Cleft palate morphology, genetic etiology, and risk of mortality in infants with Robin sequence.

Robin sequence (RS) has many genetic and nongenetic causes, including isolated Robin sequence (iRS), Stickler syndrome (SS), and other syndromes (SyndRS). The purpose of this study was to determine if the presence and type of cleft palate varies between etiologic groups. A secondary endpoint was to determine the relationship of etiologic group, cleft type, and mortality. Retrospective chart review of patients with RS at two high-volume craniofacial centers. 295 patients with RS identified. CP was identified in 97% with iRS, 95% with SS, and 70% of those with SyndRS (p < .0001). U-shaped CP was seen in 86% of iRS, 82% with SS, but only 27% with SyndRS (p < .0001). At one institution, 12 children (6%) with RS died, all from the SyndRS group (p < .0001). All died due to medical comorbidities related to their syndrome. Only 25% of children who died had a U-shaped CP. The most common palatal morphology among those who died was an intact palate. U-shaped CP was most strongly associated with iRS and SS, and with a lower risk of mortality. RS with submucous CP, cleft lip and palate or intact palate was strongly suggestive of an underlying genetic syndrome and higher risk of mortality.

Long-term survival for infants born with orofacial clefts in Western Australia.

BACKGROUND: Only two population-based studies have reported survival beyond 15 years for individuals with orofacial clefts (OFC), and only for individuals with isolated OFC. Compared with the general population, long-term survival was similar for individuals with cleft lip only, and lower for individuals with cleft palate only. Results for those born with isolated cleft lip and cleft palate were inconsistent. METHODS: Using linked population-based health data, including a congenital anomaly register with active surveillance and diagnoses up to 6 years, we compared survival at 1, 5, and 20 years for infants born 1980 to 2010 with, and without OFC. RESULTS: Of the 8112 live born infants in the cohort, 186 died before 20 years; most (81%) died during infancy. Compared with infants without OFC, infants born with all types of isolated OFC ± additional minor anomalies had similar infant survival (around 99%), but we found lower survival for infants with all cleft types and an additional major anomaly (66-84%). From 1 to 5 years, only infants with cleft palate only and an additional major anomaly had lower survival (97%) compared with children without OFC (99.9%). From 5 to 20 years, children with all cleft types, with or without additional major anomalies had similar survival to children without OFC (98-100%). CONCLUSION: Parents with a child diagnosed with an OFC ± additional minor anomalies only can be reassured that the OFC does not influence survival rates in infancy, or long-term. Infant survival was lower only for children with OFC and additional major anomalies.

Mortality among infants born with orofacial clefts in a single cleft network.

OBJECTIVE: To determine mortality rate and cause of death in infants born with orofacial clefts. METHODS: Retrospective case note review of all children with orofacial clefts within the East of England Cleft Network who have died. RESULTS: Between 2002 and 2010, of 638 children born with orofacial clefts, 23 died at a median age of 5 months (range, 1 day to 4 years). The overall mortality rate was 36 per 1000 cleft births. A total of 21 deaths were in the isolated cleft palate group, with a calculated death rate of 68.1 per 1000. One child each from the cleft lip and the cleft lip and palate groups died. Of the children who died, 21 (91%) had other structural abnormalities. Of these children, 19 (83%) died before their first birthday. The causes of death were mainly due to associated congenital anomalies (61%) and infection (17%). CONCLUSIONS: Children born with cleft palate have a 15-fold increase in mortality compared with the regional East of England infant mortality rate and at least a 10-fold increase when compared with other clefts. Pediatricians should be involved in the care of these complicated patients.

Associated anomalies among infants with oral clefts at birth and during a 1-year follow-up.

