Endometriosis and adverse maternal, fetal and neonatal outcomes, a systematic review and meta-analysis.

STUDY QUESTION: How is endometriosis associated with adverse maternal, fetal and neonatal outcomes of pregnancy? SUMMARY ANSWER: Women with endometriosis are at elevated risk for serious and important adverse maternal (pre-eclampsia, gestational diabetes, placenta praevia and Cesarean section) and fetal or neonatal outcomes (preterm birth, PPROM, small for gestational age, stillbirth and neonatal death). WHAT IS KNOWN ALREADY: A number of studies have shown an association between endometriosis and certain adverse maternal and fetal outcomes, but the results have been conflicting with potential for confounding by the use of assisted reproductive technology. STUDY DESIGN, SIZE, DURATION: A systematic review and meta-analysis of observational studies (1 January 1990-31 December 2017) that evaluated the effect of endometriosis on maternal, fetal and neonatal outcomes was conducted. PARTICIPANTS/MATERIALS, SETTING, METHODS: Studies were considered for inclusion if they were prospective or retrospective cohort or case-control studies; included women greater than 20 weeks gestational age with endometriosis; included a control group of gravid women without endometriosis; and, reported at least one of the outcomes of interest. Each study was reviewed for inclusion, data were extracted and risk of bias was assessed by two independent reviewers. MAIN RESULTS AND THE ROLE OF CHANCE: The search strategy identified 33 studies (sample size, n = 3 280 488) for inclusion. Compared with women without endometriosis, women with endometriosis had higher odds of pre-eclampsia (odds ratio [OR] = 1.18 [1.01-1.39]), gestational hypertension and/or pre-eclampsia (OR = 1.21 [1.05-1.39]), gestational diabetes (OR = 1.26 [1.03-1.55]), gestational cholestasis (OR = 4.87 [1.85-12.83]), placenta praevia (OR = 3.31 [2.37, 4.63]), antepartum hemorrhage (OR = 1.69 [1.38-2.07]), antepartum hospital admissions (OR = 3.18 [2.60-3.87]), malpresentation (OR = 1.71 [1.34, 2.18]), labor dystocia (OR = 1.45 [1.04-2.01]) and cesarean section (OR = 1.86 [1.51-2.29]). Fetuses and neonates of women with endometriosis were also more likely to have preterm premature rupture of membranes (OR = 2.33 [1.39-3.90]), preterm birth (OR = 1.70 [1.40-2.06]), small for gestational age <10th% (OR = 1.28 [1.11-1.49]), NICU admission (OR = 1.39 [1.08-1.78]), stillbirth (OR = 1.29 [1.10, 1.52]) and neonatal death (MOR = 1.78 [1.46-2.16]). Among the subgroup of women who conceived spontaneously, endometriosis was found to be associated with placenta praevia, cesarean section, preterm birth and low birth weight. Among the subgroup of women who conceived with the use of assisted reproductive technology, endometriosis was found to be associated with placenta praevia and preterm birth. LIMITATIONS, REASONS FOR CAUTION: As with any systematic review, the review is limited by the quality of the included studies. The diagnosis for endometriosis and the selection of comparison groups were not uniform across studies. However, the effect of potential misclassification would be bias towards the null hypothesis. WIDER IMPLICATIONS OF THE FINDINGS: The association between endometriosis with the important and serious pregnancy outcomes observed in our meta-analysis, in particular stillbirth and neonatal death, is concerning and warrants further studies to elucidate the mechanisms for the observed findings. STUDY FUNDING/COMPETING INTEREST(S): Dr Shifana Lalani is supported by a Physicians' Services Incorporated Foundation Research Grant, and Dr Innie Chen is supported by a University of Ottawa Clinical Research Chair in Reproductive Population Health and Health Services. Dr Singh declares conflicts of interests with Bayer, Abvie, Allergan and Cooper Surgical. All other authors have no conflicts of interests to declare. REGISTRATION NUMBER: PROSPERO CRD42015013911.

