10 Mar Optimized Care Improves Survival of Infants with Severe Genetic Bone Disorder, Osteogenesis imperfecta
MedicalResearch.com Interview with:
Dr. Carroll
Ricki S. Carroll, MD
Complex Care and Palliative Care Physician, Skeletal Dysplasia and Palliative Care Teams
Nemours Children’s Hospital
Wilmington, Delaware
MedicalResearch.com: What is the background for this study?
Response: Individuals with Osteogenesis imperfecta (OI) are often classified into one of four subtypes: type I (mild/nondeforming), type II (perinatal lethal), type III (severe/progressively deforming) and type IV (moderately deforming); however, this classification system continues to evolve with increasing knowledge (Sillence, 1979; Van Dyke & Sillence, 2014). Those with a mild phenotype are often diagnosed postnatally or in the pediatric setting after experiencing multiple unexplained fractures. Concerns for moderate to severely presenting OI are often noted in utero when fractures, shortening, and/or bowing of the long bones are found on prenatal ultrasound (Marini et al, 2017).
When Osteogenesis imperfecta is suspected and/or molecularly confirmed in the prenatal period, families may be counseled that the diagnosis is lethal or severely life-limiting based on prenatal ultrasound observations and previously reported genotype-phenotype correlations (Yoshimura et al., 1996; Krakow et al., 2009). Ultrasound parameters for predicting lethality in skeletal dysplasias have been studied and include the chest-to-abdominal circumference ratio of <0.6 and femur length-to-abdominal circumference ratio of <0.16 (Yoshimura et al., 1996; Rahemtullah et al., 1997; Ramus et al., 1998). However, there are nuances to this strategy, for instance in cases where bowing deformities and fractures limit the accuracy of true femur length measurements (Milks et al., 2017). While genotype-phenotype correlations are also considered when predicting lethality, there can be a range of clinical variability even among those with the same genotype (Rauch et al., 2004, Marini et al, 2017). Some specialized delivery centers have reported on the accuracy of these methods in predicting lethality, yet many of the pregnancies evaluated are ultimately terminated, further limiting the ability to draw conclusions (Yeh et al., 2011). These limitations pose a challenge for perinatal providers counseling families on the diagnosis and attempting to prognosticate postnatal survival probability. Consequently, this information can cloud conversations surrounding delivery planning and influence access to potential life-saving therapies including invasive mechanical ventilation and feeding support.
Advancements in medical technology and the option for life-sustaining interventions have significantly altered the prognoses for severely affected infants. In this manuscript, we describe perinatal outcomes of infants referred to a single specialized center after receiving a prior diagnosis of possibly lethal, lethal or type II OI where parents sought medical intervention after birth. We also outline advances in respiratory and feeding support needs, as well as length-of-stay for these neonates. The success of this multidisciplinary approach to neonatal OI care both challenges previously defined expectations for this patient population and offers a chance at survival.
Response: Would you briefly explain what is meant by osteogenesis imperfecta?
Osteogenesis imperfecta (OI) is a genetic condition with improperly or inadequately produced Type I collagen. Manifestations include fractures and bowing deformities that require lifelong orthopedic care. Other non-skeletal features may include blue or gray sclerae, joint hypermobility, dentinogenesis imperfecta (brittle teeth), hearing loss, a propensity for easy bruising, respiratory and feeding difficulties, and hydrocephalus. Intellect has been described as similar to the general population.
OI is known to be a spectrum condition, ranging from mild to perinatal lethal. Type I OI, or mild OI, is the most common form of OI and has the mildest presentation with, generally, typical height, no long bone deformities, and the lowest fracture rates. Type II is the most severe form of OI and is classically known as lethal in the perinatal period. Type III is the most severe form of OI in children surviving the neonatal period. Type III OI, or severe OI, is characterized by extreme short stature and progressive limb and spine deformities secondary to multiple fractures. Type IV OI, or moderate OI, is an intermediate form between Type I and Type III. In majority of patients with OI, an autosomal dominant mutation in one of the genes encoding type 1 collagen (COL1A1 or COL1A2) has been identified. However, with recent advances in understanding the molecular basis of OI, multiple other genetic causes have been identified and the number of subtypes has expanded.
The most severe types of OI can often be difficult to distinguish from each other by in utero ultrasonography. This can make it exceedingly difficult to prognosticate survival probability prenatally. In addition, heightened diagnostic awareness and improved treatments, particularly in severe forms, have increased the number of individuals living with OI. Advancements in technology and the option for life‐sustaining interventions have allowed more infants with “lethal” OI to survive.
MedicalResearch.com: What are the main findings?
Response: In examining correlations between prenatal diagnosis with gestational age, birth weight percentile, length of hospital stay, respiratory support at discharge, feeding support at discharge or need for VP shunt, we did not identify significant differences between groups. Overall, four individuals were born prior to 37 weeks (two preterm labor, one preeclampsia, one elective palliative), with one in the nonlethal prenatal diagnosis group and three in the lethal/possibly lethal group. We observed five individuals who were <1%ile for birth weight based on gestational age, with one in the nonlethal group, three in the lethal/possibly lethal group and one in the unknown group. All infants received bisphosphonates at a median age of 14 days (range 6-110 days). In the backward elimination logistic regression analysis, we did not observe significantly correlated variables, including birth weight percentile, length of hospital stay or need for support at discharge, to prenatal lethal/possibly lethal group.
