Pediatrics

There are four key findings in patients with suspected severe drug reactions: a high risk medication, mucosal involvement, presence of pustules, and laboratory abnormalities, especially a CBC with differential and liver function tests, James R. Treat, MD, said at a pediatric dermatology meeting sponsored by Rady Children’s Hospital–San Diego and UC San Diego School of Medicine.

Several cutaneous drug reactions that were discussed during the conference included acute generalized exanthematous pustulosis (AGEP), a drug reaction with eosinophilia and systemic symptoms (DRESS), and Stevens-Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN).

cnellist@frontlinemedcom.com

There are four key findings in patients with suspected severe drug reactions: a high risk medication, mucosal involvement, presence of pustules, and laboratory abnormalities, especially a CBC with differential and liver function tests, James R. Treat, MD, said at a pediatric dermatology meeting sponsored by Rady Children’s Hospital–San Diego and UC San Diego School of Medicine.

Several cutaneous drug reactions that were discussed during the conference included acute generalized exanthematous pustulosis (AGEP), a drug reaction with eosinophilia and systemic symptoms (DRESS), and Stevens-Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN).

cnellist@frontlinemedcom.com

There are four key findings in patients with suspected severe drug reactions: a high risk medication, mucosal involvement, presence of pustules, and laboratory abnormalities, especially a CBC with differential and liver function tests, James R. Treat, MD, said at a pediatric dermatology meeting sponsored by Rady Children’s Hospital–San Diego and UC San Diego School of Medicine.

Several cutaneous drug reactions that were discussed during the conference included acute generalized exanthematous pustulosis (AGEP), a drug reaction with eosinophilia and systemic symptoms (DRESS), and Stevens-Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN).

cnellist@frontlinemedcom.com

Take-Home Points

• Bipartite patella is an asymptomatic anatomical variant.
• Occasionally, some adolescent athletes can present with AKP, resulting in decreased participation and performance.
• Bipartite patella is classified in type I, inferior pole; type II, lateral margin; and type III, superior lateral pole, depending on where the accessory patellar fragment is.
• Nonoperative treatment is advocated first. If symptoms persist surgical treatment should be attempted.

In 2% to 3% of the general population, the finding of bipartite patella on knee radiographs is often incidental.^1,2 During development, the patella normally originates in a primary ossification center. Occasionally, secondary ossification centers emerge around the margins of the primary center and typically join that center. In some cases, the secondary² center remains separated, leading to patella partita and an accessory patellar fragment.^3,4

The bipartite patella is connected to the primary patella by fibrocartilage. The fibrous attachment may become irritated or separated as a result of trauma, overuse, or strenuous activity.^1,5-7 Saupe classification of bipartite patella is based on accessory patellar fragment location: type I, inferior pole; type II, lateral margin; and type III, superior lateral pole.⁸ When an individual with a bipartite patella becomes symptomatic, anterior knee pain (AKP) is the most common complaint—it has been described in adolescent athletes in numerous sports.^7,9-11For most patients, first-line treatment is nonoperative management. A typical regimen includes reduced activity, use of nonsteroidal anti-inflammatory drugs, physical therapy, and isometric quadriceps-strengthening exercises.^1,12 Other nonoperative approaches described in the literature are immobilization,^5,10 steroid and anesthetic injection, and ultrasound therapy.¹³ If symptoms do not improve, surgical treatment should be considered. Surgical treatment options include open excision of fragment,^3,9,12 arthroscopic excision of fragment,^7,14,15 tension band wiring,^5,16 open reduction and internal fixation,¹⁷ open or arthroscopic vastus lateralis release,^18-20 and lateral retinacular release.²¹ However, the optimal surgical option remains controversial.

In this case report, we present a modification of an arthroscopic surgical technique for excising a symptomatic bipartite patella and report midterm clinical outcomes. The patient provided written informed consent for print and electronic publication of this report.

Case Report

A 16-year-old elite male ice hockey player presented to clinic with a 2-week history of left AKP. He could not recall a specific injury that triggered the symptoms. Radiographs were obtained at an outside institution, and knee patellar fracture was diagnosed. The patient, placed in a straight-leg immobilizer, later presented to a referral clinic for a second opinion and further evaluation. Physical examination revealed significant tenderness to palpation of the lateral aspect of the patella. Range of motion was symmetric and fully intact. Patellar mobility was excellent. However, the patient could not perform a straight-leg raise because of the pain.

We obtained anteroposterior and lateral radiographs (Figures 1A, 1B), which showed evidence of a Saupe type III bipartite patella with separation at the superolateral pole.

Surgical Technique

The patient was positioned supine on the operating table. Medial and lateral parapatellar arthroscopic portals were created. Menisci, cruciate ligaments, and tibiofemoral articular cartilage were arthroscopically visualized and determined to be normal. The bipartite patella was easily visualized, and notably loose when probed. Grade 2 chondromalacia was present diffusely throughout the bipartite patella and on the far lateral aspect of the patella, at the fragment interface.

Attention was then turned to arthroscopic removal of the accessory patellar fragment (Figures 3A, 3B).

Postoperative Rehabilitation

Rehabilitation focused on protection of the healing patella and accelerated rehabilitation for early return to play. Range-of-motion exercises and stationary bicycling were initiated on postoperative day 1. Weight-bearing was allowed as tolerated. Quadriceps sets, straight-leg raises, and ankle pumps were performed 5 times daily for 6 weeks. Six weeks after surgery, the patient was cleared, and he returned to full on-ice activities.

Outcomes

This study was approved by an Institutional Review Board. Preoperative and postoperative outcomes were obtained and stored in a data registry. The patient’s Lysholm score²² improved from 71 before surgery to 100 at 31-month follow-up. In addition, his subjective International Knee Documentation Committee score²³ improved from 65.5 before surgery to 72.4 after surgery. At follow-up, patient satisfaction with outcome was 10/10. In addition, the patient had returned to playing hockey at a higher national level without functional limitation.

Discussion

The most important finding in this case is that arthroscopic excision of a bipartite patella with preservation of the lateral retinaculum in an elite adolescent hockey player resulted in improved subjective clinical outcomes scores and early return to competition. Arthroscopic excision was favored over open excision in this patient because of potential quicker recovery,¹⁴ less pain, and expedited return to competition. In addition, previous arthroscopic techniques were modified to shorten postoperative rehabilitation. The modified technique included preservation of the lateral retinaculum and total arthroscopic excision of the accessory bipartite patella fragment.

Although results of open techniques have been favorable,^3,8,9 these procedures are far more invasive than arthroscopic techniques and may result in loss of quadriceps strength and prolonged rehabilitation.¹⁸ Weckström and colleagues¹² followed 25 male military recruits for a minimum of 10 years after open excision of symptomatic bipartite patella. Mean Kujala score was 95 (range, 75-100), and median visual analog scale score for knee pain was 1.0 (range, 0.0-6.0). In a study by Bourne and Bianco,³ 13 of 16 patients who were followed for an average of 7 years experienced complete pain relief with an average recovery time of 2 months.

Other studies have described the arthroscopic excision technique for symptomatic bipartite patella,^7,14,15 but outcomes are underreported, especially for follow-ups longer than 2 years. Felli and colleagues⁷ described a case of arthroscopic excision and lateral release in a 23-year-old female professional volleyball player; at 1-year follow-up, the patient was symptom-free and back to full athletic participation. Azarbod and colleagues¹⁴ also reported on a patient who was symptom-free, 6 weeks after arthroscopic excision of bipartite patella. Carney and colleagues¹⁵ indicated that successful excision of bipartite patella was evident on 6-month radiographic follow-up. Our 31-month follow-up is the longest of any study on arthroscopic excision of bipartite patella. Clinical outcomes were excellent both in our patient’s case and in the earlier studies.

Our patient was a high-level hockey player who wanted to return to competition as quickly as possible. Conservative management, including physical therapy, initially resolved his symptoms and allowed him to resume on-ice activities after 6 weeks. In time, however, his symptoms returned and began limiting his on-ice performance. Arthroscopic removal of the bipartite patella accessory fragment allowed him to return to full on-ice activities after 6 weeks. His case provides evidence that arthroscopic management of bipartite patella with preservation of the vastus lateralis and lateral retinaculum may be an excellent treatment option for patients who want to return to athletics as quickly as possible.

Our technique of arthroscopic excision with preservation of lateral retinaculum is an excellent treatment option for symptomatic bipartite patella. This option, combined with an aggressive rehabilitation protocol, allows for pain relief and expedited return to competition.

Am J Orthop. 2017;46(3):135-138. Copyright Frontline Medical Communications Inc. 2017. All rights reserved.

Take-Home Points

• Bipartite patella is an asymptomatic anatomical variant.
• Occasionally, some adolescent athletes can present with AKP, resulting in decreased participation and performance.
• Bipartite patella is classified in type I, inferior pole; type II, lateral margin; and type III, superior lateral pole, depending on where the accessory patellar fragment is.
• Nonoperative treatment is advocated first. If symptoms persist surgical treatment should be attempted.

In 2% to 3% of the general population, the finding of bipartite patella on knee radiographs is often incidental.^1,2 During development, the patella normally originates in a primary ossification center. Occasionally, secondary ossification centers emerge around the margins of the primary center and typically join that center. In some cases, the secondary² center remains separated, leading to patella partita and an accessory patellar fragment.^3,4

The bipartite patella is connected to the primary patella by fibrocartilage. The fibrous attachment may become irritated or separated as a result of trauma, overuse, or strenuous activity.^1,5-7 Saupe classification of bipartite patella is based on accessory patellar fragment location: type I, inferior pole; type II, lateral margin; and type III, superior lateral pole.⁸ When an individual with a bipartite patella becomes symptomatic, anterior knee pain (AKP) is the most common complaint—it has been described in adolescent athletes in numerous sports.^7,9-11For most patients, first-line treatment is nonoperative management. A typical regimen includes reduced activity, use of nonsteroidal anti-inflammatory drugs, physical therapy, and isometric quadriceps-strengthening exercises.^1,12 Other nonoperative approaches described in the literature are immobilization,^5,10 steroid and anesthetic injection, and ultrasound therapy.¹³ If symptoms do not improve, surgical treatment should be considered. Surgical treatment options include open excision of fragment,^3,9,12 arthroscopic excision of fragment,^7,14,15 tension band wiring,^5,16 open reduction and internal fixation,¹⁷ open or arthroscopic vastus lateralis release,^18-20 and lateral retinacular release.²¹ However, the optimal surgical option remains controversial.

In this case report, we present a modification of an arthroscopic surgical technique for excising a symptomatic bipartite patella and report midterm clinical outcomes. The patient provided written informed consent for print and electronic publication of this report.

Case Report

A 16-year-old elite male ice hockey player presented to clinic with a 2-week history of left AKP. He could not recall a specific injury that triggered the symptoms. Radiographs were obtained at an outside institution, and knee patellar fracture was diagnosed. The patient, placed in a straight-leg immobilizer, later presented to a referral clinic for a second opinion and further evaluation. Physical examination revealed significant tenderness to palpation of the lateral aspect of the patella. Range of motion was symmetric and fully intact. Patellar mobility was excellent. However, the patient could not perform a straight-leg raise because of the pain.

We obtained anteroposterior and lateral radiographs (Figures 1A, 1B), which showed evidence of a Saupe type III bipartite patella with separation at the superolateral pole.

Surgical Technique

The patient was positioned supine on the operating table. Medial and lateral parapatellar arthroscopic portals were created. Menisci, cruciate ligaments, and tibiofemoral articular cartilage were arthroscopically visualized and determined to be normal. The bipartite patella was easily visualized, and notably loose when probed. Grade 2 chondromalacia was present diffusely throughout the bipartite patella and on the far lateral aspect of the patella, at the fragment interface.

Attention was then turned to arthroscopic removal of the accessory patellar fragment (Figures 3A, 3B).

Postoperative Rehabilitation

Rehabilitation focused on protection of the healing patella and accelerated rehabilitation for early return to play. Range-of-motion exercises and stationary bicycling were initiated on postoperative day 1. Weight-bearing was allowed as tolerated. Quadriceps sets, straight-leg raises, and ankle pumps were performed 5 times daily for 6 weeks. Six weeks after surgery, the patient was cleared, and he returned to full on-ice activities.

Outcomes

This study was approved by an Institutional Review Board. Preoperative and postoperative outcomes were obtained and stored in a data registry. The patient’s Lysholm score²² improved from 71 before surgery to 100 at 31-month follow-up. In addition, his subjective International Knee Documentation Committee score²³ improved from 65.5 before surgery to 72.4 after surgery. At follow-up, patient satisfaction with outcome was 10/10. In addition, the patient had returned to playing hockey at a higher national level without functional limitation.

