Diabetes mellitus in pregnancy across Canada.

BACKGROUND: Contemporary estimates of diabetes mellitus (DM) rates in pregnancy are lacking in Canada. Accordingly, this study examined trends in the rates of type 1 (T1DM), type 2 (T2DM) and gestational (GDM) DM in Canada over a 15-year period, and selected adverse pregnancy outcomes. METHODS: This study used repeated cross-sectional data from the Canadian Institute of Health Information (CIHI) hospitalization discharge abstract database (DAD). Maternal delivery records were linked to their respective birth records from 2006 to 2019. The prevalence of T1DM, T2DM and GDM were calculated, including relative changes over time, assessed by a Cochrane-Armitage test. Also assessed were differences between provinces and territories in the prevalence of DM. RESULTS: Over the 15-year study period, comprising 4,320,778 hospital deliveries in Canada, there was a statistically significant increase in the prevalence of GDM and T1DM and T2DM. Compared to pregnancies without DM, all pregnancies with any form of DM had higher rates of hypertension and Caesarian delivery, and also adverse infant outcomes, including major congenital anomalies, preterm birth and large-for-gestational age birthweight. CONCLUSION: Among 4.3 million pregnancies in Canada, there has been a rise in the prevalence of DM. T2DM and GDM are expected to increase further as more overweight women conceive in Canada.

Severity and duration of dysglycemia and brain injury among patients with neonatal encephalopathy.

Background: Evidence is needed to inform thresholds for glycemic management in neonatal encephalopathy (NE). We investigated how severity and duration of dysglycemia relate to brain injury after NE. Methods: A prospective cohort of 108 neonates ≥36 weeks gestational age with NE were enrolled between August 2014 and November 2019 at the Hospital for Sick Children, in Toronto, Canada. Participants underwent continuous glucose monitoring for 72 h, MRI at day 4 of life, and follow-up at 18 months. Receiver operating characteristic curves were used to assess the predictive value of glucose measures (minimum and maximum glucose, sequential 1 mmol/L glucose thresholds) during the first 72 h of life (HOL) for each brain injury pattern (basal ganglia, watershed, focal infarct, posterior-predominant). Linear and logistic regression analyses were used to assess the relationship between abnormal glycemia and 18-month outcomes (Bayley-III composite scores, Child Behavior Checklist [CBCL] T-scores, neuromotor score, cerebral palsy [CP], death), adjusting for brain injury severity. Findings: Of 108 neonates enrolled, 102 (94%) had an MRI. Maximum glucose during the first 48 HOL best predicted basal ganglia (AUC = 0.811) and watershed (AUC = 0.858) injury. Minimum glucose was not predictive of brain injury (AUC <0.509). Ninety-one (89%) infants underwent follow-up assessments at 19.0 ± 1.7 months. A glucose threshold of >10.1 mmol/L during the first 48 HOL was associated with 5.8-point higher CBCL Internalizing Composite T-score (P = 0.029), 0.3-point worse neuromotor score (P = 0.035), 8.6-fold higher odds for CP diagnosis (P = 0.014). While the glucose threshold of >10.1 mmol/L during the first 48 HOL was associated with higher odds of the composite outcome of severe disability or death (OR 3.0, 95% CI 1.0-8.4, P = 0.042), it was not associated with the composite outcome of moderate-to-severe disability or death (OR 0.9, 95% CI 0.4-2.2, P = 0.801). All associations with outcome lost significance after adjusting for brain injury severity. Interpretation: Maximum glucose concentration in the first 48 HOL is predictive of brain injury after NE. Further trials are needed to assess if protocols to control maximum glucose concentrations improve outcomes after NE. Funding: Canadian Institutes for Health Research, National Institutes of Health, and SickKids Foundation.

Les tests et le dépistage génétiques chez les enfants.

Les tests génétiques, qui ont évolué rapidement depuis vingt ans, deviennent monnaie courante en pédiatrie. Le présent document de principes procure un aperçu des récents développements qui peuvent avoir des répercussions sur les tests génétiques chez les enfants. La génétique est un domaine en constante évolution, et le présent document de principes s'attarde tout particulièrement au dépistage néonatal élargi, au séquençage de nouvelle génération, aux découvertes fortuites, aux tests commercialisés directement auprès des consommateurs, aux tests d'histocompatibilité et aux tests génétiques dans le contexte de la recherche.

