Hallvard Vindenes

Folic acid supplements and risk of facial clefts: national population based case-control study

Objective To explore the role of folic acid supplements, dietary folates, and multivitamins in the prevention of facial clefts. Design National population based case-control study. Setting Infants born 1996-2001 in Norway. Participants 377 infants with cleft lip with or without cleft palate; 196 infants with cleft palate alone; 763 controls. Main outcome measures Association of facial clefts with maternal intake of folic acid supplements, multivitamins, and folates in diet. Results Folic acid supplementation during early pregnancy (≥400 �g/day) was associated with a reduced risk of isolated cleft lip with or without cleft palate after adjustment for multivitamins, smoking, and other potential confounding factors (adjusted odds ratio 0.61, 95% confidence interval 0.39 to 0.96). Independent of supplements, diets rich in fruits, vegetables, and other high folate containing foods reduced the risk somewhat (adjusted odds ratio 0.75, 0.50 to 1.11). The lowest risk of cleft lip was among women with folate rich diets who also took folic acid supplements and multivitamins (0.36, 0.17 to 0.77). Folic acid provided no protection against cleft palate alone (1.07, 0.56 to 2.03). Conclusions Folic acid supplements during early pregnancy seem to reduce the risk of isolated cleft lip (with or without cleft palate) by about a third. Other vitamins and dietary factors may provide additional benefit.

Familial risk of oral clefts by morphological type and severity: population based cohort study of first degree relatives

Objective To estimate the relative risk of recurrence of oral cleft in first degree relatives in relation to cleft morphology. Design Population based cohort study. Setting Data from the medical birth registry of Norway linked with clinical data on virtually all cleft patients treated in Norway over a 35 year period. Participants 2.1 million children born in Norway between 1967 and 2001, 4138 of whom were treated for an oral cleft. Main outcome measure Relative risk of recurrence of isolated clefts from parent to child and between full siblings, for anatomic subgroups of clefts. Results Among first degree relatives, the relative risk of recurrence of cleft was 32 (95% confidence interval 24.6 to 40.3) for any cleft lip and 56 (37.2 to 84.8) for cleft palate only (P difference=0.02). The risk of clefts among children of affected mothers and affected fathers was similar. Risks of recurrence were also similar for parent-offspring and sibling-sibling pairs. The “crossover” risk between any cleft lip and cleft palate only was 3.0 (1.3 to 6.7). The severity of the primary case was unrelated to the risk of recurrence. Conclusions The stronger family recurrence of cleft palate only suggests a larger genetic component for cleft palate only than for any cleft lip. The weaker risk of crossover between the two types of cleft indicates relatively distinct causes. The similarity of mother-offspring, father-offspring, and sibling-sibling risks is consistent with genetic risk that works chiefly through fetal genes. Anatomical severity does not affect the recurrence risk in first degree relatives, which argues against a multifactorial threshold model of causation.

Altered Polymorphonuclear Neutrophilic Granulocyte Functions in Patients with Large Burns

Multiparameter flow cytometric analyses of polymorphonuclear neutrophilic granulocyte (PMNL) functions have been performed longitudinally in ten patients with large burns. The percentage of phagocytosing PMNLs was increased at admission (within 24 hours after injury) and through the first 10 days of hospitalization. The surface binding capacity and the ingestion of Staphylococcus aureus by each PMNL was increased during the same time period, and at day 2 the number of S. aureus ingested per patient PMNL was 35% higher than in the controls. The intracellular killing of Candida albicans was reduced by about 25% at admission. The microbicidal capacity was further compromised during the first 2 weeks after injury, with a reduction of intracellular killing of about 35% 5-10 days after admission. The kinetics of patient PMNL phagolysosomal acidification was altered during the first 20 days, as the initial alkalinization of the phagolysosomes documented in control PMNLs could not be demonstrated in PMNLs from patients with burns. In addition, measurements of maximal phagolysosomal acidification showed a lower pH in patient phagolysosomes than in the controls during the first 5 days. The patient PMNL H2O2 production was reduced at admission and through the first 10 days, with an oxidative burst that was 46% lower than the controls at day 5. The intracellular degradation of S. aureus proteins and DNA was slightly but significantly reduced at day 5 and day 10 after admission. The impairment of PMNL microbicidal capacity correlated with total body surface area burn.(ABSTRACT TRUNCATED AT 250 WORDS)