Discussion

The most important finding in this case is that arthroscopic excision of a bipartite patella with preservation of the lateral retinaculum in an elite adolescent hockey player resulted in improved subjective clinical outcomes scores and early return to competition. Arthroscopic excision was favored over open excision in this patient because of potential quicker recovery,¹⁴ less pain, and expedited return to competition. In addition, previous arthroscopic techniques were modified to shorten postoperative rehabilitation. The modified technique included preservation of the lateral retinaculum and total arthroscopic excision of the accessory bipartite patella fragment.

Although results of open techniques have been favorable,^3,8,9 these procedures are far more invasive than arthroscopic techniques and may result in loss of quadriceps strength and prolonged rehabilitation.¹⁸ Weckström and colleagues¹² followed 25 male military recruits for a minimum of 10 years after open excision of symptomatic bipartite patella. Mean Kujala score was 95 (range, 75-100), and median visual analog scale score for knee pain was 1.0 (range, 0.0-6.0). In a study by Bourne and Bianco,³ 13 of 16 patients who were followed for an average of 7 years experienced complete pain relief with an average recovery time of 2 months.

Other studies have described the arthroscopic excision technique for symptomatic bipartite patella,^7,14,15 but outcomes are underreported, especially for follow-ups longer than 2 years. Felli and colleagues⁷ described a case of arthroscopic excision and lateral release in a 23-year-old female professional volleyball player; at 1-year follow-up, the patient was symptom-free and back to full athletic participation. Azarbod and colleagues¹⁴ also reported on a patient who was symptom-free, 6 weeks after arthroscopic excision of bipartite patella. Carney and colleagues¹⁵ indicated that successful excision of bipartite patella was evident on 6-month radiographic follow-up. Our 31-month follow-up is the longest of any study on arthroscopic excision of bipartite patella. Clinical outcomes were excellent both in our patient’s case and in the earlier studies.

Our patient was a high-level hockey player who wanted to return to competition as quickly as possible. Conservative management, including physical therapy, initially resolved his symptoms and allowed him to resume on-ice activities after 6 weeks. In time, however, his symptoms returned and began limiting his on-ice performance. Arthroscopic removal of the bipartite patella accessory fragment allowed him to return to full on-ice activities after 6 weeks. His case provides evidence that arthroscopic management of bipartite patella with preservation of the vastus lateralis and lateral retinaculum may be an excellent treatment option for patients who want to return to athletics as quickly as possible.

Our technique of arthroscopic excision with preservation of lateral retinaculum is an excellent treatment option for symptomatic bipartite patella. This option, combined with an aggressive rehabilitation protocol, allows for pain relief and expedited return to competition.

Am J Orthop. 2017;46(3):135-138. Copyright Frontline Medical Communications Inc. 2017. All rights reserved.

Take-Home Points

• Bipartite patella is an asymptomatic anatomical variant.
• Occasionally, some adolescent athletes can present with AKP, resulting in decreased participation and performance.
• Bipartite patella is classified in type I, inferior pole; type II, lateral margin; and type III, superior lateral pole, depending on where the accessory patellar fragment is.
• Nonoperative treatment is advocated first. If symptoms persist surgical treatment should be attempted.

In 2% to 3% of the general population, the finding of bipartite patella on knee radiographs is often incidental.^1,2 During development, the patella normally originates in a primary ossification center. Occasionally, secondary ossification centers emerge around the margins of the primary center and typically join that center. In some cases, the secondary² center remains separated, leading to patella partita and an accessory patellar fragment.^3,4

The bipartite patella is connected to the primary patella by fibrocartilage. The fibrous attachment may become irritated or separated as a result of trauma, overuse, or strenuous activity.^1,5-7 Saupe classification of bipartite patella is based on accessory patellar fragment location: type I, inferior pole; type II, lateral margin; and type III, superior lateral pole.⁸ When an individual with a bipartite patella becomes symptomatic, anterior knee pain (AKP) is the most common complaint—it has been described in adolescent athletes in numerous sports.^7,9-11For most patients, first-line treatment is nonoperative management. A typical regimen includes reduced activity, use of nonsteroidal anti-inflammatory drugs, physical therapy, and isometric quadriceps-strengthening exercises.^1,12 Other nonoperative approaches described in the literature are immobilization,^5,10 steroid and anesthetic injection, and ultrasound therapy.¹³ If symptoms do not improve, surgical treatment should be considered. Surgical treatment options include open excision of fragment,^3,9,12 arthroscopic excision of fragment,^7,14,15 tension band wiring,^5,16 open reduction and internal fixation,¹⁷ open or arthroscopic vastus lateralis release,^18-20 and lateral retinacular release.²¹ However, the optimal surgical option remains controversial.

In this case report, we present a modification of an arthroscopic surgical technique for excising a symptomatic bipartite patella and report midterm clinical outcomes. The patient provided written informed consent for print and electronic publication of this report.

Case Report

A 16-year-old elite male ice hockey player presented to clinic with a 2-week history of left AKP. He could not recall a specific injury that triggered the symptoms. Radiographs were obtained at an outside institution, and knee patellar fracture was diagnosed. The patient, placed in a straight-leg immobilizer, later presented to a referral clinic for a second opinion and further evaluation. Physical examination revealed significant tenderness to palpation of the lateral aspect of the patella. Range of motion was symmetric and fully intact. Patellar mobility was excellent. However, the patient could not perform a straight-leg raise because of the pain.

We obtained anteroposterior and lateral radiographs (Figures 1A, 1B), which showed evidence of a Saupe type III bipartite patella with separation at the superolateral pole.

Surgical Technique

The patient was positioned supine on the operating table. Medial and lateral parapatellar arthroscopic portals were created. Menisci, cruciate ligaments, and tibiofemoral articular cartilage were arthroscopically visualized and determined to be normal. The bipartite patella was easily visualized, and notably loose when probed. Grade 2 chondromalacia was present diffusely throughout the bipartite patella and on the far lateral aspect of the patella, at the fragment interface.

Attention was then turned to arthroscopic removal of the accessory patellar fragment (Figures 3A, 3B).

Postoperative Rehabilitation

Rehabilitation focused on protection of the healing patella and accelerated rehabilitation for early return to play. Range-of-motion exercises and stationary bicycling were initiated on postoperative day 1. Weight-bearing was allowed as tolerated. Quadriceps sets, straight-leg raises, and ankle pumps were performed 5 times daily for 6 weeks. Six weeks after surgery, the patient was cleared, and he returned to full on-ice activities.

Outcomes

This study was approved by an Institutional Review Board. Preoperative and postoperative outcomes were obtained and stored in a data registry. The patient’s Lysholm score²² improved from 71 before surgery to 100 at 31-month follow-up. In addition, his subjective International Knee Documentation Committee score²³ improved from 65.5 before surgery to 72.4 after surgery. At follow-up, patient satisfaction with outcome was 10/10. In addition, the patient had returned to playing hockey at a higher national level without functional limitation.

Discussion

The most important finding in this case is that arthroscopic excision of a bipartite patella with preservation of the lateral retinaculum in an elite adolescent hockey player resulted in improved subjective clinical outcomes scores and early return to competition. Arthroscopic excision was favored over open excision in this patient because of potential quicker recovery,¹⁴ less pain, and expedited return to competition. In addition, previous arthroscopic techniques were modified to shorten postoperative rehabilitation. The modified technique included preservation of the lateral retinaculum and total arthroscopic excision of the accessory bipartite patella fragment.

Although results of open techniques have been favorable,^3,8,9 these procedures are far more invasive than arthroscopic techniques and may result in loss of quadriceps strength and prolonged rehabilitation.¹⁸ Weckström and colleagues¹² followed 25 male military recruits for a minimum of 10 years after open excision of symptomatic bipartite patella. Mean Kujala score was 95 (range, 75-100), and median visual analog scale score for knee pain was 1.0 (range, 0.0-6.0). In a study by Bourne and Bianco,³ 13 of 16 patients who were followed for an average of 7 years experienced complete pain relief with an average recovery time of 2 months.

Other studies have described the arthroscopic excision technique for symptomatic bipartite patella,^7,14,15 but outcomes are underreported, especially for follow-ups longer than 2 years. Felli and colleagues⁷ described a case of arthroscopic excision and lateral release in a 23-year-old female professional volleyball player; at 1-year follow-up, the patient was symptom-free and back to full athletic participation. Azarbod and colleagues¹⁴ also reported on a patient who was symptom-free, 6 weeks after arthroscopic excision of bipartite patella. Carney and colleagues¹⁵ indicated that successful excision of bipartite patella was evident on 6-month radiographic follow-up. Our 31-month follow-up is the longest of any study on arthroscopic excision of bipartite patella. Clinical outcomes were excellent both in our patient’s case and in the earlier studies.

Our patient was a high-level hockey player who wanted to return to competition as quickly as possible. Conservative management, including physical therapy, initially resolved his symptoms and allowed him to resume on-ice activities after 6 weeks. In time, however, his symptoms returned and began limiting his on-ice performance. Arthroscopic removal of the bipartite patella accessory fragment allowed him to return to full on-ice activities after 6 weeks. His case provides evidence that arthroscopic management of bipartite patella with preservation of the vastus lateralis and lateral retinaculum may be an excellent treatment option for patients who want to return to athletics as quickly as possible.

Our technique of arthroscopic excision with preservation of lateral retinaculum is an excellent treatment option for symptomatic bipartite patella. This option, combined with an aggressive rehabilitation protocol, allows for pain relief and expedited return to competition.

Am J Orthop. 2017;46(3):135-138. Copyright Frontline Medical Communications Inc. 2017. All rights reserved.

ABSTRACT

Objective To reduce unnecessary orthopedic referrals by developing a protocol for managing physiologic bow legs in the primary care environment through the use of a noninvasive technique that simultaneously tracks normal varus progression and screens for potential pathologic bowing requiring an orthopedic referral.

Methods Retrospective study of 155 patients with physiologic genu varum and 10 with infantile Blount’s disease. We used fingerbreadth measurements to document progression or resolution of bow legs. Final diagnoses were made by one orthopedic surgeon using clinical and radiographic evidence. We divided genu varum patients into 3 groups: patients presenting with bow legs before 18 months of age (MOA), patients presenting between 18 and 23 MOA, and patients presenting at 24 MOA or older for analyses relevant to the development of the follow-up protocol.

Results Physiologic genu varum patients walked earlier than average infants (10 months vs 12-15 months; P<.001). Physiologic genu varum patients presenting before 18 MOA demonstrated initial signs of correction between 18 and 24 MOA and resolution by 30 MOA. Physiologic genu varum patients presenting between 18 and 23 MOA demonstrated initial signs of correction between 24 MOA and 30 MOA and resolution by 36 MOA.

Conclusion Primary care physicians can manage most children presenting with bow legs. Management focuses on following the progression or resolution of varus with regular follow-up. For patients presenting with bow legs, we recommend a follow-up protocol using mainly well-child checkups and a simple clinical assessment to monitor varus progression and screen for pathologic bowing.

Bow legs in young children can be a concern for parents.^1,2 By far, the most common reason for bow legs is physiologic genu varum,^3-5 a nonprogressive stage of normal development in young children that generally resolves spontaneously without treatment.^1,6-11 Normally developing children undergo a varus phase between birth and 18 to 24 months of age (MOA), at which time there is usually a transition in alignment from varus to straight to valgus (knock knees), which will correct to straight or mild valgus throughout adolescence.^{1,6,7,9,10,12-17}

The most common form of pathologic bow legs is Blount’s disease, also known as tibia vara, which must be differentiated from physiologic genu varum.^{8-10,15,18-24} The progressive varus deformity of Blount’s disease usually requires orthopedic intervention.^1,10,23-26 Early diagnosis may spare patients complex interventions, improve prognosis, and limit complications that include gait abnormalities,^4,8,10,27 knee joint instability,^4,24,27 osteoarthritis,^9,20,27 meniscal tears,²⁷ and degenerative joint disease.^19,20,27

Although variables such as walking age, race, weight, and gender have been suggested as risk factors for Blount’s disease, they have not been useful in differentiating between Blount’s pathology and physiologic genu varum.^{1,4,5,7,10,20,28} In the primary care setting, distinguishing physiologic from pathologic forms of bow legs is possible with a thorough history and physical exam and with radiographs, as warranted.^1,2,15 More than 40% of genu varum/genu valgum cases referred for orthopedic consultation turn out to be the physiologic form,² suggesting a need for guidelines in the primary care setting to help direct referral and follow-up. The purpose of this study was to provide recommendations to family physicians for evaluating and managing children with bow legs.

Materials and methods

This study, approved by the Internal Review Board of Akron Children’s Hospital, is a retrospective review of children seen by a single pediatric orthopedic surgeon (DSW) from 1970 to 2012. Four-hundred twenty-four children were received for evaluation of bow legs. Excluded from our final analysis were 220 subjects seen only once for this specific referral and 39 subjects diagnosed with a condition other than genu varum or Blount’s disease (ie, rickets, skeletal dysplasia, sequelae of trauma, or infection). Ten subjects with Blount’s disease and 155 subjects with physiologic genu varum were included in the final data analysis.