Reports of birth defects rates may focus on defects observed in the newborn period or include defects diagnosed at older ages. However, little information is available on the rates of additional anomalies detected after birth or on the ages at which such anomalies are diagnosed. The aims of this work were to describe the initial diagnoses of oral clefts, isolated or associated with other defects, in newborn infants ascertained in hospitals of the ECLAMC network, and diagnostic changes that occurred due to detection of additional defects during a 1-year follow-up period. Seven hundred ten liveborn infants with cleft lip only (CLO), cleft lip with cleft palate (CLP), or cleft palate (CP) were ascertained between 2003 and 2005. Prevalence estimates of isolated and associated (ASO) clefts, diagnoses in infants with associated clefts, and the percentage of isolated clefts that were reclassified as associated were established. Birth prevalence estimates (per 1,000) were as follows: Total: 1.7; CLP: 0.94 (ASO = 23.5%); CP: 0.46 (ASO = 42.3%); CLO: 0.28 (ASO = 7.6%). Initial diagnoses in infants with associated clefts included 38 infants with chromosomal abnormalities, 33 with non-chromosomal syndromes, 16 with malformation sequences, and 98 with multiple anomalies of unknown etiology. Seven percent of newborns initially classified as isolated were later reclassified as associated. Ten infants without associated defects or clinically suspected syndromes were diagnosed as syndromic only through laboratory findings or family history, illustrating the difference between the terms associated versus isolated, which refers to presence or absence of associated anomalies, and syndromic versus non-syndromic, which refers to etiology.

The effect of systematic pediatric care on neonatal mortality and hospitalizations of infants born with oral clefts.

BACKGROUND: Cleft lip and/or palate (CL/P) increase mortality and morbidity risks for affected infants especially in less developed countries. This study aimed at assessing the effects of systematic pediatric care on neonatal mortality and hospitalizations of infants with cleft lip and/or palate (CL/P) in South America. METHODS: The intervention group included live-born infants with isolated or associated CL/P in 47 hospitals between 2003 and 2005. The control group included live-born infants with CL/P between 2001 and 2002 in the same hospitals. The intervention group received systematic pediatric care between the 7th and 28th day of life. The primary outcomes were mortality between the 7th and 28th day of life and hospitalization days in this period among survivors adjusted for relevant baseline covariates. RESULTS: There were no significant mortality differences between the intervention and control groups. However, surviving infants with associated CL/P in the intervention group had fewer hospitalization days by about six days compared to the associated control group. CONCLUSIONS: Early systematic pediatric care may significantly reduce neonatal hospitalizations of infants with CL/P and additional birth defects in South America. Given the large healthcare and financial burden of CL/P on affected families and the relatively low cost of systematic pediatric care, improving access to such care may be a cost-effective public policy intervention. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00097149.

Epidemiologic trends of infants with orofacial clefts in a multiethnic country: a retrospective population-based study.

Cleft births surveillance is essential in healthcare and prevention planning. Data are needed in precision medicine to target upstream management for at-risk individuals. This study characterizes Singapore's population-based orofacial cleft topography by ethnicity and gender, and establishes the cleft cohort's infant mortality rate. Data, in the decade 2003 to 2012, were extracted by the National Birth Defects Registry. Trend testing by linear regression was at p < 0.05 significance level. Prevalence per 10,000 for population-based cleft live births was 16.72 with no significant upward trend (p = 0.317). Prevalence rates were 8.77 in the isolated cleft group, 7.04 in the non-isolated cleft group, and 0.91 in the syndromic cleft group. There was significant upward trend in infants with non-isolated clefts (p = 0.0287). There were no significant upward trends in infants with isolated clefts and syndromic clefts. Prevalence rates were sexually dimorphic and ethnic-specific: male 17.72; female 15.78; Chinese group 17.17; Malay group 16.92; Indian group 10.74; and mixed ethnic origins group 21.73. The overall infant mortality rate (IMR) was 4.8% in the cohort of 608 cleft births, which was more than double the population-based IMR of 2.1% in the same period. Infants with non-isolated and syndromic clefts accounted for 96.6% of the deaths.

Incidence, Risk Factors, and Mortality Associated With Orofacial Cleft Among Children in Ontario, Canada.