The Cognitive and Behavioral Phenotypes of Individuals with CHRNA7 Duplications.

Chromosome 15q11q13 is among the least stable regions in the genome due to its highly complex genomic architecture. Low copy repeat elements at 15q13.3 facilitate recurrent copy number variants (CNVs), with deletions established as pathogenic and CHRNA7 implicated as a candidate gene. However, the pathogenicity of duplications of CHRNA7 is unclear, as they are found in affected probands as well as in reportedly healthy parents and unaffected control individuals. We evaluated 18 children with microduplications involving CHRNA7, identified by clinical chromosome microarray analysis (CMA). Comprehensive phenotyping revealed high prevalence of developmental delay/intellectual disability, autism spectrum disorder, and attention deficit/hyperactivity disorder. As CHRNA7 duplications are the most common CNVs identified by clinical CMA, this study provides anticipatory guidance for those involved with care of affected individuals.

THYROID DYSFUNCTION AND INFERTILITY TREATMENT.

OBJECTIVE: To find out the relationship of thyroid hormone profile of females with outcomes after intra cytoplasmic sperm injection (ICSI). METHOD: It was a cross sectional study conducted in Islamabad Clinic Serving Infertile Couple from June 2013 till August 2015. T3 (triiodo thyronine), T4 (thyroxine) and TSH (thyroid stimulating hormone) of 168 consented females was estimated after they underwent the first step of treatment protocol (ovarian down regulation) for ICSI. Pregnant group had ß hCG result more than 25 IU/mL while the rest were included in the non-pregnant group. Both groups were compared by using independent sample t-test. Pearson correlation coefficient was used to associate T3 and T4 with other pregnancy variables with their significance. RESULTS: Non pregnant women had significantly higher mean values for T3 and T4 as compared to pregnant women (p <0.05, p<0.01). Difference in mean TSH value between non-pregnant and pregnant women was not significant p=0.08. It was found that T4 gave significant negative association with grading of embryo-I, blastocysts formed, thickness of endometrium and number of gestational sacs. CONCLUSION: Disturbance in thyroid profile with raised T4 levels leads to alteration in endometrial thickness and quality of embryos required for implantation and hence conception.

Personalized medicine approach confirms a milder case of ABAT deficiency.

ABAT deficiency (OMIM 613163) is a rare inborn error of metabolism caused by recessive variants in the gene 4-aminobutyric acid transaminase (ABAT), which is responsible for both the catalysis of GABA and maintenance of nucleoside pools in the mitochondria. To date, only a few patients have been reported worldwide. Their clinical presentation has been remarkably consistent with primary features of severe psychomotor retardation, encephalopathy, hypotonia, and infantile-onset refractory epilepsy. We report a new case of ABAT deficiency that marks an important departure from previous clinical findings. The patient presented at age 6 months with global developmental delay, hypotonia, hypersomnolence and mild choreiform movements. At age 18 months, the subject's clinical presentation was still milder than all previously reported patients and, most notably, did not include seizures. Clinical whole exome sequencing revealed two heterozygous ABAT missense variants that are rare and predicted damaging, but never before reported in a patient and were reported as variants of unknown significance. To test the potential pathogenicity of the variants identified in this patient we developed a cell-based system to test both functions of the ABAT protein via GABA transaminase enzyme activity and mtDNA copy number assays. This systematic approach was validated using vigabatrin, the irreversible inhibitor of ABAT, and leveraged to test the functionality of all ABAT variants in previously reported patients plus the variants in this new case. This work confirmed the novel variants compromised ABAT function to similar levels as variants in previously characterized cases with more severe clinical presentation, thereby confirming the molecular diagnosis of this patient. Additionally, functional studies conducted in cells from both mild and severe patient fibroblasts showed similar levels of compromise in mitochondrial membrane potential, respiratory capacity, ATP production and mtDNA depletion. These results illustrate how cell-based functional studies can aid in the diagnosis of a rare, neurological disorder. Importantly, this patient marks an expansion in the clinical phenotype for ABAT deficiency to a milder presentation that is more commonly seen in pediatric genetics and neurology clinics.