More than 40% of genu varum cases referred for orthopedic consultation turn out to be the physiologic form.In addition to noting the age at which a patient walked independently, at each visit we documented age and the fingerbreadth (varus) distance between the medial femoral condyles with the child’s ankles held together. Parents reported age of independent walking for just 3 children with Blount’s disease and for 134 children with physiologic genu varum. Study variables for the genu varum data analysis were age of walking, age at presentation, age at varus correction, age at varus resolution, time between presentation and varus correction, and time between presentation and varus resolution. Varus correction is defined as any decrease in varus angulation since presentation. Varus resolution is defined as varus correction to less than or equal to half of the varus angulation at presentation. For inclusion in the age-at-resolution analysis, a child must have been evaluated at regular follow-up visits (all rechecks within 8 months).

To measure varus distance, we used the fingerbreadth method described by Weiner in a study of 600 cases (FIGURE).⁶ This simple technique, which requires no special equipment, accurately detected differences in varus angulation and tracked the normal pattern of lower limb angular development. The patient should be supine on the examination table with legs extended. With one hand, the examiner holds the child’s ankles together, ensuring the medial malleoli are in contact. With the other hand, the examiner measures the fingerbreadth distance between the medial femoral condyles. Alternatively, a ruler may be used to measure the distance. This latter method may be especially useful in practices where the patient is likely to see more than one provider for well child care.

We divided the genu varum subject group into 3 subgroups by age at presentation: 103 subjects were younger than 18 months; 47 were 18 to 23 months; and 5 were 24 months or older. We used the data analysis toolkit in Microsoft Excel 2013 to perform a statistical analysis of study variables. We assumed the genu varum population is a normally distributed population. We used a 95% confidence level (α=0.05) for all calculations of confidence intervals (CIs), student t-tests, and tolerance intervals. Based on the data analysis results, we developed a series of follow-up and referral guidelines for practitioners.

Results

The mean walking age for those diagnosed with physiologic genu varum was 10 months (95% CI, 9.8-10.4), which is significantly younger than the 12 months of age (at the earliest) typical of toddlers in general (P<.001). There was no significant difference between the walking age of male and female children diagnosed with genu varum (P=.37).

Of the children presenting with the primary complaint of bow legs, 6% subsequently developed Blount’s disease. These patients presented at a mean age of 20.9 months and were diagnosed at a mean age of 23.9 months. Following the Blount’s disease diagnosis, we initiated therapy in all cases (3 surgical, 7 bracing).

Physiologic genu varum patients presented at a mean age of 16.4 months, with only 3.23% presenting at older than 23 months. On average, physiologic genu varum patients presenting before 24 months of age showed measurable varus correction 5 months after presentation and achieved varus resolution 7.3 months after presentation (TABLE 1). Assuming the patient population is normally distributed, we can be 95% confident that 95% of physiologic genu varum patients presenting before 18 months of age will show measurable varus correction by 24 months and will resolve without intervention by 30 months (TABLE 2). Patients presenting between 18 and 23 months of age should show measurable varus correction by 30 months and resolution by 36 months (TABLE 3).

Discussion

Primary care physicians have the ability to differentiate physiologic genu varum from pathologic forms of bow legs with a thorough history, physical exam, and radiographic examination, if necessary^1,2,13 (TABLE 4^{1,7,8,10,12,14,18-20,22,24,27}). Several approaches to differentiating Blount’s disease and physiologic genu varum have been described in the literature.^{1,4,7,8,10,14,22,23}

The average age at which children begin to walk independently is between 13 and 15 months.^5,18,29-31 Recently, it has been suggested that the range be expanded to include 12 months of age.³⁰ The association between early walking (at 10-11 months)^12,20,22 and Blount’s disease is generally accepted in the orthopedic literature.^{1,4,7,10,19-22} However, some authors have suggested early walking also contributes to genu varum.^{1,5,8,10,18,28} The mean age of independent walking for children with physiologic genu varum suggested in the literature (10 months) was confirmed in our study and found to be significantly younger than the average for toddlers generally.^1,22 Early walking is clearly associated with both physiologic genu varum and Blount’s disease, but no direct causation has been identified in either case. An alternative means of differentiating these entities is needed.

Primary care physicians can differentiate physiologic genu varum from pathologic forms of bow legs with a thorough history, physical exam, and radiographic examination (if needed).Radiographic examination of the knee is essential to the diagnosis of Blount’s disease as well as other, less common causes of pathologic bow legs (skeletal dysplasia, rickets, traumatic growth plate insults, infections, neoplasms).^1,8,14,19 The common radiologic classification of staging for Blount’s disease is the Langenskiöld staging system, which involves identification of characteristic radiographic changes at the tibial physis.^{5,8,14,15,18,22,24}

The fingerbreadth method, which requires no special equipment, accurately detected differences in varus angulation and tracked the normal pattern of lower limb angular development.Sequential measurement of genu varum is most useful in differentiating between physiologic and pathologic processes. Physiologic genu varum, an exaggeration of the normal developmental pattern, characteristically resolves and evolves into physiologic genu valgum by 3 years of age.^1,6-11 The pathophysiology of Blount’s disease is believed to be related to biomechanical overloading of the posteromedial proximal tibia during gait with the knee in a varus orientation. Excess loading on the proximal medial physis contributes to varus progression.^{4,10,14,20,25,27} Patients with Blount’s disease progress with varus and concomitant internal tibial torsion associated with growth plate irregularities and eventually exhibit premature closure.^{1,10,14,18,20,23,24,26} In the months prior to Blount’s disease diagnosis, increasing varus has been reported.^4,7,10,19 Varus progression that differs from the expected pattern indicates possible pathologic bow legs and should prompt radiologic evaluation and, often, an orthopedic referral.^{3,4,7-9,12,13,21}

In our study, only 3% of children with physiologic genu varum presented at 24 months of age or older, compared with 20% of Blount’s disease patients. We recommend considering orthopedic referral for any patient presenting with bow legs at 24 months of age or older. Additionally, consider orthopedic referral for any patient whose varus has not begun to correct within 8 months or has not resolved within 14 months of presentation, as more than 95% of patients with physiologic genu varum are expected to meet these milestones (TABLE 1). And do not hesitate to refer patients at any stage of follow-up if you suspect pathology or if parents are anxious.

If no sign of pathology is immediately identified, we recommend the following course of action:

• Record a reference fingerbreadth or ruler measurement at the initial presentation.
• Re-examine the knee varus at the next regular well-child visit (TABLE 5).

In our study, only 3% of children with physiologic genu varum presented at 24 months of age or older, compared with 20% of Blount's disease patients.Re-examining the patient prior to the next well-child visit is unnecessary, as some degree of bowing is typical until age 18 to 24 months.^{1,6,7,9,12,13,17} Recommend orthopedic referral for any patient with varus that has progressed since initial presentation. Without signs of pathology, repeat varus assessment at the next well-child visit. This schedule minimizes the need for additional physician appointments by integrating follow-up into the typical well-child visits at 18, 24, 30, and 36 months of age.³² The 6-month follow-up interval was a feature of our study and is recommended in the related literature.¹²

• Consider orthopedic referral for patients whose varus has not corrected by the second follow-up appointment, as more than 95% of patients should have measurable varus correction at this visit. Most patients will have exhibited varus resolution by this time and will not require additional follow-up. For patients with observable correction who do not yet meet the criteria for resolution, we recommend a third, final follow-up appointment in another 6 months.
• Refer any patient whose varus has not resolved by the third follow-up appointment, as more than 95% of genu varum cases should have resolved by this time. This finding is echoed in the literature; any varus beyond 36 months of age is considered abnormal and suggestive of pathology.^5,7,8,13,14 If evidence of Blount’s or skeletal dysplasia is identified, orthopedic management will likely consist of bracing (orthotics) or surgical management.

CORRESPONDENCE
Dennis S. Weiner, MD, Department of Orthopedic Surgery, Akron Children’s Hospital, 300 Locust Street, Suite 250, Akron, OH, 44302; mdicintio@chmca.org.

ACKNOWLEDGEMENTS
The authors thank Meadow Newton, BS, assistant research coordinator, Akron Children’s Hospital, for her editing and technical assistance and Richard Steiner, PhD, The University of Akron, for his statistical review.

ABSTRACT

Objective To reduce unnecessary orthopedic referrals by developing a protocol for managing physiologic bow legs in the primary care environment through the use of a noninvasive technique that simultaneously tracks normal varus progression and screens for potential pathologic bowing requiring an orthopedic referral.

Methods Retrospective study of 155 patients with physiologic genu varum and 10 with infantile Blount’s disease. We used fingerbreadth measurements to document progression or resolution of bow legs. Final diagnoses were made by one orthopedic surgeon using clinical and radiographic evidence. We divided genu varum patients into 3 groups: patients presenting with bow legs before 18 months of age (MOA), patients presenting between 18 and 23 MOA, and patients presenting at 24 MOA or older for analyses relevant to the development of the follow-up protocol.

Results Physiologic genu varum patients walked earlier than average infants (10 months vs 12-15 months; P<.001). Physiologic genu varum patients presenting before 18 MOA demonstrated initial signs of correction between 18 and 24 MOA and resolution by 30 MOA. Physiologic genu varum patients presenting between 18 and 23 MOA demonstrated initial signs of correction between 24 MOA and 30 MOA and resolution by 36 MOA.

Conclusion Primary care physicians can manage most children presenting with bow legs. Management focuses on following the progression or resolution of varus with regular follow-up. For patients presenting with bow legs, we recommend a follow-up protocol using mainly well-child checkups and a simple clinical assessment to monitor varus progression and screen for pathologic bowing.

Bow legs in young children can be a concern for parents.^1,2 By far, the most common reason for bow legs is physiologic genu varum,^3-5 a nonprogressive stage of normal development in young children that generally resolves spontaneously without treatment.^1,6-11 Normally developing children undergo a varus phase between birth and 18 to 24 months of age (MOA), at which time there is usually a transition in alignment from varus to straight to valgus (knock knees), which will correct to straight or mild valgus throughout adolescence.^{1,6,7,9,10,12-17}

The most common form of pathologic bow legs is Blount’s disease, also known as tibia vara, which must be differentiated from physiologic genu varum.^{8-10,15,18-24} The progressive varus deformity of Blount’s disease usually requires orthopedic intervention.^1,10,23-26 Early diagnosis may spare patients complex interventions, improve prognosis, and limit complications that include gait abnormalities,^4,8,10,27 knee joint instability,^4,24,27 osteoarthritis,^9,20,27 meniscal tears,²⁷ and degenerative joint disease.^19,20,27

Although variables such as walking age, race, weight, and gender have been suggested as risk factors for Blount’s disease, they have not been useful in differentiating between Blount’s pathology and physiologic genu varum.^{1,4,5,7,10,20,28} In the primary care setting, distinguishing physiologic from pathologic forms of bow legs is possible with a thorough history and physical exam and with radiographs, as warranted.^1,2,15 More than 40% of genu varum/genu valgum cases referred for orthopedic consultation turn out to be the physiologic form,² suggesting a need for guidelines in the primary care setting to help direct referral and follow-up. The purpose of this study was to provide recommendations to family physicians for evaluating and managing children with bow legs.

Materials and methods

This study, approved by the Internal Review Board of Akron Children’s Hospital, is a retrospective review of children seen by a single pediatric orthopedic surgeon (DSW) from 1970 to 2012. Four-hundred twenty-four children were received for evaluation of bow legs. Excluded from our final analysis were 220 subjects seen only once for this specific referral and 39 subjects diagnosed with a condition other than genu varum or Blount’s disease (ie, rickets, skeletal dysplasia, sequelae of trauma, or infection). Ten subjects with Blount’s disease and 155 subjects with physiologic genu varum were included in the final data analysis.

More than 40% of genu varum cases referred for orthopedic consultation turn out to be the physiologic form.In addition to noting the age at which a patient walked independently, at each visit we documented age and the fingerbreadth (varus) distance between the medial femoral condyles with the child’s ankles held together. Parents reported age of independent walking for just 3 children with Blount’s disease and for 134 children with physiologic genu varum. Study variables for the genu varum data analysis were age of walking, age at presentation, age at varus correction, age at varus resolution, time between presentation and varus correction, and time between presentation and varus resolution. Varus correction is defined as any decrease in varus angulation since presentation. Varus resolution is defined as varus correction to less than or equal to half of the varus angulation at presentation. For inclusion in the age-at-resolution analysis, a child must have been evaluated at regular follow-up visits (all rechecks within 8 months).

To measure varus distance, we used the fingerbreadth method described by Weiner in a study of 600 cases (FIGURE).⁶ This simple technique, which requires no special equipment, accurately detected differences in varus angulation and tracked the normal pattern of lower limb angular development. The patient should be supine on the examination table with legs extended. With one hand, the examiner holds the child’s ankles together, ensuring the medial malleoli are in contact. With the other hand, the examiner measures the fingerbreadth distance between the medial femoral condyles. Alternatively, a ruler may be used to measure the distance. This latter method may be especially useful in practices where the patient is likely to see more than one provider for well child care.