Importance: Orofacial cleft (OFC) is one of the most common congenital malformations, with a wide variation in incidence worldwide. However, population-based studies on the incidence of OFC in North America are lacking. Objectives: To examine the incidence of OFC in Ontario, Canada, and to compare risk factors and mortality associated with children with OFC vs children without OFC. Design, Setting, and Participants: This population-based retrospective cohort study used health administrative data from the province of Ontario, Canada. Children with OFC who were born from April 1, 1994, to March 31, 2017, in Ontario were each matched to 5 children without OFC based on sex, date of birth (±30 days), and mother's age (±5 years). Analyses were conducted from September 2018 to January 2019. Exposures: Children born with OFC. Main Outcomes and Measures: Incidence of OFC over time and regional variation. Risk factors for OFC were assessed using 1-way analysis of variance for means, Kruskal-Wallis for medians, and χ2 tests for categorical variables. Adjusted Cox regression models were used to assess mortality. Results: From 1994 to 2017, 3262 children were born with OFC in Ontario, Canada, and they were matched to 15 222 children born without OFC. Incidence of OFC in Ontario was 1.12 cases per 1000 live births, with wide geographic variation and a lower incidence from 2004 to 2017 compared with 1994 to 2003 (1.02 vs 1.13 cases per 1000 live births; P = .002), especially for the subgroup with cleft palate (0.52 vs 0.44 cases per 1000 live births; P = .006). Children with OFC, compared with children without OFC, were more likely to be born prematurely (406 children [13.3%] vs 1086 children [7.1%]; P < .001; standardized difference, 0.21) and had lower mean (SD) birth weight (3215.3 [687.6] g vs 3382.6 [580.0] g; P < .001; standardized difference, 0.26). The mortality rate among children with OFC was higher than among matched children without OFC (hazard ratio, 10.60; 95% CI, 7.79-14.44; P < .001). When mortality was adjusted for the presence of congenital or chromosomal anomalies, the risk of death was not significantly different between children with OFC and those without OFC (hazard ratio, 1.35; 95% CI, 0.73-2.72). Conclusions and Relevance: These findings suggest that incidence of OFC In Ontario, Canada, decreased from 1994 to 2017. Mortality in children with OFC was high, especially in the first 2 years of life, and was predominantly associated with the presence of other congenital or chromosomal anomalies. Further research is required to better understand the causes of wide geographical variations of OFC incidence and improve the survival of these patients.

Antenatal detection of cleft lip with or without cleft palate: incidence of associated chromosomal and structural anomalies.

OBJECTIVE: To ascertain how many fetuses with prenatally diagnosed cleft lip with or without cleft palate have associated congenital structural and/or chromosomal abnormalities and whether there is an association with the anatomical type of cleft lip or palate. METHODS: This was a retrospective review of infants referred to the North-West England Regional Cleft Lip and Palate (CLAP) team between January 2000 and January 2006. Referrals made to the Regional Fetal Management Unit (FMU) in the same time period were investigated to identify the corresponding antenatal ultrasound findings and data on termination of pregnancy and intrauterine fetal death. RESULTS: Over the 6-year period investigated, 570 infants were referred to the FMU and/or CLAP team. Among these, there were 24 terminations of pregnancy, two intrauterine fetal deaths and one early neonatal death identified. Data on 69 of the 543 patients that survived were incomplete. Of 188 cases with unilateral and 34 cases with bilateral cleft lip +/- palate there were no karyotypical abnormalities without other structural abnormalities. The incidence of associated structural abnormalities varied with the anatomical type of cleft: that of unilateral cleft lip +/- palate was 9.8% (19/194), that of bilateral cleft lip and palate was 25% (11/44) and that of midline cleft lip and palate was 100% (11/11). None of 252 cases with isolated cleft palate was identified antenatally; of these, 5.6% (n = 14) had either karyotypical or associated structural abnormalities and 21.0% (n = 53) had a genetic syndrome as an underlying diagnosis. CONCLUSIONS: It is essential to tailor the antenatal counseling of patients to the specific scan diagnosis, considering both the anatomical type of cleft and the presence or absence of associated abnormalities. It is inappropriate to offer invasive testing to all patients. The use of three-dimensional ultrasound as an adjunct should be considered in these patients to improve the accuracy of prenatal diagnosis.