De novo deletions and duplications of 17q25.3 cause susceptibility to cardiovascular malformations.

BACKGROUND: Genomic disorders resulting from deletion or duplication of genomic segments are known to be an important cause of cardiovascular malformations (CVMs). In our previous study, we identified a unique individual with a de novo 17q25.3 deletion from a study of 714 individuals with CVM. METHODS: To understand the contribution of this locus to cardiac malformations, we reviewed the data on 60,000 samples submitted for array comparative genomic hybridization (CGH) studies to Medical Genetics Laboratories at Baylor College of Medicine, and ascertained seven individuals with segmental aneusomy of 17q25. We validated our findings by studying another individual with a de novo submicroscopic deletion of this region from Cytogenetics Laboratory at Cincinnati Children's Hospital. Using bioinformatic analyses including protein-protein interaction network, human tissue expression patterns, haploinsufficiency scores, and other annotation systems, including a training set of 251 genes known to be linked to human cardiac disease, we constructed a pathogenicity score for cardiac phenotype for each of the 57 genes within the terminal 2.0 Mb of 17q25.3. RESULTS: We found relatively high penetrance of cardiovascular defects (~60 %) with five deletions and three duplications, observed in eight unrelated individuals. Distinct cardiac phenotypes were present in four of these subjects with non-recurrent de novo deletions (range 0.08 Mb-1.4 Mb) in the subtelomeric region of 17q25.3. These included coarctation of the aorta (CoA), total anomalous pulmonary venous return (TAPVR), ventricular septal defect (VSD) and atrial septal defect (ASD). Amongst the three individuals with variable size duplications of this region, one had patent ductus arteriosus (PDA) at 8 months of age. CONCLUSION: The distinct cardiac lesions observed in the affected patients and the bioinformatics analyses suggest that multiple genes may be plausible drivers of the cardiac phenotype within this gene-rich critical interval of 17q25.3.

OS032. Pharmacotherapy for pre-eclampsia in low and middle income countries: An analysis of essential medicines lists (EMLS).

INTRODUCTION: Pre-eclampsia is the second leading cause of maternal mortality in low and middle income countries (LMIC). Pharmacological management of pre-eclampsia has five major components including antihypertensive therapy for severe and non-severe hypertension, magnesium sulphate for prevention or treatment of eclampsia, treatment of pre-eclampsia-related end-organ complications, antenatal corticosteroids for acceleration of fetal pulmonary maturity given iatrogenic preterm delivery for maternal and/or fetal indications, and labour induction for such indicated deliveries. Essential medicines are defined by the World Health Organization (WHO) as "drugs that satisfy the health care needs of the majority of the population". Essential Medicines Lists (EMLs) detail these essential medicines within an individual country and support the argument that the medication should be routinely available. OBJECTIVES: To determine how many drugs required for comprehensive pre-eclampsia management are listed in national EMLs of LMIC. METHODS: We conducted a descriptive analysis of relevant drug prevalence on identified EMLs. We searched for the national EMLs of the 144 LMIC identified by the World Bank. EMLs were collected by broad based internet searches and in collaboration with the WHO. The EMLs were surveyed for therapies for the different aspects of pre-eclampsia management: hypertension (non-severe and severe with oral or parenteral agents), eclampsia, pre-eclampsia complications (e.g., pulmonary oedema, thrombosis), preterm birth, and labour induction. RESULTS: EMLs were located and reviewed for 58(40.3%) of LMIC. One or more parenteral antihypertensive agents were listed in 51(87.9%) EMLs. The most common agents were: hydralazine (67.2%), verapamil (58.6%), propranolol (39.7%) and sodium nitroprusside (37.9%); parenteral labetalol was listed by only 19.0% of EMLs. The most prevalent oral antihypertensive therapies listed were: nifedipine (96.6%, usually 10 or 20mg intermediate-acting tablets), methyldopa (94.8%), propranolol (89.7%), and atenolol (87.9%). Captopril, enalapril, hydrochlorothiazide and spironolactone were commonly listed. Magnesium sulphate for prevention and management of eclampsia was present in 86.2% of EMLs (and its antidote, calcium gluconate in 82.8%). To manage complications of pre-eclampsia, oral frusemide was listed in 94.8% of EMLs and parenteral heparin in 91.4%. Most EMLs listed parenteral dexamethasone (91.4%) for acceleration of fetal pulmonary maturity and oxytocin (98.3%) or a prostanoid (usually misoprostol, 39.7%) for labour induction. CONCLUSION: EMLs of LMIC provide comprehensive coverage of all aspects of recommended pre-eclampsia pharmacotherapy. These EMLs may be used as advocacy tools to ensure the availability of these therapies within each country.