Completeness of registration of oral clefts in a medical birth registry: a population-based study

Background. Epidemiological surveillance and research on birth defects require accurate diagnosis and adequate registration. In this regard, the performance of national birth registries is not well described. Methods. We linked clinical data from all 3,616 cleft cases treated in Norway between 1967 and 1998 with data from the Medical Birth Registry of Norway, and calculated the proportion of clinically verified cases reported to the Registry, stratified by severity. Results. The cleft type most completely ascertained was cleft lip and palate (CLP), of which 94% were reported. Ascertainment was less complete for cleft lip alone (83% recorded), and cleft palate only (CPO) (57% recorded). For each of the three types of clefts, completeness of reporting depended on severity of the cleft. For example, 71% of cases with severe CPO were reported, while only 11% of cases with mild CPO were reported. Conclusions. Ascertainment was strongly related to cleft type and severity. To the degree that severity of birth defects may be related to their cause, these patterns of registration have implications for surveillance of birth defects as well as the conduct of etiologic studies. The large proportion of cleft palate cases unrecorded at birth suggests that clinical examination of the newborn palate is often inadequate.

Prevalence of duplications and deletions of the 22q11 DiGeorge syndrome region in a population-based sample of infants with cleft palate.

The prevalence of duplications and deletions of the 22q11.2 (DiGeorge syndrome) region was studied among babies born in Norway with open cleft palate without cleft lip (cleft palate only, CPO). During a 5‐year period (1996–2001), there were 245 live births with CPO that were referred for surgery. DNA was available from 174 cases with overt cleft palate. DNA copy number was analyzed with the multiplex ligation‐dependent probe amplification (MLPA) technique, and an unambiguous result was obtained in 169 (97%) of the samples. We found no 22q11.2 duplications, and one known, and two previously undiagnosed cases with 22q11.2 deletions. All three del22q11‐syndrome cases also had heart malformations, which represent one‐third of the 10 babies with heart malformations in our study population. The prevalence of del22q11‐syndrome among babies with cleft palate with or without additional malformations was 1 of 57 (1.8%). Because the prevalence of CPO in the 35 22q11.2 duplication cases published was 20%, we also investigated if dup22q11‐testing was warranted in this group. However, no 22q11.2 duplications were found, indicating that the duplication cases ascertained so far might not be representative of the dup22q11‐group as a whole. We conclude that neither del22q11 nor dup22q11 testing is warranted in babies with overt cleft palate as the only finding.

Interdisciplinary evaluation of consecutive patients with unilateral cleft lip and palate at age 6, 15, and 25 years: a concurrent standardized procedure and documentation by plastic surgeon; speech and language pathologist; ear, nose, and throat specialist; and orthodontist.