Bilateral cleft lip and palate without premaxillary protrusion is associated with lethal aneuploidies.

OBJECTIVE: To investigate the clinical implications of two categories of fetal bilateral cleft lip and palate (BCLP): with premaxillary protrusion and with a flattened profile. METHODS: This was a retrospective study of fetuses with a prenatal diagnosis of BCLP at the Department of Obstetrics and Gynecology of the University of Bologna in the period 1991-2005. RESULTS: BCLP was diagnosed prenatally in 14 cases (mean gestational age at diagnosis, 21 (range, 12-36) weeks). In nine of these, there was a premaxillary pseudomass; in the remaining five, the profile was flat. Associated structural and/or chromosomal anomalies were found in two of the nine with a premaxillary pseudomass and in all five of those with a flat profile (P = 0.02). All fetuses with a flat profile had aneuploidies (three trisomy 18, one trisomy 13, one trisomy 8 mosaic), as did one of the nine with a premaxillary pseudomass. Eight of the pregnancies were terminated, including three of those with a premaxillary pseudomass and all five of those without. All continuing pregnancies resulted in live births, although one neonate affected by Krabbe's disease died shortly after birth. CONCLUSIONS: Our findings suggest that a third of cases of BCLP diagnosed in utero have a flat profile and these are at high risk of lethal aneuploidies.

Description of the methodology used in an ongoing pediatric care interventional study of children born with cleft lip and palate in South America [NCT00097149].

BACKGROUND: The contribution of birth defects, including cleft lip and palate, to neonatal and infant mortality and morbidity is substantial. As other mortality and morbidity causes including infections, hygiene, prematurity, and nutrition are eradicated in less developed countries, the burden of birth defects will increase proportionally. METHODS/DESIGN: We are using cleft lip and palate as a sentinel birth defect to evaluate its burden on neonatal and infant health and to assess the effectiveness of systematic pediatric care during the first month and first two years of life in decreasing this burden. The neonatal intervention, consisting of weekly pediatric evaluation and referral to appropriate care, is delivered to about 696 infants born with cleft lip and/or palate in 47 hospitals in South America. Neonatal mortality in this group will be compared to that in a retrospective control group of about 464 infants born with cleft lip and/or palate in the same hospitals. The subgroup of infants with isolated clefts of both the lip and palate (about 264) is also randomized into two groups, intervened and non-intervened, and further followed up over 2 years. Intervened cases are evaluated by pediatricians every three months and referred for appropriate care. The intervened and non-intervened cases will be compared over study outcomes to evaluate the intervention effectiveness. Non-intervened cases are matched and compared to healthy controls to assess the burden of cleft lip and palate. Outcomes include child's neurological and physical development and family social and economic conditions. DISCUSSION: Large-scale clinical trials to improve infant health in developing countries are commonly suggested, making it important to share the methods used in ongoing studies with other investigators implementing similar research. We describe here the content of our ongoing pediatric care study in South America. We hope that this may help researchers targeting this area to plan their studies more effectively and encourage the development of similar research efforts to target other birth defects or infant outcomes such as prematurity and low birth weight.

Are isolated facial cleft lip and palate associated with increased perinatal mortality? A cohort study from the West Midlands Region, 1995-1997.

