributions to birth defects etiology. Accumulating evidence is uncovering developmental networks that when disrupted can cause birth defect syndromes.26 Some of these networks could besides exist influenced by environmental exposures, such as the midline patterning network related to the sonic hedgehog gene, which straight involves cholesterol metabolism. For example, the adventure for holoprosencephaly could exist increased not only by mutations in sonic hedgehog just potentially also by environmental influences (yet undiscovered) that change the embryonic cholesterol biosynthesis, perhaps interacting with sonic hedgehog variants.26
Nascence defects know no geographic boundary and occur in every land of the world. Because many countries exercise non have the capacity to monitor nascence defects that occur amidst all pregnancy outcomes, it is difficult to approximate their true worldwide prevalence and global burden. Based on the findings of this study, however, if we count merely those infants alive born with an isolated birth defect, 25% of the cases will be missed. The resulting underestimation of the brunt of disease can have serious policy implications and hinder the investments in research and interventions to better prevent and treat these major threats to babyhood survival and lifelong wellness.
Inquiry to understand birth defect etiology requires a well defined and clinically characterized case grouping. Cases with known etiology must be carefully identified and excluded to maximize the chance of discovery.27 While commonly used nascency defect nomenclature schemes (such every bit ICD-ix or ICD-10) are valuable for general purposes such every bit studies on morbidity and bloodshed, they are not ideal in the evaluation of etiologies or trends28 and could overestimate prevalence.29 30 31 32 These coding systems are typically organized by beefcake or function rather than cause or embryologic process. Few studies have applied classifications specific to birth defects to population based cohorts. One of these, the National Birth Defects Prevention Study, has leveraged the collaboration of clinical geneticists and epidemiologists to pursue discovery of modifiable causes of nascency defects.33 34 35 Continued progress will crave the combined endeavour and a multidisciplinary approach that incorporates non simply the clinical evaluation past dysmorphologists/clinical geneticists and the methodological expertise of epidemiologists but also includes experts in developmental biology, pharmacology, infectious diseases, immunology, and bioinformatics, in addition to a more objective assessment of periconceptional exposures that improve on the typical maternal self reports. Finally, it would be helpful to integrate etiology, morphology, and pathogenesis assessment into the basic framework of epidemiologic studies. Such integration will meliorate precision and assist researchers to focus research initiatives and investigate mutual pathways amidst birth defects.
Limitations
This study has potential limitations. The birth prevalence of two.03% reported in this study is lower than the ii.24-5.5% reported elsewhere.ii 16 17 Such lower prevalence estimates could relate to the eligibility criteria of the Utah surveillance system, which exclude some common mostly milder weather that are variably defined and ascertained (such every bit muscular ventricular septal defects, clubfoot, cryptorchidism). Also, considering cases were classified based on data abstracted from mother and babe medical records, there is a possibility that critical data for appropriate classification was unavailable at the fourth dimension of medical record abstraction. In addition, we could accept underestimated the proportion acquired past a teratogen if an exposure (such as maternal pregestational diabetes) was non noted in the medical tape or not queried by the physician of tape. The information in these medical records comes from different specialists, frequently including perinatologists, genetic counselors, neonatologists, and/or pediatric geneticists. Whereas some level of etiologic under-ascertainment cannot be excluded, information technology is unlikely that an established environmental crusade of birth defects would be missed by anybody involved in the care of the female parent and the child. For a genetic investigation, the laboratory evaluation (such every bit karyotype, microarray) was adamant by the clinician(s) caring for the infant and was tailored to the clinical presentation. Nosotros would expect some variation within the practice of medicine.
Conclusion and public health implications
Understanding the etiology of birth defects should be both a public wellness and research priority. Our findings underscore the big gaps in current knowledge of the causes of birth defects. These gaps in turn stand for opportunities for both basic and translational researchers. Such inquiry can be specially powerful and efficient if done in collaboration with population based nativity defect surveillance programs enhanced with clinical expertise and meaningful case classification.36 Advances in the cognition of the causal pathway leading to nativity defects tin can be the basis for better primary prevention interventions, resulting in longer and better lives. For clinicians and parents, it is important to sympathise what can be done today to prevent birth defects, in item the role of preconception intendance focusing on optimal women'due south health (including screening/treating chronic illnesses, attaining folic acid sufficiency, etc). In add-on, investigation of potential causes of a nascency defect at the time of diagnosis (such as whether a genetic status is present) can help to improve plan management and appropriately counsel families, including the relief of anxiety related to unfounded information and guilt.
Notes
Contributors: MLF, JCC, JLBB, and LDB conceived and designed the project. SK and MLF cleaned and conducted the analysis for the project. All authors interpreted the information, drafted the manuscript, and assisted with manuscript revisions. MLF is guarantor.
Funding: This publication was supported by a cooperative understanding (No U01DD000490) from the Centers for Illness Command and Prevention. Its contents are solely the responsibleness of the authors and practise not necessarily correspond the official views of the Centers for Disease Control and Prevention. Data were provided by the Utah Birth Defect Network, a program within the Utah Department of Wellness. This project is supported past the Health Resources and Services Administration (HRSA) of the U.s. Department of Health and Human Services (HHS) under grant No B04MC25374. This information or content and conclusions are those of the author and should not be construed equally the official position or policy of, nor should any endorsements be inferred by HRSA, the U.s.a. Government, or the Utah Department of Health.
Competing interests: All authors have completed the ICMJE uniform disclosure class and declare no support from any organization for the submitted work, no fiscal relationships with any organizations that might take an interest in the submitted work in the previous three years, and no other relationships or activities that could appear to have influenced the submitted work.
Upstanding approval: Not required.
Data sharing: No additional data available.
Transparency: The lead writer (the manuscript'due south guarantor) affirms that this manuscript is an honest, accurate, and transparent account of the study beingness reported; that no important aspects of the study have been omitted; and that any discrepancies from the report every bit planned (and, if relevant, registered) have been explained.
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Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5448402/
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