PP088. Oral antihypertensive therapy for severe hypertension in pregnancy.

INTRODUCTION: The hypertensive disorders of pregnancy are among the leading causes of maternal mortality and morbidity. The vast majority occurs in low and middle income countries. It is widely accepted that women with severe hypertension are at increased risk of stroke and benefit from blood pressure (BP) reduction. Although traditionally, parenteral antihypertensive agents have been studied for treatment of severe hypertension in pregnancy, oral agents would be ideal for use in the community and in under-resourced settings. OBJECTIVES: To review the published evidence for the effectiveness of oral antihypertensive therapy for severe hypertension in pregnancy. METHODS: The following databases were searched (to May/11) for randomised controlled trials (RCT) of oral antihypertensive therapy for severe hypertension in pregnancy: MEDLINE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Database of Abstracts of Reviews. Inclusion criteria were: severe hypertension [an inclusion criterion or average enrollment BP of: systolic BP ⩾160mmHg and/or diastolic BP ⩾110mmHg), use of oral or sublingual antihypertensive therapy in at least one of the treatment arms, and at least one relevant measure of maternal or perinatal outcome within a week of administration. Data were abstracted independently by two reviewers and discrepancies resolved by consensus. The Cochrane Revman 5.1 software was used for statistical analysis according to standardised methodology. RESULTS: We identified 14 eligible trials (796 women). Most compared oral/sublingual (SL) nifedipine 5-10mg (10 trials, 606 women, 8/10 trials specified capsule preparation), with either: intravenous (iv) hydralazine 5-20mg (6 trials, 282 women), oral nifedipine 10mg PA tablets (1 trial), oral prazosin 1mg (1 trial), iv labetalol (1 trial), or iv/intramuscular (im) chlorpromazine 12.5 (1 trial). Three trials (154 women) compared oral methyldopa (250-500mg initially) with either oral labetalol (100mg), atenolol (50-200mg) or kentanserin (80-120mg) (1 trial each). One trial (36 women) compared SL isosorbide 1.25mg with iv magnesium sulphate (4g iv then 1g/hr). No trials were identified that compared oral labetalol with either parenteral hydralazine or oral nifedipine. Nifedipine compared favourably with parenteral hydralazine with no differences seen in BP control or maternal or perinatal outcomes. Heterogeneity between trial results was seen within the oral/SL nifedipine vs. iv hydralazine subgroup in which one trial evaluated treatment success and side effects over 20min, and found that nifedipine was associated with relatively lower success and fewer side effects. The incidence of maternal hypotension in the nifedipine capsule arms of these trials was low (1/102, 3 trials), but hypotension was common in both arms of a trial of nifedipine 10mg capsule vs. 10mg PA tablet trial (i.e., 11/31 vs. 3/33, risk difference 26%, 95% CI7% to 46%). CONCLUSION: Given the available RCT data on which to base oral antihypertensive treatment of severe hypertension in pregnancy, the choice of antihypertensive agent may need to be driven by the availability of the drug, setting in which it is to be administered, and by whom. For facility use, the evidence supports oral nifedipine capsules.