OBJECTIVE: To investigate the association between cleft lip and/or palate and perinatal mortality. METHODS: A retrospective review was performed of cases of cleft lip/palate born to West Midlands residents from 1995 to 1997. Perinatal mortality for identified cases was compared with all births from 1995 to 1997. RESULTS: 347 cases of cleft lip and/or cleft palate were delivered from 1995 to 1997. Thirty-six pregnancies were terminated due to parental wishes--2 were registerable births. There were 310 spontaneous registerable births (stillbirths/livebirths) with cleft lip and/or palate and 1 further late fetal loss. In 220 (70.5%), the lesion was isolated. Of these, there were 7 perinatal deaths, 5 had post mortems and no additional anomalies were identified. In 92 (29.5%) cases other abnormalities were identified. The overall perinatal mortality rate (PNMR) in the West Midlands, was 10.0/1000 total births. The overall PNMR for babies with facial clefts was 89.7/1000 total births. The PNMR for those with associated anomalies was 228.3/1000 live/still births. The PNMR for isolated facial clefts was 31.8/1000 live/still births, significantly higher than the background population (OR 3.3, 95% CI: 1.5-7.0). CONCLUSION: Consideration should be given to screening the fetus at 20-24 weeks for facial deformity. This has implications for detection both of fetal anomalies and of a population at risk for adverse outcome.

The burden of selected congenital anomalies amenable to surgery in low and middle-income regions: cleft lip and palate, congenital heart anomalies and neural tube defects.

OBJECTIVE: To quantify the burden of selected congenital anomalies in low and middle-income countries (LMICs) that could be reduced should surgical programmes cover the entire population with access to quality care. DESIGN: Burden of disease and epidemiological modelling. SETTING: LMICs from all global regions. POPULATION: All prevalent cases of selected congenital anomalies at birth in 2010. MAIN OUTCOME MEASURES: Disability-adjusted life years (DALYs). INTERVENTIONS AND METHODS: Surgical programmes for three congenital conditions were analysed: clefts (lip and palate); congenital heart anomalies; and neural tube defects. Data from the Global Burden of Disease 2010 Study were used to estimate the combination of fatal burden that could be addressed by surgical care and the additional long-term non-fatal burden associated with increased survival. RESULTS: Of the estimated 21.6 million DALYs caused by these three conditions in LMICs, 12.4 million DALYs (57%) are potentially addressable by surgical care among the population born with such conditions. Neural tube defects have the largest potential with 76% of burden amenable by surgery, followed by clefts (59%) and congenital heart anomalies (49%). Sub-Saharan Africa and South Asia have the greatest proportion of surgically addressable burden for clefts (68%), North Africa and Middle East for congenital heart anomalies (73%), and South Asia for neural tube defects (81%). CONCLUSIONS: There is an important and neglected role surgical programmes can play in reducing the burden of congenital anomalies in LMICs.

Oesophageal atresia with cleft lip and palate: a marker for associated lethal anomalies?

An adverse association between oesophageal atresia (OA) and cleft lip-palate (3% incidence) has been reported. The present study analyses outcomes of this rare association at a UK paediatric surgical centre. Hospital charts of newborns diagnosed with OA were reviewed. Demographics, associated anomalies and prognostic classification (after Spitz 1994) were recorded. Mortality rates and causes of death were examined in OA babies with cleft lip-palate. Of 152 patients treated for OA, five babies (3%) had cleft lip-palate. All of these newborns had common variant OA-TEF and were Spitz group II category. Deaths occurred in 3 of 5 patients (60%) in the OA-cleft group compared to only 8 of 147 patients (5%) without clefts (p < 0.005; Fisher's exact test). OA-cleft non-survivors succumbed to tetralogy of Fallot (n = 2) and trisomy 18 (n = 1; treatment withdrawn). Both survivors with cleft lip-palate had features of the VACTERL sequence: one baby also had Goldenhaar syndrome, the other aortic coarctation. These children now attend mainstream school. Although high-quality survival is possible in OA with cleft lip-palate, this rare phenotype is associated with a substantially decreased survival. Rather than causing death directly, the combination of OA and cleft lip-palate appears to be a marker for further lethal anomalies.

Fetal mortality in oral cleft families(IV): the "doubling effect".