We divided the genu varum subject group into 3 subgroups by age at presentation: 103 subjects were younger than 18 months; 47 were 18 to 23 months; and 5 were 24 months or older. We used the data analysis toolkit in Microsoft Excel 2013 to perform a statistical analysis of study variables. We assumed the genu varum population is a normally distributed population. We used a 95% confidence level (α=0.05) for all calculations of confidence intervals (CIs), student t-tests, and tolerance intervals. Based on the data analysis results, we developed a series of follow-up and referral guidelines for practitioners.

Results

The mean walking age for those diagnosed with physiologic genu varum was 10 months (95% CI, 9.8-10.4), which is significantly younger than the 12 months of age (at the earliest) typical of toddlers in general (P<.001). There was no significant difference between the walking age of male and female children diagnosed with genu varum (P=.37).

Of the children presenting with the primary complaint of bow legs, 6% subsequently developed Blount’s disease. These patients presented at a mean age of 20.9 months and were diagnosed at a mean age of 23.9 months. Following the Blount’s disease diagnosis, we initiated therapy in all cases (3 surgical, 7 bracing).

Physiologic genu varum patients presented at a mean age of 16.4 months, with only 3.23% presenting at older than 23 months. On average, physiologic genu varum patients presenting before 24 months of age showed measurable varus correction 5 months after presentation and achieved varus resolution 7.3 months after presentation (TABLE 1). Assuming the patient population is normally distributed, we can be 95% confident that 95% of physiologic genu varum patients presenting before 18 months of age will show measurable varus correction by 24 months and will resolve without intervention by 30 months (TABLE 2). Patients presenting between 18 and 23 months of age should show measurable varus correction by 30 months and resolution by 36 months (TABLE 3).

Discussion

Primary care physicians have the ability to differentiate physiologic genu varum from pathologic forms of bow legs with a thorough history, physical exam, and radiographic examination, if necessary^1,2,13 (TABLE 4^{1,7,8,10,12,14,18-20,22,24,27}). Several approaches to differentiating Blount’s disease and physiologic genu varum have been described in the literature.^{1,4,7,8,10,14,22,23}

The average age at which children begin to walk independently is between 13 and 15 months.^5,18,29-31 Recently, it has been suggested that the range be expanded to include 12 months of age.³⁰ The association between early walking (at 10-11 months)^12,20,22 and Blount’s disease is generally accepted in the orthopedic literature.^{1,4,7,10,19-22} However, some authors have suggested early walking also contributes to genu varum.^{1,5,8,10,18,28} The mean age of independent walking for children with physiologic genu varum suggested in the literature (10 months) was confirmed in our study and found to be significantly younger than the average for toddlers generally.^1,22 Early walking is clearly associated with both physiologic genu varum and Blount’s disease, but no direct causation has been identified in either case. An alternative means of differentiating these entities is needed.

Primary care physicians can differentiate physiologic genu varum from pathologic forms of bow legs with a thorough history, physical exam, and radiographic examination (if needed).Radiographic examination of the knee is essential to the diagnosis of Blount’s disease as well as other, less common causes of pathologic bow legs (skeletal dysplasia, rickets, traumatic growth plate insults, infections, neoplasms).^1,8,14,19 The common radiologic classification of staging for Blount’s disease is the Langenskiöld staging system, which involves identification of characteristic radiographic changes at the tibial physis.^{5,8,14,15,18,22,24}

The fingerbreadth method, which requires no special equipment, accurately detected differences in varus angulation and tracked the normal pattern of lower limb angular development.Sequential measurement of genu varum is most useful in differentiating between physiologic and pathologic processes. Physiologic genu varum, an exaggeration of the normal developmental pattern, characteristically resolves and evolves into physiologic genu valgum by 3 years of age.^1,6-11 The pathophysiology of Blount’s disease is believed to be related to biomechanical overloading of the posteromedial proximal tibia during gait with the knee in a varus orientation. Excess loading on the proximal medial physis contributes to varus progression.^{4,10,14,20,25,27} Patients with Blount’s disease progress with varus and concomitant internal tibial torsion associated with growth plate irregularities and eventually exhibit premature closure.^{1,10,14,18,20,23,24,26} In the months prior to Blount’s disease diagnosis, increasing varus has been reported.^4,7,10,19 Varus progression that differs from the expected pattern indicates possible pathologic bow legs and should prompt radiologic evaluation and, often, an orthopedic referral.^{3,4,7-9,12,13,21}

In our study, only 3% of children with physiologic genu varum presented at 24 months of age or older, compared with 20% of Blount’s disease patients. We recommend considering orthopedic referral for any patient presenting with bow legs at 24 months of age or older. Additionally, consider orthopedic referral for any patient whose varus has not begun to correct within 8 months or has not resolved within 14 months of presentation, as more than 95% of patients with physiologic genu varum are expected to meet these milestones (TABLE 1). And do not hesitate to refer patients at any stage of follow-up if you suspect pathology or if parents are anxious.

If no sign of pathology is immediately identified, we recommend the following course of action:

• Record a reference fingerbreadth or ruler measurement at the initial presentation.
• Re-examine the knee varus at the next regular well-child visit (TABLE 5).

In our study, only 3% of children with physiologic genu varum presented at 24 months of age or older, compared with 20% of Blount's disease patients.Re-examining the patient prior to the next well-child visit is unnecessary, as some degree of bowing is typical until age 18 to 24 months.^{1,6,7,9,12,13,17} Recommend orthopedic referral for any patient with varus that has progressed since initial presentation. Without signs of pathology, repeat varus assessment at the next well-child visit. This schedule minimizes the need for additional physician appointments by integrating follow-up into the typical well-child visits at 18, 24, 30, and 36 months of age.³² The 6-month follow-up interval was a feature of our study and is recommended in the related literature.¹²

• Consider orthopedic referral for patients whose varus has not corrected by the second follow-up appointment, as more than 95% of patients should have measurable varus correction at this visit. Most patients will have exhibited varus resolution by this time and will not require additional follow-up. For patients with observable correction who do not yet meet the criteria for resolution, we recommend a third, final follow-up appointment in another 6 months.
• Refer any patient whose varus has not resolved by the third follow-up appointment, as more than 95% of genu varum cases should have resolved by this time. This finding is echoed in the literature; any varus beyond 36 months of age is considered abnormal and suggestive of pathology.^5,7,8,13,14 If evidence of Blount’s or skeletal dysplasia is identified, orthopedic management will likely consist of bracing (orthotics) or surgical management.

CORRESPONDENCE
Dennis S. Weiner, MD, Department of Orthopedic Surgery, Akron Children’s Hospital, 300 Locust Street, Suite 250, Akron, OH, 44302; mdicintio@chmca.org.

ACKNOWLEDGEMENTS
The authors thank Meadow Newton, BS, assistant research coordinator, Akron Children’s Hospital, for her editing and technical assistance and Richard Steiner, PhD, The University of Akron, for his statistical review.

ABSTRACT

Objective To reduce unnecessary orthopedic referrals by developing a protocol for managing physiologic bow legs in the primary care environment through the use of a noninvasive technique that simultaneously tracks normal varus progression and screens for potential pathologic bowing requiring an orthopedic referral.

Methods Retrospective study of 155 patients with physiologic genu varum and 10 with infantile Blount’s disease. We used fingerbreadth measurements to document progression or resolution of bow legs. Final diagnoses were made by one orthopedic surgeon using clinical and radiographic evidence. We divided genu varum patients into 3 groups: patients presenting with bow legs before 18 months of age (MOA), patients presenting between 18 and 23 MOA, and patients presenting at 24 MOA or older for analyses relevant to the development of the follow-up protocol.

Results Physiologic genu varum patients walked earlier than average infants (10 months vs 12-15 months; P<.001). Physiologic genu varum patients presenting before 18 MOA demonstrated initial signs of correction between 18 and 24 MOA and resolution by 30 MOA. Physiologic genu varum patients presenting between 18 and 23 MOA demonstrated initial signs of correction between 24 MOA and 30 MOA and resolution by 36 MOA.

Conclusion Primary care physicians can manage most children presenting with bow legs. Management focuses on following the progression or resolution of varus with regular follow-up. For patients presenting with bow legs, we recommend a follow-up protocol using mainly well-child checkups and a simple clinical assessment to monitor varus progression and screen for pathologic bowing.

Bow legs in young children can be a concern for parents.^1,2 By far, the most common reason for bow legs is physiologic genu varum,^3-5 a nonprogressive stage of normal development in young children that generally resolves spontaneously without treatment.^1,6-11 Normally developing children undergo a varus phase between birth and 18 to 24 months of age (MOA), at which time there is usually a transition in alignment from varus to straight to valgus (knock knees), which will correct to straight or mild valgus throughout adolescence.^{1,6,7,9,10,12-17}

The most common form of pathologic bow legs is Blount’s disease, also known as tibia vara, which must be differentiated from physiologic genu varum.^{8-10,15,18-24} The progressive varus deformity of Blount’s disease usually requires orthopedic intervention.^1,10,23-26 Early diagnosis may spare patients complex interventions, improve prognosis, and limit complications that include gait abnormalities,^4,8,10,27 knee joint instability,^4,24,27 osteoarthritis,^9,20,27 meniscal tears,²⁷ and degenerative joint disease.^19,20,27

Although variables such as walking age, race, weight, and gender have been suggested as risk factors for Blount’s disease, they have not been useful in differentiating between Blount’s pathology and physiologic genu varum.^{1,4,5,7,10,20,28} In the primary care setting, distinguishing physiologic from pathologic forms of bow legs is possible with a thorough history and physical exam and with radiographs, as warranted.^1,2,15 More than 40% of genu varum/genu valgum cases referred for orthopedic consultation turn out to be the physiologic form,² suggesting a need for guidelines in the primary care setting to help direct referral and follow-up. The purpose of this study was to provide recommendations to family physicians for evaluating and managing children with bow legs.

Materials and methods

This study, approved by the Internal Review Board of Akron Children’s Hospital, is a retrospective review of children seen by a single pediatric orthopedic surgeon (DSW) from 1970 to 2012. Four-hundred twenty-four children were received for evaluation of bow legs. Excluded from our final analysis were 220 subjects seen only once for this specific referral and 39 subjects diagnosed with a condition other than genu varum or Blount’s disease (ie, rickets, skeletal dysplasia, sequelae of trauma, or infection). Ten subjects with Blount’s disease and 155 subjects with physiologic genu varum were included in the final data analysis.

More than 40% of genu varum cases referred for orthopedic consultation turn out to be the physiologic form.In addition to noting the age at which a patient walked independently, at each visit we documented age and the fingerbreadth (varus) distance between the medial femoral condyles with the child’s ankles held together. Parents reported age of independent walking for just 3 children with Blount’s disease and for 134 children with physiologic genu varum. Study variables for the genu varum data analysis were age of walking, age at presentation, age at varus correction, age at varus resolution, time between presentation and varus correction, and time between presentation and varus resolution. Varus correction is defined as any decrease in varus angulation since presentation. Varus resolution is defined as varus correction to less than or equal to half of the varus angulation at presentation. For inclusion in the age-at-resolution analysis, a child must have been evaluated at regular follow-up visits (all rechecks within 8 months).

To measure varus distance, we used the fingerbreadth method described by Weiner in a study of 600 cases (FIGURE).⁶ This simple technique, which requires no special equipment, accurately detected differences in varus angulation and tracked the normal pattern of lower limb angular development. The patient should be supine on the examination table with legs extended. With one hand, the examiner holds the child’s ankles together, ensuring the medial malleoli are in contact. With the other hand, the examiner measures the fingerbreadth distance between the medial femoral condyles. Alternatively, a ruler may be used to measure the distance. This latter method may be especially useful in practices where the patient is likely to see more than one provider for well child care.

We divided the genu varum subject group into 3 subgroups by age at presentation: 103 subjects were younger than 18 months; 47 were 18 to 23 months; and 5 were 24 months or older. We used the data analysis toolkit in Microsoft Excel 2013 to perform a statistical analysis of study variables. We assumed the genu varum population is a normally distributed population. We used a 95% confidence level (α=0.05) for all calculations of confidence intervals (CIs), student t-tests, and tolerance intervals. Based on the data analysis results, we developed a series of follow-up and referral guidelines for practitioners.

Results

The mean walking age for those diagnosed with physiologic genu varum was 10 months (95% CI, 9.8-10.4), which is significantly younger than the 12 months of age (at the earliest) typical of toddlers in general (P<.001). There was no significant difference between the walking age of male and female children diagnosed with genu varum (P=.37).