22q13.3 deletion syndrome: clinical and molecular analysis using array CGH.

The 22q13.3 deletion syndrome results from loss of terminal segments of varying sizes at 22qter. Few genotype-phenotype correlations have been found but all patients have mental retardation and severe delay, or absence of, expressive speech. We carried out clinical and molecular characterization of 13 patients. Developmental delay and speech abnormalities were common to all and comparable in frequency and severity to previously reported cases. Array-based comparative genomic hybridization showed the deletions to vary from 95 kb to 8.5 Mb. We also carried out high-resolution 244K array comparative genomic hybridization in 10 of 13 patients, that defined the proximal and distal breakpoints of each deletion and helped determine the size, extent, and gene content within the deletion. Two patients had a smaller 95 kb terminal deletion with breakpoints within the SHANK3 gene while three other patients had a similar 5.5 Mb deletion implying the recurrent nature of these deletions. The two largest deletions were found in patients with ring chromosome 22. No correlation could be made with deletion size and phenotype although complete/partial SHANK3 was deleted in all patients. There are very few reports on array comparative genomic hybridization analysis on patients with the 22q13.3 deletion syndrome, and we aim to accurately characterize these patients both clinically and at the molecular level, to pave the way for further genotype-phenotype correlations. (c) 2010 Wiley-Liss, Inc.

The relationship between changes in self-reported disability (measured by the Health Assessment Questionnaire - HAQ) in scleroderma and improvement of disease status in clinical practice.

OBJECTIVES: To determine if a low Health Assessment Questionnaire Disability Index (HAQ-DI) score predicts subsequent improvement over the next one to two years in clinical practice and if a low HAQ is predictive of improvement in early, late, diffuse and limited SSc subsets. METHODS: HAQs collected at one site annually were used to determine serial relationships in low baseline HAQ and improvement in overall status over the following one to two years. Data were divided into early (< or =3 years) and late, and then further into limited and diffuse SSc subgroups. We verified our results in the Canadian Scleroderma Research Group (CSRG) database. RESULTS: 120 SSc patients had a baseline HAQ-DI of 0.97+/-0.07 (SEM). Low HAQs predicted improvement in overall HAQ at one and two years, but was not statistically significant in predicting physician improvement rating. However, improving HAQs were associated with improvement in physician assessment (better vs. same vs. worse) for overall SSc (p=0.005), early diffuse SSc (p=0.008), overall limited SSc (p=0.02) and late limited SSc (p=0.03) at 1 year (but not at 2 years). The relationship was similar for severity of disease where changes in damage were related to changes in HAQ only over the first year for all 4 subgroups. CONCLUSION: The HAQ is a useful 'marker' of change in status in clinical practice, where an improved HAQ is associated with improved physician global assessment. The relationship is only helpful for an interval of one year. Low HAQ did not predict subsequent improvement by physician rating in SSc patients.

Defects in neural stem cell proliferation and olfaction in Chd7 deficient mice indicate a mechanism for hyposmia in human CHARGE syndrome.

Mutations in CHD7, a chromodomain gene, are present in a majority of individuals with CHARGE syndrome, a multiple anomaly disorder characterized by ocular Coloboma, Heart defects, Atresia of the choanae, Retarded growth and development, Genital hypoplasia and Ear anomalies. The clinical features of CHARGE syndrome are highly variable and incompletely penetrant. Olfactory dysfunction is a common feature in CHARGE syndrome and has been potentially linked to primary olfactory bulb defects, but no data confirming this mechanistic link have been reported. On the basis of these observations, we hypothesized that loss of Chd7 disrupts mammalian olfactory tissue development and function. We found severe defects in olfaction in individuals with CHD7 mutations and CHARGE, and loss of odor evoked electro-olfactogram responses in Chd7 deficient mice, suggesting reduced olfaction is due to a dysfunctional olfactory epithelium. Chd7 expression was high in basal olfactory epithelial neural stem cells and down-regulated in mature olfactory sensory neurons. We observed smaller olfactory bulbs, reduced olfactory sensory neurons, and disorganized epithelial ultrastructure in Chd7 mutant mice, despite apparently normal functional cilia and sustentacular cells. Significant reductions in the proliferation of neural stem cells and regeneration of olfactory sensory neurons in the mature Chd7(Gt/+) olfactory epithelium indicate critical roles for Chd7 in regulating neurogenesis. These studies provide evidence that mammalian olfactory dysfunction due to Chd7 haploinsufficiency is linked to primary defects in olfactory neural stem cell proliferation and may influence olfactory bulb development.