Purpose: To evaluate surgical results, speech, hearing, and craniofacial morphology after primary cleft repair performed from 1973 to 1979. Methods: During the years 1972 to 1985, all primary cleft surgeries were performed by 1 plastic surgeon, using Tennison lip closure combined with a periosteoplasty on the clefted alveolus at age 3 months. By mobilizing mucoperiosteal flaps, bony bridges were induced in the alveolar process in approximately 60% of the cases. All patients had the soft palate closed at age 24 months by a pushback technique. All children with complete unilateral clefts without soft tissue bands (unilateral cleft lip and palate) primary operated on 1973 to 1979 were included in the material, except 3 patients with a syndrome and 2 patients of foreign ethnicity. The material involved 30 consecutive patients with unilateral cleft lip and palate (20 boys and 10 girls; 16 left-sided and 14 right-sided clefts) who were operated on. Standardized records including photos, radiographs, lateral cephalograms, plaster model, and recording of speech and hearing were collected according to the treatment protocol at age 6, 15, and approximately 25 years. Results: Evaluation included craniofacial descriptive cephalometric analysis, dentoalveolar morphology, dentofacial aesthetics, speech concerning articulation and nasality, and hearing status. Number of surgical interventions after primary surgery was recorded. Secondary revisions and candidates for orthognathic surgery are reported. Ten consecutive patients (case nos. 11-20) are demonstrated as clinical reports. Conclusions: This longitudinal study shows how a multidisciplinary evaluation adequate for intercenter comparison can be performed when standardized procedures, registrations, and documentations are available.

Hearing Outcomes in Patients With Cleft Lip/Palate

Objective Children with cleft lip and palate or cleft palate only have a high incidence of conductive hearing loss from otitis media with effusion. Studies demonstrating longitudinal results are lacking. This study was undertaken to investigate long-term longitudinal hearing outcomes of children with cleft lip and/or cleft palate and cleft palate only. Design Retrospective chart review. Setting Clinical charts of patients born with cleft lip and palate or cleft palate only in 1985 to 1994 who were referred to the cleft team in Bergen, Norway. Study findings include 15 years of follow-up. Participants The study population consisted of 317 children of whom 159 had nonsyndromic cleft lip and palate and 158 had nonsyndromic cleft palate. Main Outcome Measures Pure tone average calculated from pure tone audiometry at ages 4, 6, and 15 years. Results The median pure tone average significantly improved with increasing age. For the cleft lip and palate group, the median pure tone average at ages 4, 6, and 15 years was 16 dB hearing level (HL), 13 dB HL, and 9 dB HL, respectively (P ≤ .001). In the cleft palate group the median pure tone average at ages 4, 6, and 15 years was 15 dB HL, 12 dB HL, and 9 dB HL, respectively (P ≤ .001). There was no significant difference in the hearing levels between the two groups. Patients who had surgical closure of the palate at age 18 months had a significantly better pure tone average outcome at age 15 compared with patients who had surgery at 12 months. Conclusions Hearing improves significantly from childhood to adolescence in patients with cleft lip and palate and cleft palate only.

First-trimester nonsystemic corticosteroid use and the risk of oral clefts in Norway

PURPOSE Exposure of pregnant mice to corticosteroids can produce oral clefts in offspring. Although data in humans are more mixed, recent reports have suggested that dermatologic steroids are associated with oral clefts. METHODS We investigated maternal first-trimester exposure to corticosteroids (focusing on dermatologic uses) and oral clefts in offspring using two population-based studies. The Norway Cleft Study (1996-2001) is a national case-control study including 377 infants with cleft lip ± palate (CLP), 196 infants with cleft palate only (CPO), and 763 controls. The Norwegian Mother and Child Cohort Study (MoBa, 1998-2008) is a national birth cohort including 123 infants with CLP, 61 infants with CPO, and 551 controls. RESULTS In the case-control study, there was the suggestion of an association of dermatologic corticosteroids with both CLP (adjusted OR [aOR], 2.3; 95% confidence interval [CI], 0.71-7.7) and CPO (aOR, 3.4; CI, 0.87-13). There was no evidence of this association in the cohort data (odds ratio for CLP, 1.2; CI, 0.50-2.8 and odds ratio for CPO, 1.0; CI, 0.30-3.4), although exposure to dermatologic steroids was less specifically ascertained. There were no associations with other types of corticosteroids. CONCLUSIONS Our data add to the suggestive but inconsistent findings for this association.