Genetic testing and screening in children.

Genetic testing has progressed rapidly over the past two decades and is becoming common in paediatrics. This statement provides an overview of recent developments that may impact genetic testing in children. Genetics is a rapidly evolving field, and this statement focuses specifically on expanded newborn screening, next generation sequencing (NGS), incidental findings, direct-to-consumer testing, histocompatibility testing, and genetic testing in a research context.

Risk factors for prolonged mechanical ventilation in neonates following gastrointestinal surgery.

Background: Prolonged mechanical ventilation (MV) should be avoided in neonates. Noninvasive ventilation (NIV) can facilitate weaning from MV but has risks for patients immediately following foregut surgery due to the potential risk of anastomotic leak. We evaluated the risk factors for prolonged MV following intestinal surgery in neonates. Methods: We retrospectively reviewed 253 neonates undergoing intestinal surgery in 2017-2018 to identify risk factors for prolonged MV, and determine the correlation between NIV and anastomotic leak in a tertiary neonatal intensive care unit that performs the greatest number of neonatal surgeries in Ontario. Results: The most common diagnoses were necrotizing enterocolitis/spontaneous intestinal perforation (NEC/SIP) 21%, intestinal atresia 16%, esophageal atresia/tracheoesophageal fistula 14%, ano-rectal malformation 13%, malrotation/volvulus 11%, gastroschisis 9% and omphalocele 4%. The median (IQR) duration of MV post-surgery was 3 (1-8) days with 25.7 % (n=65) of neonates on MV for >7 days. Compared to infants on MV post-surgery for ≤7 days, those with MV>7 days were of lower gestational age, birth weight and weight at surgery, but a higher proportion underwent stoma creation, had a longer duration of opioid administration and higher rates of moderate to severe bronchopulmonary dysplasia (BPD) and mortality (P<0.05). Generalized linear regression analysis showed lower gestational age (GA) and longer opioid administration were associated with longer duration of MV (P<0.001), but indication for surgery, weight at surgery and stoma creation didn't correlate with longer duration of MV (P>0.05). Of the 122 patients handled by one-stage resection with primary anastomosis, 22.1% (n=27) received NIV with 74.1% (n=20) commenced on NIV after 7 days post-surgery, anastomotic leak was detected in 2.5 % (3/122) patients and didn't correlate with NIV. Conclusions: Lower GA and longer opioid administration were risk factors for prolonged MV in neonates following intestinal surgery. Further research is needed to investigate modifiable practices around pain assessment/ventilation in these patients, and the correlation between NIV and anastomotic leak.

Hyperglycemia associated with acute brain injury in neonatal encephalopathy.

OBJECTIVE: To identify how alterations in glucose levels are associated with regional brain injury in neonatal encephalopathy. METHODS: This was a prospective cohort study of 102 newborns with neonatal encephalopathy, with continuous glucose monitoring for 72 h. 97 (95%) completed 72 h of therapeutic hypothermia. Brain imaging around day 5 of life included diffusion tensor imaging and MR spectroscopy. Regions of interest were placed for both DTI and MR spectroscopy, and tractography of the optic radiation and corticospinal tract were evaluated. Linear regression models related each MR metric with minimum and maximum glucose values during each day of life, adjusting for 5-minute Apgar scores and umbilical artery pH. RESULTS: Higher maximum glucose levels on the first day of life were associated with widespread changes in mean diffusivity in the anterior and posterior white matter, splenium of the corpus callosum, lentiform nucleus, pulvinar nucleus of the thalamus, posterior limb of the internal capsule, and optic radiations, thus including regions traditionally associated with hypoxia-ischemia or hypoglycemia. No associations were found between lower minimum glucose levels and DTI changes in any regions tested, or between glucose levels and MR spectroscopy. CONCLUSIONS: In this cohort of neonatal encephalopathy with therapeutic hypothermia, higher maximal glucose on the first day of life was associated with widespread microstructural changes, but lower minimum glucose levels were not associated with changes in any of the regions tested. Long-term follow-up will determine if imaging findings translate to long-term outcomes.

Population-based surveillance of severe microcephaly and congenital Zika syndrome in Canada.