Of the children presenting with the primary complaint of bow legs, 6% subsequently developed Blount’s disease. These patients presented at a mean age of 20.9 months and were diagnosed at a mean age of 23.9 months. Following the Blount’s disease diagnosis, we initiated therapy in all cases (3 surgical, 7 bracing).

Physiologic genu varum patients presented at a mean age of 16.4 months, with only 3.23% presenting at older than 23 months. On average, physiologic genu varum patients presenting before 24 months of age showed measurable varus correction 5 months after presentation and achieved varus resolution 7.3 months after presentation (TABLE 1). Assuming the patient population is normally distributed, we can be 95% confident that 95% of physiologic genu varum patients presenting before 18 months of age will show measurable varus correction by 24 months and will resolve without intervention by 30 months (TABLE 2). Patients presenting between 18 and 23 months of age should show measurable varus correction by 30 months and resolution by 36 months (TABLE 3).

Discussion

Primary care physicians have the ability to differentiate physiologic genu varum from pathologic forms of bow legs with a thorough history, physical exam, and radiographic examination, if necessary^1,2,13 (TABLE 4^{1,7,8,10,12,14,18-20,22,24,27}). Several approaches to differentiating Blount’s disease and physiologic genu varum have been described in the literature.^{1,4,7,8,10,14,22,23}

The average age at which children begin to walk independently is between 13 and 15 months.^5,18,29-31 Recently, it has been suggested that the range be expanded to include 12 months of age.³⁰ The association between early walking (at 10-11 months)^12,20,22 and Blount’s disease is generally accepted in the orthopedic literature.^{1,4,7,10,19-22} However, some authors have suggested early walking also contributes to genu varum.^{1,5,8,10,18,28} The mean age of independent walking for children with physiologic genu varum suggested in the literature (10 months) was confirmed in our study and found to be significantly younger than the average for toddlers generally.^1,22 Early walking is clearly associated with both physiologic genu varum and Blount’s disease, but no direct causation has been identified in either case. An alternative means of differentiating these entities is needed.

Primary care physicians can differentiate physiologic genu varum from pathologic forms of bow legs with a thorough history, physical exam, and radiographic examination (if needed).Radiographic examination of the knee is essential to the diagnosis of Blount’s disease as well as other, less common causes of pathologic bow legs (skeletal dysplasia, rickets, traumatic growth plate insults, infections, neoplasms).^1,8,14,19 The common radiologic classification of staging for Blount’s disease is the Langenskiöld staging system, which involves identification of characteristic radiographic changes at the tibial physis.^{5,8,14,15,18,22,24}

The fingerbreadth method, which requires no special equipment, accurately detected differences in varus angulation and tracked the normal pattern of lower limb angular development.Sequential measurement of genu varum is most useful in differentiating between physiologic and pathologic processes. Physiologic genu varum, an exaggeration of the normal developmental pattern, characteristically resolves and evolves into physiologic genu valgum by 3 years of age.^1,6-11 The pathophysiology of Blount’s disease is believed to be related to biomechanical overloading of the posteromedial proximal tibia during gait with the knee in a varus orientation. Excess loading on the proximal medial physis contributes to varus progression.^{4,10,14,20,25,27} Patients with Blount’s disease progress with varus and concomitant internal tibial torsion associated with growth plate irregularities and eventually exhibit premature closure.^{1,10,14,18,20,23,24,26} In the months prior to Blount’s disease diagnosis, increasing varus has been reported.^4,7,10,19 Varus progression that differs from the expected pattern indicates possible pathologic bow legs and should prompt radiologic evaluation and, often, an orthopedic referral.^{3,4,7-9,12,13,21}

In our study, only 3% of children with physiologic genu varum presented at 24 months of age or older, compared with 20% of Blount’s disease patients. We recommend considering orthopedic referral for any patient presenting with bow legs at 24 months of age or older. Additionally, consider orthopedic referral for any patient whose varus has not begun to correct within 8 months or has not resolved within 14 months of presentation, as more than 95% of patients with physiologic genu varum are expected to meet these milestones (TABLE 1). And do not hesitate to refer patients at any stage of follow-up if you suspect pathology or if parents are anxious.

If no sign of pathology is immediately identified, we recommend the following course of action:

• Record a reference fingerbreadth or ruler measurement at the initial presentation.
• Re-examine the knee varus at the next regular well-child visit (TABLE 5).

In our study, only 3% of children with physiologic genu varum presented at 24 months of age or older, compared with 20% of Blount's disease patients.Re-examining the patient prior to the next well-child visit is unnecessary, as some degree of bowing is typical until age 18 to 24 months.^{1,6,7,9,12,13,17} Recommend orthopedic referral for any patient with varus that has progressed since initial presentation. Without signs of pathology, repeat varus assessment at the next well-child visit. This schedule minimizes the need for additional physician appointments by integrating follow-up into the typical well-child visits at 18, 24, 30, and 36 months of age.³² The 6-month follow-up interval was a feature of our study and is recommended in the related literature.¹²

• Consider orthopedic referral for patients whose varus has not corrected by the second follow-up appointment, as more than 95% of patients should have measurable varus correction at this visit. Most patients will have exhibited varus resolution by this time and will not require additional follow-up. For patients with observable correction who do not yet meet the criteria for resolution, we recommend a third, final follow-up appointment in another 6 months.
• Refer any patient whose varus has not resolved by the third follow-up appointment, as more than 95% of genu varum cases should have resolved by this time. This finding is echoed in the literature; any varus beyond 36 months of age is considered abnormal and suggestive of pathology.^5,7,8,13,14 If evidence of Blount’s or skeletal dysplasia is identified, orthopedic management will likely consist of bracing (orthotics) or surgical management.

CORRESPONDENCE
Dennis S. Weiner, MD, Department of Orthopedic Surgery, Akron Children’s Hospital, 300 Locust Street, Suite 250, Akron, OH, 44302; mdicintio@chmca.org.

ACKNOWLEDGEMENTS
The authors thank Meadow Newton, BS, assistant research coordinator, Akron Children’s Hospital, for her editing and technical assistance and Richard Steiner, PhD, The University of Akron, for his statistical review.

Pediatric asthma is the most commonly encountered childhood chronic disease, occurring in approximately 13.5% of children.¹ Due to the interplay between patient, family physician (FP), and the environment, asthma often proves challenging to control. Although national guidelines for the treatment of asthma have not changed since 2007, significant research continues to examine the optimal means of preventing, controlling, and treating asthma in children. This review summarizes the evidence to date so that you can maximize your care for these young patients.

A stepwise approach to asthma control

The 2007 National Heart, Lung, and Blood Institute (NHLBI) guidelines provide a common pathway for the management of asthma (FIGURE).² These guidelines emphasize stepwise treatment, based on symptom severity, which maximizes quality of life while minimizing morbidity. Treatment is escalated after careful assessment of frequency of daytime symptoms, frequency of nighttime symptoms, forced expiratory volume in one second (FEV1), and the number of exacerbations requiring systemic steroids over the past year. It’s also appropriate to de-escalate care when symptoms are controlled to minimize adverse effects.

The 2017 Global Initiative for Asthma (GINA) guidelines recommend a similar stepwise approach, with generally the same progression of control medications as the NHLBI guidelines. One variation is that GINA guidelines recommend considering inhaled corticosteroids (ICS) for all asthma patients—even those with intermittent symptoms.³

The Asthma Control Test and Asthma Control Questionnaire are also available for assessment of efficacy of asthma control and can help guide FPs with the decision of when to escalate control medications. (They are available at: http://bit.ly/2o3CzGX and http://bit.ly/2p1LvAc, respectively.)

A systematic review found that both tools were effective in determining if a patient was well controlled vs not well controlled.⁴ Similarly, a 2012 study found that using the Asthma Control Test score was useful for assessing control and directing changes to treatment.⁵ In addition, using these tools consistently in a primary care setting increased the frequency of assessment without negatively impacting patient flow through a clinic.⁶

Short-acting beta-agonists: A mainstay for intermittent asthma

Inhaled short-acting beta-agonists (SABAs) are the mainstay of treatment for intermittent asthma as well as asthma exacerbations. Short-acting beta-agonists are effective for symptomatic relief and preventing exacerbations prior to known exposures because they dilate smooth muscle in bronchioles and relieve bronchospasm.

Albuterol, the most commonly used SABA, is a mixture of the active R-enantiomer and inactive L-enantiomer. Levalbuterol, which consists of only the active R-enantiomer, is also available and is theoretically more effective with fewer adverse effects. Studies examining the difference in efficacy between albuterol and levalbuterol, however, have been mixed, and current guidelines do not recommend one over the other.⁷

Metered-dose inhalers vs nebulizers

SABAs are typically prescribed in metered-dose inhalers (MDIs), dry powder inhalers, or nebulizers. A meta-analysis comparing the efficacy of nebulizers to MDIs with spacers in both the outpatient and emergency department (ED) settings indicated that MDIs work at least as well as nebulizers and may also reduce length of ED stay.⁸ This trend appears consistent even with children younger than 24 months.⁹

Guidelines emphasize stepwise treatment, based on symptom severity, to maximize quality of life while minimizing morbidity.

If you are prescribing an MDI, be sure to routinely prescribe spacers to help ensure the medication is properly administered. Various types of spacers are available; some consist of an extension of the mouthpiece, while others serve as a chamber with a one-way valve to help improve the ability of the child to inhale the medication. Spacers that do not have antistatic coating should be gently washed with water and detergent.

Masks are also available for younger children and should be properly sized. The same spacer can be used for multiple medications, although they should be administered one at a time. Generally, albuterol should be administered prior to other medications to maximize distribution of subsequent inhaled medications.

Start low with inhaled corticosteroids

Treatment of persistent asthma consists of regular use of inhaled corticosteroids (ICSs; first line) with SABAs, as needed, for exacerbations. Guidelines recommend starting at a low dose and increasing the dose based on symptom control. Patients must consistently use ICSs for one to 2 weeks prior to obtaining full effect of the medication, and parents should be counseled to set appropriate expectations.^2,3 ICSs are dispensed as MDIs, dry powder inhalers, and nebulizers; spacers should be considered.

Studies have shown a slight decrease in height for children on ICSs, with long-term studies indicating a persistent 1- to 2-cm decrease in adult height.^10,11

Patient isn’t well controlled? Time for a long-acting beta-agonist

For patients not well controlled on low-dose ICSs, the dose can be increased or a long-acting beta-agonist (LABA) or leukotriene receptor antagonist (LTRA) can be added. A recent meta-analysis examining children not well controlled with ICSs, found that the addition of LABAs resulted in improved FEV1 and nighttime symptoms, and reduced the requirement for rescue inhalers when compared to increasing the ICS dose alone.¹² In addition, there was no difference in adverse events between the 2 agents, although patients taking ICSs and LABAs had greater growth in height than those with an increased dose of ICS.¹² Adding a LABA, however, did not decrease the need for systemic steroids and also did not reduce the number of exacerbations requiring hospitalizations.¹²

Another recent study demonstrated that the combination of ICSs and LABAs was noninferior to ICSs alone in preventing hospitalizations, intubations, and deaths.¹³ There are limited data on whether patients already on LABAs and ICSs should be continued on dual medications. Additionally, there is no clear method describing how to de-escalate therapy for those patients who are well controlled on ICSs and LABAs. A reasonable approach is to reduce doses of both medications and discontinue the LABA if tolerated.^14,15 The US Food and Drug Administration has issued a black box warning that LABAs should not be used as a single controller medication because patients may be at increased risk of asthma-related deaths.^16,17

What role for leukotriene receptor antagonists?

According to NHLBI guidelines, LTRAs can be considered as an alternative to ICSs when starting a control medication for mild persistent asthma.² A recent meta-analysis, however, showed that there were increased rates of hospitalizations with LTRAs alone when compared to ICSs.¹⁸ The NHLBI guidelines also suggest that LTRAs can be used as adjunctive medication for those patients not well controlled on ICSs rather than increasing the ICS dose or adding a LABA.²

Consider de-escalating care when symptoms are controlled to minimize adverse effects.

A 2011 clinical trial found no difference in quality of life measures between LTRAs and LABAs as adjunctive therapy at 2 months, but LABAs were more effective when patients were reassessed in 2 years.¹⁹ Similarly, the same study also found that adding LTRAs to low-dose ICSs rather than increasing the ICS dose was equivalent in the short term but not at 2 years.¹⁹

2 other adjunctive therapy options: Xanthines, cromolyn

Similar to LTRAs, xanthines can be considered as adjunctive therapy for children older than 5 years who are not well controlled on a low-dose ICS. Although xanthines decrease asthma symptoms when compared to placebo alone, they are not more effective than ICSs alone and should be considered only as adjunctive therapy.^2,20 There have been few studies comparing xanthines to other adjunctive medications.²¹

Cromolyn is another adjunctive medication cited in the NHLBI guidelines for escalation of therapy.² Although the medication has few adverse effects, its use is generally limited in the United States because data supporting its efficacy are lacking.