Health Status Among Adults Born With an Oral Cleft in Norway

Importance Parents regularly express concern about long-term health outcomes for children who are born with an oral cleft. Objective To assess whether oral clefts affect the health and ability to work of young adults. Design, Setting, and Participants A population-based cohort study was conducted on all individuals born in Norway between calendar years 1967 and 1992 (n = 1 490 401). All patients treated for clefts in Norway during the study period were invited to participate (n = 2860). This study used population-based, long-term follow-up data from national registries to focus on the future health outcomes of individuals with cleft and no additional chronic medical conditions or congenital anomalies. A total of 523 individuals were excluded from the study cohort because they declined participation, could not be reached by mail, or had birth defects other than clefts. The final cohort, consisting of 2337 cases with isolated clefts and 1 413 819 unaffected individuals, was followed up until December 31, 2010, using compulsory national registries and clinical data. Data analysis was conducted from February 13, 2014, to April 18, 2016. Exposures Oral clefts. Main Outcomes and Measures Death, intellectual disability, schizophrenia, mood affective disorders, anxiety disorders, autism spectrum disorders, attention deficit/hyperactivity disorder, severe learning disability, cerebral palsy, epilepsy, muscle or skeletal disorders, trauma, and episodes of reduced health. Results Of 2860 individuals born with an oral cleft, 2337 were included in the analysis; of these, 1401 were male (59.9%). Mean (SD) age in 2010 was 30.6 (7.7) years. Compared with unaffected individuals, no increased risks were found regarding morbidity or mortality among persons with isolated cleft lip only. Among individuals with isolated cleft lip and cleft palate, increased risks of intellectual disability (relative risk [RR], 2.2; 95% CI, 1.2-4.1) and cerebral palsy (RR, 2.6; 95% CI, 1.1-6.2) were found. Individuals with isolated cleft palate (ie, without cleft lip) had increased mortality (hazard ratio, 3.4; 95% CI, 2.1-5.7) in addition to an increased risk of intellectual disability (RR, 11.5; 95% CI, 8.5-15.6), anxiety disorders (RR, 2.9; 95% CI, 1.3-6.5), autism spectrum disorders (RR, 6.6; 95% CI, 2.8-15.7), severe learning disabilities (RR, 10.6; 95% CI, 5.5-20.2), cerebral palsy (RR, 4.8; 95% CI, 2.3-10.0), epilepsy (RR, 4.9; 95% CI, 2.2-10.8), and muscle or skeletal disorders (RR, 2.7; 95% CI, 1.4-5.4). Conclusions and Relevance Young adults who were born with isolated cleft lip only did not differ significantly from unaffected individuals in their risk of health problems. However, individuals with isolated cleft palate had increased health risks and mortality. This information should be provided to genetic counselors, parents of children with clefts, and health care workers involved in the treatment or follow-up of these children.

Socio-Economic Status and Reproduction among Adults Born with an Oral Cleft: A Population-Based Cohort Study in Norway.

Background It has been reported that people born with orofacial clefts do worse in life than their peers regarding a range of social markers, such as academic achievement and reproduction. We have compared otherwise healthy individuals with and without clefts, to investigate if these differences are due to the cleft or other background factors. Materials and Methods In a retrospective national cohort study, based on compulsory registers with data collected prospectively, we included everybody born in Norway between 1967 and 1992 (1490279 individuals, 2584 with clefts). This cohort was followed until the year 2010, when the youngest individuals were 18 years old. In order to ensure that the individuals were not affected by unknown syndromes or diseases, we excluded all individuals with any chronic medical condition, or who had other birth defects than clefts, hydroceles and dislocated hips. Individuals with oral clefts who were included in the study are said to have isolated clefts. Results Isolated cleft patients are similar to the general population regarding education, income and social class. Isolated cleft patients have lower fertility than the background population, but considering only married couples this difference in fertility disappeared. Conclusions An oral cleft did not appear to affect future socioeconomic status or chances of becoming a parent for children born in Norway. An exception was males with cleft lip and palate, but differences were small.