Genomic duplication resulting in increased copy number of genes encoding the sister chromatid cohesion complex conveys clinical consequences distinct from Cornelia de Lange.

BACKGROUND: Cornelia de Lange syndrome (CdLS) is a multisystem congenital anomaly disorder. Heterozygous point mutations in three genes (NIPBL, SMC3 and SMC1A), encoding components of the sister chromatid cohesion apparatus, are responsible for approximately 50-60% of CdLS cases. Recent studies have revealed a high degree of genomic rearrangements (for example, deletions and duplications) in the human genome, which result in gene copy number variations (CNVs). CNVs have been associated with a wide range of both Mendelian and complex traits including disease phenotypes such as Charcot-Marie-Tooth type 1A, Pelizaeus-Merzbacher, Parkinson, Alzheimer, autism and schizophrenia. Increased versus decreased copy number of the same gene can potentially cause either similar or different clinical features. METHODS AND RESULTS: This study identified duplications on chromosomes 5 or X using genome wide array comparative genomic hybridisation (aCGH). The duplicated regions contain either the NIPBL or the SMC1A genes. Junction sequences analyses revealed the involvement of three genomic rearrangement mechanisms. The patients share some common features including mental retardation, developmental delay, sleep abnormalities, and craniofacial and limb defects. The systems affected are the same as in CdLS, but clinical manifestations are distinct from CdLS; particularly the absence of the CdLS facial gestalt. CONCLUSIONS: The results confirm the notion that duplication CNV of genes can be a common mechanism for human genetic diseases. Defining the clinical consequences for a specific gene dosage alteration represents a new "reverse genomics" trend in medical genetics that is reciprocal to the traditional approach of delineation of the common clinical phenotype preceding the discovery of the genetic aetiology.

20p12.3 microdeletion predisposes to Wolff-Parkinson-White syndrome with variable neurocognitive deficits.

BACKGROUND: Wolff-Parkinson-White syndrome (WPW) is a bypass re-entrant tachycardia that results from an abnormal connection between the atria and ventricles. Mutations in PRKAG2 have been described in patients with familial WPW syndrome and hypertrophic cardiomyopathy. Based on the role of bone morphogenetic protein (BMP) signalling in the development of annulus fibrosus in mice, it has been proposed that BMP signalling through the type 1a receptor and other downstream components may play a role in pre-excitation. METHODS AND RESULTS: Using the array comparative genomic hybridisation (CGH), we identified five individuals with non-recurrent deletions of 20p12.3. Four of these individuals had WPW syndrome with variable dysmorphisms and neurocognitive delay. With the exception of one maternally inherited deletion, all occurred de novo, and the smallest of these harboured a single gene, BMP2. In two individuals with additional features of Alagille syndrome, deletion of both JAG1 and BMP2 were identified. Deletion of this region has not been described as a copy number variant in the Database of Genomic Variants and has not been identified in 13 321 individuals from other cohort examined by array CGH in our laboratory. CONCLUSIONS: Our findings demonstrate a novel genomic disorder characterised by deletion of BMP2 with variable cognitive deficits and dysmorphic features and show that individuals bearing microdeletions in 20p12.3 often present with WPW syndrome.