PURPOSE: To estimate the minimum incidence of congenital Zika syndrome (CZS) and severe microcephaly in Canada and describe key clinical, epidemiological, aetiological and outcome features of these conditions. METHODS: Two separate national surveillance studies were conducted on CZS and severe microcephaly using the well-established Canadian Paediatric Surveillance Program from 2016 to 2019. Over 2700 paediatricians across Canada were surveyed monthly and asked to report demographic details, pregnancy and travel history, infant anthropometry, clinical features and laboratory findings of newly identified cases. Reports were reviewed to assign an underlying aetiology of severe microcephaly. Incidence rates were estimated using monthly live birth denominators. RESULTS: Thirty-four infants met the case definition for severe microcephaly and <5 met the case definition for CZS. The associated minimum incidence rates were 4.5 per 100 000 live births for severe microcephaly and 0.1-0.5 per 100 000 live births for CZS. Of severe microcephaly cases, 53% were attributed to genetic causes, 15% to infectious or ischaemic causes and 32% to unknown causes. The median head circumference-for-age Z-score at birth was -3.2 (IQR -3.8 to -2.6), and catch-up growth was often not achieved. Common clinical features included intracranial abnormalities (n=23), dysmorphology (n=19) and developmental delays (n=14). Mothers of infants with non-genetic aetiologies travelled during pregnancy more often (10/16) than mothers of infants with genetic aetiologies (<5/18; p<0.01). CONCLUSION: Severe microcephaly and CZS are both rare in Canada. Minimum incidence rates can be used as a baseline against which novel or re-emergent causes of severe microcephaly or CZS can be compared.

Abnormalities in evoked potentials associated with abnormal glycemia and brain injury in neonatal hypoxic-ischemic encephalopathy.

OBJECTIVE: To investigate how functional integrity of ascending sensory pathways measured by visual and somatosensory evoked potentials (VEP & SEP) is associated with abnormal glycemia and brain injury in newborns treated with hypothermia for hypoxic-ischemic encephalopathy (HIE). METHODS: Fifty-four neonates ≥ 36 weeks gestational age with HIE underwent glucose testing, VEPs, SEPs, and magnetic resonance imaging (MRI) the first week of life. Minimum and maximum glucose values recorded prior to evoked potential (EP) testing were compared with VEP and SEP measures using generalized estimating equations. Relationships between VEP and SEP measures and brain injury on MRI were assessed. RESULTS: Maximum glucose is associated with decreased P200 amplitude, and increased odds that N300 peak will be delayed/absent. Minimum glucose is associated with decreased P22 amplitude. Presence of P200 and N300 peaks is associated with decreased odds of brain injury in the visual processing pathway, with delayed/absent N300 peak associated with increased odds of brain injury in posterior white matter. CONCLUSIONS: Deviations from normoglycemia are associated with abnormal EPs, and abnormal VEPs are associated with brain injury on MRI in cooled neonates with HIE. SIGNIFICANCE: Glucose is a modifiable risk factor associated with atypical brain function in neonates with HIE despite hypothermia treatment.

Data Quality Assessment on Congenital Anomalies in Ontario, Canada.

Background: Congenital anomalies (CAs) are a major cause of infant morbidity and mortality in Canada. Reliably identifying CAs is essential for CA surveillance and research. The main objective of this study was to assess the agreement of eight sentinel anomalies including: neural tube defects (NTD), orofacial clefts, limb deficiency defects (LDD), Down syndrome (DS), tetralogy of Fallot (TOF), gastroschisis (GS), hypoplastic left heart syndrome (HLHS) and transposition of great vessels (TGA) captured in the BORN Information System (BIS) database and the Canadian Institute for Health Information (CIHI) Discharge Abstract Database (DAD). Methods: Live birth and stillbirth records between the BIS and CIHI-DAD in the fiscal years of 2012-2013 to 2015-2016 were linked using 10 digit infant Ontario Health Insurance Plan (OHIP) numbers. Percent agreement and Kappa statistics were performed to assess the reliability (agreement) of CAs identified in the linked BIS and CIHI-DAD birth records. Then, further investigations were conducted on those CA cases identified in the CIHI-DAD only. Results: Kappa coefficients of the eight selected CAs between BIS ("Confirmed" or "Suspected" cases) and CIHI-DAD were 0.96 (95% CI: 0.93-0.98) for GS; 0.81 (95% CI: 0.78-0.83) for Orofacial clefts; 0.75 (95% CI: 0.72-0.77) for DS; 0.71 (95% CI: 0.65-0.77) for TOF; 0.62 (95% CI: 0.55-0.68) for TGA; 0.59 (95% CI: 0.49-0.68) for HLHS, 0.53 (95% CI: 0.46-0.60) for NTD-all; and 0.30 (95% CI: 0.23-0.37) for LDD. Conclusions: The degree of agreement varied among sentinel CAs identified between the BIS and CIHI. The potential reasons for discrepancies include incompleteness of capturing CAs using existing picklist values, especially for certain sub-types, incomplete neonatal special care data in the BIS, and differences between clinical diagnosis in the BIS and ICD-10-CA classification in the DAD. A future data abstraction study will be conducted to investigate the potential reasons for discrepancies of CA capture between two databases. This project helps quantify the quality of CA data collection in the BIS, enhances understanding of CA prevalence in Ontario and provides direction for future data quality improvement activities.