Omalizumab for allergy-related asthma exacerbations

Omalizumab, an anti-IgE antibody injected every 2 to 4 weeks, is available for children older than 6 years with moderate to severe asthma that is not responsive to ICSs and LABAs.²² The medication is effective in reducing allergy-related asthma exacerbations and hospitalizations, but data comparing it to other adjunctive medications are limited.²² Due to their significant systemic effects, the role of oral steroids as control medications is reserved for patients with severe asthma who are refractory to other medications. Children should be placed on oral steroids for the least amount of time required to achieve symptom control.

Acute exacerbation treatment: What to consider

Although there is no agreed-upon definition for an acute asthma exacerbation, the American Thoracic Society defines it as "an event characterized by a change from the patient’s previous status."²³ All patients should be given an asthma action plan that clearly delineates the escalation of therapy in the event of an exacerbation, although only half of all patients report experiencing one.²⁴ Symptom-based plans may prevent more acute care visits when compared to plans that use peak-flow measurements, although children on peak-flow plans may have fewer symptomatic days.²⁵

Start with short-acting beta-agonists

The SABAs serve as the initial treatment of choice for management of asthma exacerbations. In young children (0-3 years), SABAs delivered by MDI with a spacer were more effective in reducing admission rates (11.3% vs 21.7%) when compared to SABAs delivered by nebulizers, resulting in a number needed to treat to prevent one admission of 10.²⁶

In older children (3-18 years), SABAs delivered via spacer reduced ED length of stay, but did not significantly affect hospitalization rates. Additionally, SABAs administered with anticholinergics such as ipratropium bromide were more effective than SABAs alone in reducing admissions (16.9% vs 23.2%), particularly in older children with moderate to severe asthma, while also minimizing adverse effects.^8,26

Corticosteroids: A mainstay in the ED

In addition to albuterol administration, corticosteroids remain the mainstay of ED management for asthma exacerbations. Administration of systemic steroids has been shown to reduce hospitalizations in children under 6 years, although, paradoxically, studies examining outpatient administration have demonstrated an increase in hospitalizations when compared to placebo.²⁷

Dexamethasone and prednisone are the 2 most commonly used systemic steroids, and studies haven't indicated superiority of either.^28,29 There is no difference in efficacy between oral and intravenous steroids.³⁰ A recent clinical trial found a 2-day course of dexamethasone (0.6 mg/kg) had similar efficacy with fewer adverse effects when compared to a 5-day course of prednisone (1-2 mg/kg/day).²⁸

Patient isn’t responding? Try IV magnesium

For patients who don't respond to corticosteroids and albuterol treatments, IV magnesium sulfate (usual dose, 25-75 mg/kg/d; maximum dose, 2000 mg/d) has been shown to improve respiratory function, but not necessarily decrease admission rates.³¹ Inhaled magnesium sulfate hasn't been shown to be more effective than IV administration and isn'trecommended.³²

Evidence doesn’t support use of heliox

Heliox, which consists of 80% helium, is theorized to be effective in the treatment of asthma by increasing laminar flow and increasing the delivery of medications to the alveoli.³² Overall, the evidence does not support the use of heliox, which is typically restricted to patients with severe asthma exacerbations.³³

Is it worth considering noninvasive positive pressure ventilation?

If patients don't improve with medical treatment, noninvasive positive pressure ventilation can be considered. A recent meta-analysis suggests that there is no definitive benefit or harm from this treatment, although several studies have indicated a decrease in symptom severity.³⁴

Inhaled short-acting beta-agonists are the mainstay of treatment for intermittent asthma, as well as asthma exacerbations.

Intubation should be considered for hypoxemia unresponsive to medications, or in cases of exhaustion, worsening mental status, or respiratory acidosis unresponsive to medication. Ventilation should allow for a permissive respiratory acidosis (pH, 7.2), while maintaining adequate oxygenation.³⁵

Reducing the burden of asthma

Due to the complex task of reducing triggers and providing effective controller medications, working with parents and children is integral to improving the quality of life for patients with asthma. Although there is an obvious genetic predisposition, family physicians can help reduce the risk of developing asthma by encouraging healthy behaviors at home before the child is born. In the prenatal period, this includes avoiding tobacco-smoke exposure, lessening maternal obesity, decreasing maternal antibiotic and acetaminophen use, and curtailing stress.

Evidence suggests that after birth, breastfeeding and reducing childhood obesity can help lower the risk of asthma.³⁶ Atopic disease, in general, can be reduced by breastfeeding until at least 4 months, as well as encouraging a varied diet that does not restrict potential allergens during pregnancy or lactation, and introducing foods (including potential allergens) after the age of 4 months.

The risk of atopic disease can also be lowered by lessening potential triggers at home. These include restricting exposure to cats (but not dogs), reducing home mold by decreasing humidity and ensuring adequate ventilation, avoiding volatile organic compounds, such as chlorine, and curtailing exposure to vehicle emissions. Although often marketed to be effective in reducing allergies, dust-mite covers and soy-based formulas don't prevent or minimize allergies and are often costly.^37,38 In addition, there is no evidence that vaccinations areassociated with allergies.³⁹

CORRESPONDENCE
Douglas M. Maurer, 9040A Jackson Ave, Joint-Base Lewis-McChord, WA 98431; douglas.m.maurer.mil@mail.mil.

Pediatric asthma is the most commonly encountered childhood chronic disease, occurring in approximately 13.5% of children.¹ Due to the interplay between patient, family physician (FP), and the environment, asthma often proves challenging to control. Although national guidelines for the treatment of asthma have not changed since 2007, significant research continues to examine the optimal means of preventing, controlling, and treating asthma in children. This review summarizes the evidence to date so that you can maximize your care for these young patients.

A stepwise approach to asthma control

The 2007 National Heart, Lung, and Blood Institute (NHLBI) guidelines provide a common pathway for the management of asthma (FIGURE).² These guidelines emphasize stepwise treatment, based on symptom severity, which maximizes quality of life while minimizing morbidity. Treatment is escalated after careful assessment of frequency of daytime symptoms, frequency of nighttime symptoms, forced expiratory volume in one second (FEV1), and the number of exacerbations requiring systemic steroids over the past year. It’s also appropriate to de-escalate care when symptoms are controlled to minimize adverse effects.

The 2017 Global Initiative for Asthma (GINA) guidelines recommend a similar stepwise approach, with generally the same progression of control medications as the NHLBI guidelines. One variation is that GINA guidelines recommend considering inhaled corticosteroids (ICS) for all asthma patients—even those with intermittent symptoms.³

The Asthma Control Test and Asthma Control Questionnaire are also available for assessment of efficacy of asthma control and can help guide FPs with the decision of when to escalate control medications. (They are available at: http://bit.ly/2o3CzGX and http://bit.ly/2p1LvAc, respectively.)

A systematic review found that both tools were effective in determining if a patient was well controlled vs not well controlled.⁴ Similarly, a 2012 study found that using the Asthma Control Test score was useful for assessing control and directing changes to treatment.⁵ In addition, using these tools consistently in a primary care setting increased the frequency of assessment without negatively impacting patient flow through a clinic.⁶

Short-acting beta-agonists: A mainstay for intermittent asthma

Inhaled short-acting beta-agonists (SABAs) are the mainstay of treatment for intermittent asthma as well as asthma exacerbations. Short-acting beta-agonists are effective for symptomatic relief and preventing exacerbations prior to known exposures because they dilate smooth muscle in bronchioles and relieve bronchospasm.

Albuterol, the most commonly used SABA, is a mixture of the active R-enantiomer and inactive L-enantiomer. Levalbuterol, which consists of only the active R-enantiomer, is also available and is theoretically more effective with fewer adverse effects. Studies examining the difference in efficacy between albuterol and levalbuterol, however, have been mixed, and current guidelines do not recommend one over the other.⁷

Metered-dose inhalers vs nebulizers

SABAs are typically prescribed in metered-dose inhalers (MDIs), dry powder inhalers, or nebulizers. A meta-analysis comparing the efficacy of nebulizers to MDIs with spacers in both the outpatient and emergency department (ED) settings indicated that MDIs work at least as well as nebulizers and may also reduce length of ED stay.⁸ This trend appears consistent even with children younger than 24 months.⁹

Guidelines emphasize stepwise treatment, based on symptom severity, to maximize quality of life while minimizing morbidity.

If you are prescribing an MDI, be sure to routinely prescribe spacers to help ensure the medication is properly administered. Various types of spacers are available; some consist of an extension of the mouthpiece, while others serve as a chamber with a one-way valve to help improve the ability of the child to inhale the medication. Spacers that do not have antistatic coating should be gently washed with water and detergent.

Masks are also available for younger children and should be properly sized. The same spacer can be used for multiple medications, although they should be administered one at a time. Generally, albuterol should be administered prior to other medications to maximize distribution of subsequent inhaled medications.

Start low with inhaled corticosteroids

Treatment of persistent asthma consists of regular use of inhaled corticosteroids (ICSs; first line) with SABAs, as needed, for exacerbations. Guidelines recommend starting at a low dose and increasing the dose based on symptom control. Patients must consistently use ICSs for one to 2 weeks prior to obtaining full effect of the medication, and parents should be counseled to set appropriate expectations.^2,3 ICSs are dispensed as MDIs, dry powder inhalers, and nebulizers; spacers should be considered.

Studies have shown a slight decrease in height for children on ICSs, with long-term studies indicating a persistent 1- to 2-cm decrease in adult height.^10,11

Patient isn’t well controlled? Time for a long-acting beta-agonist

For patients not well controlled on low-dose ICSs, the dose can be increased or a long-acting beta-agonist (LABA) or leukotriene receptor antagonist (LTRA) can be added. A recent meta-analysis examining children not well controlled with ICSs, found that the addition of LABAs resulted in improved FEV1 and nighttime symptoms, and reduced the requirement for rescue inhalers when compared to increasing the ICS dose alone.¹² In addition, there was no difference in adverse events between the 2 agents, although patients taking ICSs and LABAs had greater growth in height than those with an increased dose of ICS.¹² Adding a LABA, however, did not decrease the need for systemic steroids and also did not reduce the number of exacerbations requiring hospitalizations.¹²

Another recent study demonstrated that the combination of ICSs and LABAs was noninferior to ICSs alone in preventing hospitalizations, intubations, and deaths.¹³ There are limited data on whether patients already on LABAs and ICSs should be continued on dual medications. Additionally, there is no clear method describing how to de-escalate therapy for those patients who are well controlled on ICSs and LABAs. A reasonable approach is to reduce doses of both medications and discontinue the LABA if tolerated.^14,15 The US Food and Drug Administration has issued a black box warning that LABAs should not be used as a single controller medication because patients may be at increased risk of asthma-related deaths.^16,17

What role for leukotriene receptor antagonists?

According to NHLBI guidelines, LTRAs can be considered as an alternative to ICSs when starting a control medication for mild persistent asthma.² A recent meta-analysis, however, showed that there were increased rates of hospitalizations with LTRAs alone when compared to ICSs.¹⁸ The NHLBI guidelines also suggest that LTRAs can be used as adjunctive medication for those patients not well controlled on ICSs rather than increasing the ICS dose or adding a LABA.²

Consider de-escalating care when symptoms are controlled to minimize adverse effects.

A 2011 clinical trial found no difference in quality of life measures between LTRAs and LABAs as adjunctive therapy at 2 months, but LABAs were more effective when patients were reassessed in 2 years.¹⁹ Similarly, the same study also found that adding LTRAs to low-dose ICSs rather than increasing the ICS dose was equivalent in the short term but not at 2 years.¹⁹

2 other adjunctive therapy options: Xanthines, cromolyn

Similar to LTRAs, xanthines can be considered as adjunctive therapy for children older than 5 years who are not well controlled on a low-dose ICS. Although xanthines decrease asthma symptoms when compared to placebo alone, they are not more effective than ICSs alone and should be considered only as adjunctive therapy.^2,20 There have been few studies comparing xanthines to other adjunctive medications.²¹

Cromolyn is another adjunctive medication cited in the NHLBI guidelines for escalation of therapy.² Although the medication has few adverse effects, its use is generally limited in the United States because data supporting its efficacy are lacking.

Omalizumab for allergy-related asthma exacerbations

Omalizumab, an anti-IgE antibody injected every 2 to 4 weeks, is available for children older than 6 years with moderate to severe asthma that is not responsive to ICSs and LABAs.²² The medication is effective in reducing allergy-related asthma exacerbations and hospitalizations, but data comparing it to other adjunctive medications are limited.²² Due to their significant systemic effects, the role of oral steroids as control medications is reserved for patients with severe asthma who are refractory to other medications. Children should be placed on oral steroids for the least amount of time required to achieve symptom control.