In total, 12 of the 18 patients were given the diagnosis of lethal or possibly lethal OI. The families in this cohort pursued care at a specialized neonatal OI center. No infants required chest compressions in the delivery room, and only one received intubation and invasive mechanical ventilation in the delivery room. All patients survived to initial hospital discharge, and 16 of the 18 are alive today. The majority of these infants do not rely on breathing or feeding support. Furthermore, while there is a trend, infants with predicted lethal or possibly lethal OI did not demonstrate significantly longer lengths of stay or need for respiratory or feeding support at discharge compared to those predicted to have milder phenotype.
What is the quality of life of surviving infants after NICU discharge?
Response: We did not specifically study parent-perceived quality of life of their children with OI in this study. We know that psychosocial quality of life measures of people living with OI are described as similar to the general population.
Of the 18 infants included in this paper, 16 are alive today, with a median current age of 23.5 months (range 2-58 months). Of the seven individuals that required respiratory support at discharge, five were diagnosed with lethal/possibly lethal OI. Of the 12 infants diagnosed with lethal/possibly lethal OI prenatally, one was discharged on nasal cannula, three were discharged on nasal CPAP, and one with a tracheostomy and ventilator; the other 7 were discharged on room air. Currently two (ages 29 and 50 months) have tracheostomies, and the remainder do not require respiratory support. One of the individuals with a tracheostomy had been discharged on CPAP, but due to increasing respiratory support, tracheostomy was pursued at six months of age. For those who were weaned off respiratory support, it was discontinued between 9 and 14 months of age.
Of the nine individuals requiring feeding support at discharge, six were diagnosed with lethal/possibly lethal OI. Of the 12 infants diagnosed with lethal/possibly lethal OI prenatally, three were discharged with an NG-tube, three were discharged with a G-tube, and six were discharged eating by mouth. Currently, five individuals continue to require enteral support, four via G-tube and one via NG-tube. For those who were weaned off feeding support, it was discontinued between 2 and 9 months of age.
Five children have undergone lower extremity realignment/rodding (median 36 months; range 14-39 months), and one has undergone upper extremity realignment/rodding (53 months). Of the eight individuals older than two years old, one is walking without support (age 44 months), one is walking with support (age 39 months), one scoots, stands with support and is independent in a power wheel chair (age 58 months), two are crawling or scooting and standing with support (ages 24 and 47 months), and the remaining three are rolling (25, 29 and 50 months).
Of the four individuals with a genetic finding associated with lethal OI, three are living at median age six months (range 5-47 months). None require respiratory support. Patient 2 is able to bear weight on lower extremities and has feeding support (G-tube). Of the 4 individuals with FL/AC < 0.16, all are living, with median age 23.5 months (range 11 – 47 months). Both individuals who are above age two from this group are able to stand, bearing weight on lower extremities.
MedicalResearch.com: What should readers take away from your report?
Response: Moderate or severe OI is often diagnosed prenatally based on ultrasound findings and genetic testing may be labeled as lethal. In our experience, we do not observe that lethal or possibly lethal diagnoses prenatally were correlated with medically relevant outcomes such as need for respiratory support at discharge or need for feeding support at discharge. 16/18 individuals are alive, with a minority requiring either respiratory or feeding support. With a multidisciplinary team approach to neonatal care, outcomes may be optimized. Infants formerly diagnosed with lethal OI may survive. Given our findings, and lack of correlation of prenatal assessments with survival and other medical outcomes, we recommend all families be given the option to pursue medical interventions.
MedicalResearch.com: What recommendations do you have for future research as a results of this study?
Response: Our cohort demonstrated variation in methodology of prognostication, and therefore counseling. Standardization of assessment is needed in future studies to validate the predictive value of any prenatal findings alone or in various combinations. Further studies are needed to evaluate the efficacy of prenatal assessments in predicting lethality in OI. In the meantime, we recommend that ultrasound measurements and genetic testing results are utilized with caution in this patient population.
MedicalResearch.com: Is there anything else you would like to add? Any disclosures?
Response: We are thankful to the families for allowing us to care for their children and share their stories.
Ricki S. Carroll: RSC received honoraria from BioMarin, Guidepoint, and Actio for consulting, advisory board and/or speaking for educational purposes, and participates as an investigator in clinical trials funded by BioMarin, Ascendis, Ultragenyx, and Medlife.
Sarah Little: participates as a co-investigator in clinical trials funded by BioMarin, Ascendis, and Ultragenyx.
Tina McGreal: participates as a co-investigator in clinical trials funded by Ultragenyx.
Shannon Bonner: Nothing to disclose
Daria Willis: Nothing to disclose
Jeanne Franzone: Consultant, Orthopediatrics; participates as a co-investigator in clinical trials funded by Ultragenyx.
Jeffrey Campbell: Receives honoraria from BioMarin, Tyra for consulting, advisory board and/or speaking for educational purposes, and participates as an investigator in clinical trials funded by BioMarin.
Margaret Chou: Nothing to disclose
Megan Raymond: Nothing to disclose
Andrea Schelhaas: receives consulting fees from Tyra Biosciences
Joanna Costa: Nothing to disclose
Mahim Jain: MJ received honoraria from Travere Therapeutics and PWN Genomics for consulting, advisory board and/or speaking for educational purposes, and participates as an investigator in clinical trials funded by BioMarin, Ascendis, Ultragenyx, Amgen, Sanofi and Medlife.
Citation: Ricki S Carroll et al, Most infants with prenatal Osteogenesis Imperfecta diagnosis and poor prognosis survive: experience of a quaternary care OI Center, JBMR Plus (2025). DOI: 10.1093/jbmrpl/ziaf022
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Last Updated on March 10, 2025 by Marie Benz MD FAAD