Gastrointestinal hemodynamic changes during therapeutic hypothermia and after rewarming in neonatal hypoxic-Ischemic encephalopathy.

BACKGROUND: Hypoxic-ischemic encephalopathy (HIE) is associated with disturbances in visceral blood flow velocities. Therapeutic Hypothermia (TH) is a standard of care; however, its impact on gastrointestinal blood flow in infants with HIE is unknown. The objective of this study was to assess gastrointestinal (GI) blood flow and left ventricle output (LVO) in infants with hypoxic-ischemic encephalopathy during whole body TH and after rewarming. METHODS: Serial echocardiography and Doppler evaluation of intestinal blood flow (celiac (CA) and superior mesenteric (SMA) arteries) were prospectively performed in a cohort of 20 newborn infants with HIE at 4 time points during hypothermia and after rewarming. Demographic, clinical and biochemical data were collected and analyzed for their relevance. RESULTS: Median gestational age and birth weight was 40 weeks (37-41) and 3410 g (2190-4950) respectively. Celiac and mesenteric artery flow remained low during hypothermia and rose significantly after rewarming [peak systolic velocity in CA (0.63 m/s to 0.77 m/s, p = 0.004) and SMA (0.43 m/s to 0.55 m/s, p = 0.001)]. This increase was temporally associated with increased left ventricular output (106 ml/kg/min to 149 ml/kg/min, p < 0.0001). Median age to reach 25% of the feeds was 5 days (1-7 days). All patients survived. CONCLUSIONS: CA and SMA blood flow velocity and LVO did not vary during hypothermia but rose after rewarming. This may suggest protective effect of therapeutic hypothermia on gastrointestinal system. The association of these physiological changes with neonatal outcome needs further assessment.

Outcomes of multi-gestational pregnancies affected by esophageal atresia - tracheoesophageal fistula.

BACKGROUND: Contemporary outcomes of infants with esophageal atresia with or without tracheoesophageal fistula (EA/TEF) from multi-gestational pregnancies compared to those of singleton pregnancies have not been reported. METHODS: A single-center retrospective review of EA/TEF patients born from 1999 to 2013 was performed. Patient demographics, gestational age (GA), birth weight, associated anomalies, requirement for gastrostomy tube and mortality were reviewed. RESULTS: Singleton EA/TEF patients outnumbered those from multi-gestational pregnancies nearly 10:1 (214 vs 22 patients). EA/TEF patients from multi-gestational pregnancies were more likely to be premature (77% vs. 32%), have lower birth weight (mean 1766 g vs. 2695 g), have associated duodenal atresia (18% vs. 6%) and require gastrostomy tube (41% vs. 33%) for feeding challenges compared to EA/TEF singletons. Mortality was also significantly greater for multi-gestational EA/TEF patients compared to singleton EA/TEF patients (18% vs. 6%). CONCLUSION: EA/TEF infants from multi-gestational pregnancies have greater clinical complexity and mortality than singleton EA/TEF patients. Parents of EA/TEF multi-gestational infants should be appropriately counseled and supported.

Hyperglycemia and Glucose Variability Are Associated with Worse Brain Function and Seizures in Neonatal Encephalopathy: A Prospective Cohort Study.