Acute exacerbation treatment: What to consider

Although there is no agreed-upon definition for an acute asthma exacerbation, the American Thoracic Society defines it as "an event characterized by a change from the patient’s previous status."²³ All patients should be given an asthma action plan that clearly delineates the escalation of therapy in the event of an exacerbation, although only half of all patients report experiencing one.²⁴ Symptom-based plans may prevent more acute care visits when compared to plans that use peak-flow measurements, although children on peak-flow plans may have fewer symptomatic days.²⁵

Start with short-acting beta-agonists

The SABAs serve as the initial treatment of choice for management of asthma exacerbations. In young children (0-3 years), SABAs delivered by MDI with a spacer were more effective in reducing admission rates (11.3% vs 21.7%) when compared to SABAs delivered by nebulizers, resulting in a number needed to treat to prevent one admission of 10.²⁶

In older children (3-18 years), SABAs delivered via spacer reduced ED length of stay, but did not significantly affect hospitalization rates. Additionally, SABAs administered with anticholinergics such as ipratropium bromide were more effective than SABAs alone in reducing admissions (16.9% vs 23.2%), particularly in older children with moderate to severe asthma, while also minimizing adverse effects.^8,26

Corticosteroids: A mainstay in the ED

In addition to albuterol administration, corticosteroids remain the mainstay of ED management for asthma exacerbations. Administration of systemic steroids has been shown to reduce hospitalizations in children under 6 years, although, paradoxically, studies examining outpatient administration have demonstrated an increase in hospitalizations when compared to placebo.²⁷

Dexamethasone and prednisone are the 2 most commonly used systemic steroids, and studies haven't indicated superiority of either.^28,29 There is no difference in efficacy between oral and intravenous steroids.³⁰ A recent clinical trial found a 2-day course of dexamethasone (0.6 mg/kg) had similar efficacy with fewer adverse effects when compared to a 5-day course of prednisone (1-2 mg/kg/day).²⁸

Patient isn’t responding? Try IV magnesium

For patients who don't respond to corticosteroids and albuterol treatments, IV magnesium sulfate (usual dose, 25-75 mg/kg/d; maximum dose, 2000 mg/d) has been shown to improve respiratory function, but not necessarily decrease admission rates.³¹ Inhaled magnesium sulfate hasn't been shown to be more effective than IV administration and isn'trecommended.³²

Evidence doesn’t support use of heliox

Heliox, which consists of 80% helium, is theorized to be effective in the treatment of asthma by increasing laminar flow and increasing the delivery of medications to the alveoli.³² Overall, the evidence does not support the use of heliox, which is typically restricted to patients with severe asthma exacerbations.³³

Is it worth considering noninvasive positive pressure ventilation?

If patients don't improve with medical treatment, noninvasive positive pressure ventilation can be considered. A recent meta-analysis suggests that there is no definitive benefit or harm from this treatment, although several studies have indicated a decrease in symptom severity.³⁴

Inhaled short-acting beta-agonists are the mainstay of treatment for intermittent asthma, as well as asthma exacerbations.

Intubation should be considered for hypoxemia unresponsive to medications, or in cases of exhaustion, worsening mental status, or respiratory acidosis unresponsive to medication. Ventilation should allow for a permissive respiratory acidosis (pH, 7.2), while maintaining adequate oxygenation.³⁵

Reducing the burden of asthma

Due to the complex task of reducing triggers and providing effective controller medications, working with parents and children is integral to improving the quality of life for patients with asthma. Although there is an obvious genetic predisposition, family physicians can help reduce the risk of developing asthma by encouraging healthy behaviors at home before the child is born. In the prenatal period, this includes avoiding tobacco-smoke exposure, lessening maternal obesity, decreasing maternal antibiotic and acetaminophen use, and curtailing stress.

Evidence suggests that after birth, breastfeeding and reducing childhood obesity can help lower the risk of asthma.³⁶ Atopic disease, in general, can be reduced by breastfeeding until at least 4 months, as well as encouraging a varied diet that does not restrict potential allergens during pregnancy or lactation, and introducing foods (including potential allergens) after the age of 4 months.

The risk of atopic disease can also be lowered by lessening potential triggers at home. These include restricting exposure to cats (but not dogs), reducing home mold by decreasing humidity and ensuring adequate ventilation, avoiding volatile organic compounds, such as chlorine, and curtailing exposure to vehicle emissions. Although often marketed to be effective in reducing allergies, dust-mite covers and soy-based formulas don't prevent or minimize allergies and are often costly.^37,38 In addition, there is no evidence that vaccinations areassociated with allergies.³⁹

CORRESPONDENCE
Douglas M. Maurer, 9040A Jackson Ave, Joint-Base Lewis-McChord, WA 98431; douglas.m.maurer.mil@mail.mil.

Pediatric asthma is the most commonly encountered childhood chronic disease, occurring in approximately 13.5% of children.¹ Due to the interplay between patient, family physician (FP), and the environment, asthma often proves challenging to control. Although national guidelines for the treatment of asthma have not changed since 2007, significant research continues to examine the optimal means of preventing, controlling, and treating asthma in children. This review summarizes the evidence to date so that you can maximize your care for these young patients.

A stepwise approach to asthma control

The 2007 National Heart, Lung, and Blood Institute (NHLBI) guidelines provide a common pathway for the management of asthma (FIGURE).² These guidelines emphasize stepwise treatment, based on symptom severity, which maximizes quality of life while minimizing morbidity. Treatment is escalated after careful assessment of frequency of daytime symptoms, frequency of nighttime symptoms, forced expiratory volume in one second (FEV1), and the number of exacerbations requiring systemic steroids over the past year. It’s also appropriate to de-escalate care when symptoms are controlled to minimize adverse effects.

The 2017 Global Initiative for Asthma (GINA) guidelines recommend a similar stepwise approach, with generally the same progression of control medications as the NHLBI guidelines. One variation is that GINA guidelines recommend considering inhaled corticosteroids (ICS) for all asthma patients—even those with intermittent symptoms.³

The Asthma Control Test and Asthma Control Questionnaire are also available for assessment of efficacy of asthma control and can help guide FPs with the decision of when to escalate control medications. (They are available at: http://bit.ly/2o3CzGX and http://bit.ly/2p1LvAc, respectively.)

A systematic review found that both tools were effective in determining if a patient was well controlled vs not well controlled.⁴ Similarly, a 2012 study found that using the Asthma Control Test score was useful for assessing control and directing changes to treatment.⁵ In addition, using these tools consistently in a primary care setting increased the frequency of assessment without negatively impacting patient flow through a clinic.⁶

Short-acting beta-agonists: A mainstay for intermittent asthma

Inhaled short-acting beta-agonists (SABAs) are the mainstay of treatment for intermittent asthma as well as asthma exacerbations. Short-acting beta-agonists are effective for symptomatic relief and preventing exacerbations prior to known exposures because they dilate smooth muscle in bronchioles and relieve bronchospasm.

Albuterol, the most commonly used SABA, is a mixture of the active R-enantiomer and inactive L-enantiomer. Levalbuterol, which consists of only the active R-enantiomer, is also available and is theoretically more effective with fewer adverse effects. Studies examining the difference in efficacy between albuterol and levalbuterol, however, have been mixed, and current guidelines do not recommend one over the other.⁷

Metered-dose inhalers vs nebulizers

SABAs are typically prescribed in metered-dose inhalers (MDIs), dry powder inhalers, or nebulizers. A meta-analysis comparing the efficacy of nebulizers to MDIs with spacers in both the outpatient and emergency department (ED) settings indicated that MDIs work at least as well as nebulizers and may also reduce length of ED stay.⁸ This trend appears consistent even with children younger than 24 months.⁹

Guidelines emphasize stepwise treatment, based on symptom severity, to maximize quality of life while minimizing morbidity.

If you are prescribing an MDI, be sure to routinely prescribe spacers to help ensure the medication is properly administered. Various types of spacers are available; some consist of an extension of the mouthpiece, while others serve as a chamber with a one-way valve to help improve the ability of the child to inhale the medication. Spacers that do not have antistatic coating should be gently washed with water and detergent.

Masks are also available for younger children and should be properly sized. The same spacer can be used for multiple medications, although they should be administered one at a time. Generally, albuterol should be administered prior to other medications to maximize distribution of subsequent inhaled medications.

Start low with inhaled corticosteroids

Treatment of persistent asthma consists of regular use of inhaled corticosteroids (ICSs; first line) with SABAs, as needed, for exacerbations. Guidelines recommend starting at a low dose and increasing the dose based on symptom control. Patients must consistently use ICSs for one to 2 weeks prior to obtaining full effect of the medication, and parents should be counseled to set appropriate expectations.^2,3 ICSs are dispensed as MDIs, dry powder inhalers, and nebulizers; spacers should be considered.

Studies have shown a slight decrease in height for children on ICSs, with long-term studies indicating a persistent 1- to 2-cm decrease in adult height.^10,11

Patient isn’t well controlled? Time for a long-acting beta-agonist

For patients not well controlled on low-dose ICSs, the dose can be increased or a long-acting beta-agonist (LABA) or leukotriene receptor antagonist (LTRA) can be added. A recent meta-analysis examining children not well controlled with ICSs, found that the addition of LABAs resulted in improved FEV1 and nighttime symptoms, and reduced the requirement for rescue inhalers when compared to increasing the ICS dose alone.¹² In addition, there was no difference in adverse events between the 2 agents, although patients taking ICSs and LABAs had greater growth in height than those with an increased dose of ICS.¹² Adding a LABA, however, did not decrease the need for systemic steroids and also did not reduce the number of exacerbations requiring hospitalizations.¹²

Another recent study demonstrated that the combination of ICSs and LABAs was noninferior to ICSs alone in preventing hospitalizations, intubations, and deaths.¹³ There are limited data on whether patients already on LABAs and ICSs should be continued on dual medications. Additionally, there is no clear method describing how to de-escalate therapy for those patients who are well controlled on ICSs and LABAs. A reasonable approach is to reduce doses of both medications and discontinue the LABA if tolerated.^14,15 The US Food and Drug Administration has issued a black box warning that LABAs should not be used as a single controller medication because patients may be at increased risk of asthma-related deaths.^16,17

What role for leukotriene receptor antagonists?

According to NHLBI guidelines, LTRAs can be considered as an alternative to ICSs when starting a control medication for mild persistent asthma.² A recent meta-analysis, however, showed that there were increased rates of hospitalizations with LTRAs alone when compared to ICSs.¹⁸ The NHLBI guidelines also suggest that LTRAs can be used as adjunctive medication for those patients not well controlled on ICSs rather than increasing the ICS dose or adding a LABA.²

Consider de-escalating care when symptoms are controlled to minimize adverse effects.

A 2011 clinical trial found no difference in quality of life measures between LTRAs and LABAs as adjunctive therapy at 2 months, but LABAs were more effective when patients were reassessed in 2 years.¹⁹ Similarly, the same study also found that adding LTRAs to low-dose ICSs rather than increasing the ICS dose was equivalent in the short term but not at 2 years.¹⁹

2 other adjunctive therapy options: Xanthines, cromolyn

Similar to LTRAs, xanthines can be considered as adjunctive therapy for children older than 5 years who are not well controlled on a low-dose ICS. Although xanthines decrease asthma symptoms when compared to placebo alone, they are not more effective than ICSs alone and should be considered only as adjunctive therapy.^2,20 There have been few studies comparing xanthines to other adjunctive medications.²¹

Cromolyn is another adjunctive medication cited in the NHLBI guidelines for escalation of therapy.² Although the medication has few adverse effects, its use is generally limited in the United States because data supporting its efficacy are lacking.

Omalizumab for allergy-related asthma exacerbations

Omalizumab, an anti-IgE antibody injected every 2 to 4 weeks, is available for children older than 6 years with moderate to severe asthma that is not responsive to ICSs and LABAs.²² The medication is effective in reducing allergy-related asthma exacerbations and hospitalizations, but data comparing it to other adjunctive medications are limited.²² Due to their significant systemic effects, the role of oral steroids as control medications is reserved for patients with severe asthma who are refractory to other medications. Children should be placed on oral steroids for the least amount of time required to achieve symptom control.