Characterization of de novo microdeletions involving 17q11.2q12 identified through chromosomal comparative genomic hybridization.

High-resolution array-comparative genome hybridization (CGH) is a powerful tool for detection of submicroscopic chromosome deletions and duplications. We describe two patients with mild mental retardation (MR) and de novo microdeletions of 17q11.2q12. Although the deletions did not involve the neurofibromatosis type 1 (NF1) gene, they overlap with long-range deletions of the NF1 region which have been encountered in a small group of NF1 patients with more severe MR. Given the overlap of the deletions in our two patients with the large-sized NF1 microdeletions but not with the more frequent and smaller NF1 deletions, we hypothesize that more than one gene in the 17q11.2q12 region may be involved in MR. We discuss candidate genes for MR within this interval that was precisely defined through array-CGH analysis.

Identification of proximal 1p36 deletions using array-CGH: a possible new syndrome.

Monosomy 1p36 is the most common terminal deletion syndrome with an estimated occurrence of 1:5000 live births. Typically, the deletions span <10 Mb of 1pter-1p36.23 and result in mental retardation, developmental delay, sensorineural hearing loss, seizures, cardiomyopathy and cardiovascular malformations, and distinct facies including large anterior fontanel, deep-set eyes, straight eyebrows, flat nasal bridge, asymmetric ears, and pointed chin. We report five patients with 'atypical' proximal interstitial deletions from 1p36.23-1p36.11 using array-comparative genomic hybridization. Four patients carry large overlapping deletions of approximately 9.38-14.69 Mb in size, and one patient carries a small 2.97 Mb deletion. Interestingly, these patients manifest many clinical characteristics that are different from those seen in 'classical' monosomy 1p36 syndrome. The clinical presentation in our patients included: pre- and post-natal growth deficiency (mostly post-natal), feeding difficulties, seizures, developmental delay, cardiovascular malformations, microcephaly, limb anomalies, and dysmorphic features including frontal and parietal bossing, abnormally shaped and posteriorly rotated ears, hypertelorism, arched eyebrows, and prominent and broad nose. Most children also displayed hirsutism. Based on the analysis of the clinical and molecular data from our patients and those reported in the literature, we suggest that this chromosomal abnormality may constitute yet another deletion syndrome distinct from the classical distal 1p36 deletion syndrome.

Effects of vagal denervation on cardiorespiratory and behavioral responses in the newborn lamb.

Recently, Wong et al. (Wong KA, Bano A, Rigaux A, Wang B, Bharadwaj B, Schurch S, Green F, Remmers JE, and Hasan SU, J Appl Physiol 85: 849-859, 1998) demonstrated that fetal lambs that have undergone vagal denervation prenatally do not establish adequate alveolar ventilation shortly after birth. In their study, however, vagal denervation was performed prenatally and the deleterious effects of vagal denervation on breathing patterns and gas exchange could have resulted from the prenatal actions of the neurotomy. To quantify the relative roles of pre- vs. postnatal vagal denervation on control of breathing, we studied 14 newborn lambs; 6 were sham operated, and 8 were vagally denervated below the origin of the recurrent laryngeal nerve. Postoperatively, all denervated animals became hypoxemic and seven of eight succumbed to respiratory failure. In vagally denervated lambs, expiratory time increased, whereas respiratory rate, minute ventilation, and lung compliance decreased compared with the sham-operated animals. In the early postoperative period, the frequency of augmented breaths was lower but gradually increased over time in the denervated vs. sham-operated group. The dynamic functional residual capacity was significantly higher than the passive functional residual capacity among the sham-operated group compared with the denervated group. No significant differences were observed in the prevalence of various sleep states and in the amount of total phospholipids or large- and small-aggregate surfactants between the two groups. We provide new evidence indicating that intrauterine actions of denervation are not required to explain the effects of vagal denervation on postnatal survival. Our data suggest that vagal input is critical in the maintenance of normal breathing patterns, end-expiratory lung volume, and gas exchange during the early neonatal period.