OBJECTIVES: To investigate how glucose abnormalities correlate with brain function on amplitude-integrated electroencephalography (aEEG) in infants with neonatal encephalopathy. STUDY DESIGN: Neonates born at full term with encephalopathy were enrolled within 6 hours of birth in a prospective cohort study at a pediatric academic referral hospital. Continuous interstitial glucose monitors and aEEG were placed soon after birth and continued for 3 days. Episodes of hypoglycemia (≤50 mg/dL; ≤2.8 mmol/L) and hyperglycemia (>144 mg/dL; >8.0 mmol/L) were identified. aEEG was classified in 6-hour epochs for 3 domains (background, sleep-wake cycling, electrographic seizures). Generalized estimating equations assessed the relationship of hypo- or hyperglycemia with aEEG findings, adjusting for clinical markers of hypoxia-ischemia (Apgar scores, umbilical artery pH, and base deficit). RESULTS: Forty-five infants (gestational age 39.5 ± 1.4 weeks) were included (24 males). During aEEG monitoring, 16 episodes of hypoglycemia were detected (9 infants, median duration 77.5, maximum 220 minutes) and 18 episodes of hyperglycemia (13 infants, median duration 237.5, maximum 3125 minutes). Epochs of hypoglycemia were not associated with aEEG changes. Compared with epochs of normoglycemia, epochs of hyperglycemia were associated with worse aEEG background scores (B 1.120, 95% CI 0.501-1.738, P < .001), less sleep-wake cycling (B 0.587, 95% CI 0.417-0.757, P < .001) and more electrographic seizures (B 0.433, 95% CI 0.185-0.681, P = .001), after adjusting for hypoxia-ischemia severity. CONCLUSIONS: In neonates with encephalopathy, epochs of hyperglycemia were temporally associated with worse global brain function and seizures, even after we adjusted for hypoxia-ischemia severity. Whether hyperglycemia causes neuronal injury or is simply a marker of severe brain injury requires further study.

Adverse childhood experiences: Basics for the paediatrician.

In 1998, the Centers for Disease Control and Prevention Adverse Childhood Experiences study established the profound effects of early childhood adversity on life course health. The burden of cumulative adversities can affect gene expression, immune system development and condition stress response. A scientific framework provides explanation for numerous childhood and adult health problems and high-risk behaviours that originate in early life. In our review, we discuss adverse childhood experiences, toxic stress, the neurobiological basis and multigenerational and epigenetic transmission of trauma and recognized health implications. Further, we outline building resilience, screening in the clinical setting, primary care interventions, applying trauma-informed care and future directions. We foresee that enhancing knowledge of the far-reaching effects of adverse childhood events will facilitate mitigation of toxic stress, promote child and family resilience and optimize life course health trajectories.

Early life environment and social determinants of cardiac health in children with congenital heart disease.

Congenital heart disease is a significant cause of infant mortality. Epidemiology and social context play a crucial role in conditioning disease burden and modulating outcomes, while diagnosis and treatment remain resource intensive. This review will address the role of social demographics, environmental exposure, epigenetics and nutrition in the aetiology of congenital heart disease. We then discuss the determinant effect of social factors on the provision and outcomes of care for congenital heart disease and implications for practice. It is our hope that enhanced knowledge of the intersection of social determinants of health and congenital heart disease will facilitate effective preventative strategies at the individual and population levels to optimize heart health outcomes across the life course.

Neonatal oesophageal perforation: The role for non-operative management.

AIM: Isolated oesophageal perforation in neonates is a rare but potentially life-threatening condition. Although management has historically been operative, conservative management (antibiotics, bowel rest, parenteral nutrition) is now more routinely used. The aim of this study was to evaluate the management of this condition in two large neonatal surgical centres. METHODS: A retrospective cohort study was conducted for neonates admitted to The Hospital for Sick Children (Toronto, Canada) or The Royal Children's Hospital (Melbourne, Australia) with a diagnosis of oesophageal perforation, from 2006 to 2016. Patients with oesophageal atresia or tracheo-oesophageal fistula were excluded. Data were collected from chart review regarding demographics, clinical course, management and outcomes. RESULTS: Eleven neonates with oesophageal perforation were identified over a 10-year period at the two centres. Median gestational age at birth was 25.3 weeks (interquartile range 24.2-28.8) and the majority (7/11, 64%) of neonates were extremely low birthweight. Diagnosis was made on day 1 of life for 9 of 11 (81%) neonates and was secondary to nasogastric tube insertion in 10 of 11 (91%) neonates. Only four (36%) neonates had symptomatic complications. All neonates were managed with bowel rest and intravenous antibiotics for a median of 7 days (interquartile range 7-10); two patients required operative intervention. Three neonates (27%) developed chronic lung disease and two (19%) died prior to discharge. CONCLUSIONS: Oesophageal perforation is severe complication secondary to instrumentation of the upper gastrointestinal tract in neonates. Prompt and accurate diagnosis is crucial. Non-operative management is effective for the majority, though morbidity is common.