Fetal mortality data from Lancaster, Penn., Chicago, Ill. and Minneapolis, Minn. are presented which support the authors' earlier findings in Indiana and Montreal that a positive relationship exists between the degree of liability to malformation and the incidence of fetal deaths in probands' sibships. Altogether, the study involved 189 CL sibships, 690 CLP sibships, and 3,416 pregnancies. On the basis of these data, which are derived from families of several different backgrounds of European ancestry, it is generalized that, as we proceed from CL sibships to CLP sibships, there is a doubling effect on fetal mortality. The consistency of this finding in several population samples is impressive. The implications of this observation are discussed with reference to genetic counseling.

Long term follow up study of survival associated with cleft lip and palate at birth.

OBJECTIVE: To assess the overall and cause specific mortality of people from birth to 55 years with cleft lip and palate. DESIGN: Long term follow up study. SETTING: Danish register of deaths. PARTICIPANTS: People born with cleft lip and palate between 1943 and 1987, followed to 1998. MAIN OUTCOME MEASURES: Observed and expected numbers of deaths, summarised as overall and cause specific standardised mortality ratios. RESULTS: 5331 people with cleft lip and palate were followed for 170 421 person years. The expected number of deaths was 259, but 402 occurred, corresponding to a standardised mortality ratio of 1.4 (95% confidence interval 1.3 to 1.6) for males and 1.8 (1.5 to 2.1) for females. The increased risk of mortality was nearly constant for the three intervals at follow up: first year of life, 1-17 years, and 18-55 years. The participants had an increased risk of all major causes of death. CONCLUSIONS: People with cleft lip and palate have increased mortality up to age 55. Children born with cleft lip and palate and possibly other congenital malformations may benefit from specific preventive health measures into and throughout adulthood.

First-year mortality among infants with facial clefts.

Children born with a facial cleft are not thought to be at a greater risk for infant mortality than are those without congenital anomalies. The purpose of this study was to investigate whether the presence of a facial cleft alone or its coexistence with other anomalies increases a child's risk for dying. Birth and death certificate data from Washington State for the years 1984 to 1988 were linked for infants who died before 1 year of age. Mortality rates for different types of facial clefts and for births without noted abnormalities were compared. Relative to infants with no diagnosed abnormalities noted in the birth certificate, infants with facial clefts without other abnormalities have a 3.7 fold increased odds for dying during their first year of life. This elevated risk for dying was fairly consistent during the first year of life. When facial clefts are associated with other abnormalities there is an 82.3 fold increase in odds for mortality during the first year of life. This elevated risk is highest during the neonatal period; 77% of all deaths occurred during the first 27 days. It is concluded that infants with facial clefts with or without associated anomalies have a significantly increased mortality risk when compared to infants without any diagnosed abnormalities at birth.

The effects of zero population growth on the incidence of cleft lip and palate in Western Australia.

A total of 613 cases of cleft lip, cleft palate, and combinations of both (CLP(P)) has been ascertained in the period from 1958 to 1975 in Western Australia. Near-total ascertainment of cases during this period was obtained from multiple sources. There has been a significant decline in the total incidence and the cleft lip and palate (CLP) incidence in males. The hypothesis is presented that these changes are linked to the changing fertility pattern throughout Australia (as technological improvements are made in the simplicity and efficacy of birth control), and abortion (as social attitudes change); and as the birthrate drops towards zero population growth (ZPG). The paper presents two critical observations: (i) the link between CLP(P) incidence, and demographic changes; (ii) in differing behaviour of cleft lip (CL) and CLP, which were previously regarded as linked conditions.

Thyroxin-induced differential mortality of mouse embryos with cleft lip.

Administration of thyroxin in midgestation has been reported to prevent spontaneous cleft lip in term fetuses of genetically predisposed mice. Attempts to repeat this finding have given ambiguous results. The experiment was therefore repeated using CL/Fr and A/HeJ mice, and various thyroxin dosages. The embryos were examined on days 13 and 14, earlier in gestation than in previous studies. The usual complement of cleft-lip embryos, 21% in CL/Fr and 10% in A/HeJ, was present, but they were often dead. At all dosages of thyroxin that caused embryonic mortality, differential mortality of cleft-lip embryos at term after thyroxin treatment is thus due to their increased mortality, not to prevention of the lip defect.