Cardiovascular Associations with Abnormal Brain Magnetic Resonance Imaging in Neonates with Hypoxic Ischemic Encephalopathy Undergoing Therapeutic Hypothermia and Rewarming.

OBJECTIVE: This article compares hemodynamic characteristics of neonates with hypoxic ischemic encephalopathy (HIE) receiving therapeutic hypothermia (TH) with normal versus abnormal brain magnetic resonance imaging (MRI). METHODS: Serial echocardiography (echo) was performed within 24 hours, after 48 to 72 hours of cooling, within 24 hours of normothermia, and after starting feeds. Pulmonary hemodynamics, cardiac output, and ventricular function were evaluated. All neonates underwent brain MRI (day 4-5), per clinical standard of care. Clinical cardiovascular and echocardiography characteristics were compared between patients with normal versus abnormal MRI. Cardiovascular changes during TH and after rewarming were identified. RESULTS: Twenty neonates at median gestation and birth weight of 40 weeks (interquartile range [IQR]: 39, 41) and 3,410 g (IQR: 2,885, 4,093), respectively, were enrolled. Increased median left ventricular output (LVO) (106-159 mL/kg/min, p < 0.001) and reduced isovolumic relaxation time (IVRT) (48-42 ms, p < 0.001) were seen after rewarming. Echocardiography evidence of pulmonary hypertension (PH) was identified in five neonates. Eight neonates (40%) had brain injury identified on MRI (watershed [n = 4], basal ganglia [n = 4]); this subgroup were more likely to have echo evidence of PH at 24 hours. CONCLUSION: Longitudinal changes in cardiac output were noted in neonates with HIE during TH and rewarming. Echocardiography evidence of PH, however, was associated with abnormal MRI brain. The prognostic relevance of these physiologic changes requires more comprehensive delineation.

Neurodevelopmental outcomes of infants with esophageal atresia and tracheoesophageal fistula.

BACKGROUND: Esophageal atresia with or without tracheoesophageal fistula (EA/TEF) is a complex disorder, and most outcome data are confined to mortality and feeding-related morbidities. Our objective was to examine mortality, growth and neurodevelopmental outcomes in a large recent cohort of infants with EA/TEF. METHODS: Single center study of EA/TEF infants referred from January 2000 to December 2015. Data collected included associated defects, neonatal morbidity and mortality and growth and neurodevelopmental outcomes at age 12-36months. Multiple regression analysis was used to determine variables associated with adverse outcome. RESULTS: Of the 253 infants identified, 102 infants (40%) were preterm. Overall mortality was 8.3%, the majority from major cardiac malformations (p<0.001) Neurodevelopmental assessments (n=182) showed that 76% were within normal, while some delay was seen in 24%, most often in expressive and receptive language. Nine infants had hearing impairment and 5 had visual impairment. Gastrostomy tubes were required in 47 patients and 15% continued to have weight growth velocities less than the 10th centile. A number of specialist interventions were required, Speech/Language being frequent. CONCLUSION: Mortality in EA/TEF is primarily related to concomitant anomalies, especially cardiac. Multidisciplinary follow up is important for early identification and intervention for growth failure and developmental delay. TYPE OF STUDY: Retrospective study LEVEL OF EVIDENCE: Level II.

Enzyme replacement therapy in perinatal hypophosphatasia: Case report of a negative outcome and lessons for clinical practice.

Enzyme replacement therapy (ERT) is a newly approved disease-modifying treatment for hypophosphatasia (HPP), a rare metabolic bone disorder. With an orphan drug and ultra-rare disease, sharing information about responders and non-responders is particularly important, as any one centre's familiarity with its use will be limited. Nearly all published data in infants and very young children with life-threatening HPP are from three small clinical trials that have reported generally positive outcomes. We describe in detail a patient with perinatal HPP for whom treatment with ERT was not successful. Lessons learned from this case can inform clinical decision-making and provide topics for the research agenda. We also discuss practical and ethical challenges related to treatment of an ultra-rare disease with an expensive new medication in a publicly funded healthcare system.