Acute exacerbation treatment: What to consider

Although there is no agreed-upon definition for an acute asthma exacerbation, the American Thoracic Society defines it as "an event characterized by a change from the patient’s previous status."²³ All patients should be given an asthma action plan that clearly delineates the escalation of therapy in the event of an exacerbation, although only half of all patients report experiencing one.²⁴ Symptom-based plans may prevent more acute care visits when compared to plans that use peak-flow measurements, although children on peak-flow plans may have fewer symptomatic days.²⁵

Start with short-acting beta-agonists

The SABAs serve as the initial treatment of choice for management of asthma exacerbations. In young children (0-3 years), SABAs delivered by MDI with a spacer were more effective in reducing admission rates (11.3% vs 21.7%) when compared to SABAs delivered by nebulizers, resulting in a number needed to treat to prevent one admission of 10.²⁶

In older children (3-18 years), SABAs delivered via spacer reduced ED length of stay, but did not significantly affect hospitalization rates. Additionally, SABAs administered with anticholinergics such as ipratropium bromide were more effective than SABAs alone in reducing admissions (16.9% vs 23.2%), particularly in older children with moderate to severe asthma, while also minimizing adverse effects.^8,26

Corticosteroids: A mainstay in the ED

In addition to albuterol administration, corticosteroids remain the mainstay of ED management for asthma exacerbations. Administration of systemic steroids has been shown to reduce hospitalizations in children under 6 years, although, paradoxically, studies examining outpatient administration have demonstrated an increase in hospitalizations when compared to placebo.²⁷

Dexamethasone and prednisone are the 2 most commonly used systemic steroids, and studies haven't indicated superiority of either.^28,29 There is no difference in efficacy between oral and intravenous steroids.³⁰ A recent clinical trial found a 2-day course of dexamethasone (0.6 mg/kg) had similar efficacy with fewer adverse effects when compared to a 5-day course of prednisone (1-2 mg/kg/day).²⁸

Patient isn’t responding? Try IV magnesium

For patients who don't respond to corticosteroids and albuterol treatments, IV magnesium sulfate (usual dose, 25-75 mg/kg/d; maximum dose, 2000 mg/d) has been shown to improve respiratory function, but not necessarily decrease admission rates.³¹ Inhaled magnesium sulfate hasn't been shown to be more effective than IV administration and isn'trecommended.³²

Evidence doesn’t support use of heliox

Heliox, which consists of 80% helium, is theorized to be effective in the treatment of asthma by increasing laminar flow and increasing the delivery of medications to the alveoli.³² Overall, the evidence does not support the use of heliox, which is typically restricted to patients with severe asthma exacerbations.³³

Is it worth considering noninvasive positive pressure ventilation?

If patients don't improve with medical treatment, noninvasive positive pressure ventilation can be considered. A recent meta-analysis suggests that there is no definitive benefit or harm from this treatment, although several studies have indicated a decrease in symptom severity.³⁴

Inhaled short-acting beta-agonists are the mainstay of treatment for intermittent asthma, as well as asthma exacerbations.

Intubation should be considered for hypoxemia unresponsive to medications, or in cases of exhaustion, worsening mental status, or respiratory acidosis unresponsive to medication. Ventilation should allow for a permissive respiratory acidosis (pH, 7.2), while maintaining adequate oxygenation.³⁵

Reducing the burden of asthma

Due to the complex task of reducing triggers and providing effective controller medications, working with parents and children is integral to improving the quality of life for patients with asthma. Although there is an obvious genetic predisposition, family physicians can help reduce the risk of developing asthma by encouraging healthy behaviors at home before the child is born. In the prenatal period, this includes avoiding tobacco-smoke exposure, lessening maternal obesity, decreasing maternal antibiotic and acetaminophen use, and curtailing stress.

Evidence suggests that after birth, breastfeeding and reducing childhood obesity can help lower the risk of asthma.³⁶ Atopic disease, in general, can be reduced by breastfeeding until at least 4 months, as well as encouraging a varied diet that does not restrict potential allergens during pregnancy or lactation, and introducing foods (including potential allergens) after the age of 4 months.

The risk of atopic disease can also be lowered by lessening potential triggers at home. These include restricting exposure to cats (but not dogs), reducing home mold by decreasing humidity and ensuring adequate ventilation, avoiding volatile organic compounds, such as chlorine, and curtailing exposure to vehicle emissions. Although often marketed to be effective in reducing allergies, dust-mite covers and soy-based formulas don't prevent or minimize allergies and are often costly.^37,38 In addition, there is no evidence that vaccinations areassociated with allergies.³⁹

CORRESPONDENCE
Douglas M. Maurer, 9040A Jackson Ave, Joint-Base Lewis-McChord, WA 98431; douglas.m.maurer.mil@mail.mil.

MONTREAL – Hypertension is a frequent, but underrecognized and undertreated, complication of chemotherapy for acute lymphoblastic leukemia (ALL), the most common childhood malignancy, investigators in a single-center U.S. study reported.

Additionally, there is a “concerningly high” incidence of acute kidney injury among children and young adults who undergo multiagent chemotherapy for acute myeloid leukemia (AML), said the authors of a study conducted in Canada.

Both studies were reported in a scientific poster session at the annual meeting of the American Society for Pediatric Hematology/Oncology.

Hypertension in ALL

Although standard induction regimens for childhood ALL contain high-dose steroids, which are known to be associated with increased risk for hypertension, the incidence of hypertension throughout induction, consolidation, and maintenance for ALL in children has not been adequately evaluated, according to Andrew S. Freiberg, MD, and his colleagues at Penn State Children’s Hospital in Hershey, Penn.

Kidney injury in AML

Like Dr. Freiberg and his colleagues, Liezl du Plessis, MBChB, from the British Columbia Children’s Hospital in Vancouver, Canada, and her colleagues were similarly taken aback when they looked into the incidence of acute kidney injury (AKI) in children and adolescents undergoing multidrug chemotherapy for AML.

“Chemotherapy agents that are used in acute myeloid leukemia are not considered to be nephrotoxic, so it was quite alarming to us to see that there is such a high rate of kidney injury in these patients,” Dr. du Plessis said in an interview.

MONTREAL – Hypertension is a frequent, but underrecognized and undertreated, complication of chemotherapy for acute lymphoblastic leukemia (ALL), the most common childhood malignancy, investigators in a single-center U.S. study reported.

Additionally, there is a “concerningly high” incidence of acute kidney injury among children and young adults who undergo multiagent chemotherapy for acute myeloid leukemia (AML), said the authors of a study conducted in Canada.

Both studies were reported in a scientific poster session at the annual meeting of the American Society for Pediatric Hematology/Oncology.

Hypertension in ALL

Although standard induction regimens for childhood ALL contain high-dose steroids, which are known to be associated with increased risk for hypertension, the incidence of hypertension throughout induction, consolidation, and maintenance for ALL in children has not been adequately evaluated, according to Andrew S. Freiberg, MD, and his colleagues at Penn State Children’s Hospital in Hershey, Penn.

Kidney injury in AML

Like Dr. Freiberg and his colleagues, Liezl du Plessis, MBChB, from the British Columbia Children’s Hospital in Vancouver, Canada, and her colleagues were similarly taken aback when they looked into the incidence of acute kidney injury (AKI) in children and adolescents undergoing multidrug chemotherapy for AML.

“Chemotherapy agents that are used in acute myeloid leukemia are not considered to be nephrotoxic, so it was quite alarming to us to see that there is such a high rate of kidney injury in these patients,” Dr. du Plessis said in an interview.

MONTREAL – Hypertension is a frequent, but underrecognized and undertreated, complication of chemotherapy for acute lymphoblastic leukemia (ALL), the most common childhood malignancy, investigators in a single-center U.S. study reported.

Additionally, there is a “concerningly high” incidence of acute kidney injury among children and young adults who undergo multiagent chemotherapy for acute myeloid leukemia (AML), said the authors of a study conducted in Canada.

Both studies were reported in a scientific poster session at the annual meeting of the American Society for Pediatric Hematology/Oncology.

Hypertension in ALL

Although standard induction regimens for childhood ALL contain high-dose steroids, which are known to be associated with increased risk for hypertension, the incidence of hypertension throughout induction, consolidation, and maintenance for ALL in children has not been adequately evaluated, according to Andrew S. Freiberg, MD, and his colleagues at Penn State Children’s Hospital in Hershey, Penn.

Kidney injury in AML

Like Dr. Freiberg and his colleagues, Liezl du Plessis, MBChB, from the British Columbia Children’s Hospital in Vancouver, Canada, and her colleagues were similarly taken aback when they looked into the incidence of acute kidney injury (AKI) in children and adolescents undergoing multidrug chemotherapy for AML.

“Chemotherapy agents that are used in acute myeloid leukemia are not considered to be nephrotoxic, so it was quite alarming to us to see that there is such a high rate of kidney injury in these patients,” Dr. du Plessis said in an interview.

BOSTON – Cannabidiol add-on treatment significantly reduces the frequency of drop seizures in patients with Lennox-Gastaut syndrome, according to findings from the randomized, double-blind, placebo-controlled GWPCARE4 and GWPCARE3 trials.

In GWPCARE4 – the first controlled trial of cannabidiol in Lennox-Gastaut syndrome (LGS) – 171 patients were randomized to receive either placebo or cannabidiol oral solution at a dose of 20 mg/kg per day for 14 weeks, including 2 weeks of titration and 12 weeks of maintenance therapy. The drop seizure frequency decreased by a median of 44% in the cannabidiol group vs. 22% in the placebo group. The difference between the groups was statistically significant and was apparent within the first 4 weeks of the maintenance period, Jacqueline French, MD, director of translational research and clinical trials in epilepsy at New York University Langone Medical Center reported at the annual meeting of the American Academy of Neurology.

Study participants had a mean age of 15 years, and 34% were aged 18 years or older. The median drop seizure frequency was 74 per month at baseline.

“That is a very high seizure burden,” Dr. French said, noting that the median total drop and non-drop seizure frequency was in the mid to high 100s. “So you can see that these children were very afflicted by seizures.”

Interestingly, there was a “very substantial drop” in non-drop seizures, as well, she said.

“And that’s really hard to demonstrate, so that’s impressive to me, at least,” she added.

Patients had taken a median of six antiepileptic drugs (AEDs) in their past and were taking a median of three AEDs in addition to the cannabidiol throughout the study period.

Adverse events were common, occurring in 86% of cannabidiol patients and 69% of placebo patients. The most common were diarrhea, somnolence, pyrexia, decreased appetite, and vomiting, but most were mild or moderate. Treatment-related serious adverse events were reported in nine cannabidiol patients and one placebo patient. All patients who completed the trial entered an open-label extension study, Dr. French said.

GWPCARE4 was followed by GWPCARE3, which compared both 20 mg/kg per day and 10 mg/kg per day doses of cannabidiol with placebo.

In that study, 225 patients with a mean age of 16 years (30% were aged 18 years or older) were randomized, and the median drop in seizure frequency was 42% with 20 mg/kg of cannabidiol and 37% with 10 mg/kg of cannabidiol versus 17% with placebo, Anup D. Patel, MD, reported at the meeting.

Approximately 40% and 36% of patients in the 20 mg/kg and 10 mg/kg groups, respectively, achieved the secondary outcome of a 50% or greater drop in seizure frequency, compared with 15% of placebo patients.

“Overall, 5 patients in the 20 mg/kg per day arm, 3 in the 10 [mg/kg per day arm], and 1 in the placebo arm achieved drop seizure freedom during the maintenance period of our study,” said Dr. Patel, a pediatric neurologist at Nationwide Children’s Hospital, Columbus, Ohio.

The median monthly drop seizure frequency at baseline was 80-87 in the three groups, and patients had previously failed a median of six to seven AEDs. They took a median of three AEDs during the study.

Adverse events occurred in 94% of patients in the 20-mg/kg cannabidiol group, 84% of those in the 10-mg/kg group, and 72% of placebo patients, and most were mild or moderate. The most common were somnolence and decreased appetite.

Treatment-related serious adverse events were reported in 5, 2, and 0 patients in the groups, respectively. Some elevations in transaminases were seen (in 11 patients in the 20-mg/kg dose group, and 2 in the 10-mg/kg dose group), but no patients met criteria for drug-induced liver injury with concurrent elevated bilirubin, and all cases resolved, Dr. Patel said.

Similar findings were noted in GWPCARE4, and both Dr. Patel and Dr. French noted that most patients with elevated transaminases were also taking valproic acid.

No deaths occurred in either GWPCARE4 or GWPCARE3.

“We feel both doses... produce significantly greater reductions in drop seizures as compared to placebo,” Dr. Patel said.

In an interview, he noted that the two cannabidiol doses were not compared directly to determine if the differences in response rates and adverse events were statistically significant, but said that the rates appeared comparable, and that the adverse event rates were high in all of the groups, reflecting a very sick patient population.

Of the 212 patients who completed GWPCARE3, 99% entered an open-label extension study.

Eligible patients in both trials were children and adults aged 2-55 years with a clinical diagnosis of LGS, at least two drop seizures (including tonic, atonic, and tonic-clonic seizures) each week at baseline, and documented failures on at least one AED.

Patients and caregivers in both trials were more likely to report improvement in overall condition among treated vs. placebo patients, as measured using the Subject/Caregiver Global Impression of Change scale.

The findings provide class 1 evidence that cannabidiol as add-on therapy in LGS is efficacious for reducing seizure frequency, and is generally well tolerated, Dr. French and Dr. Patel said.

Dr. French noted that enthusiasm for the trials was high, with many study sites reporting waiting lists for patient enrollment.

Some of the authors in each study have consulted for, conducted studies funded by, or received honoraria from GW Pharmaceuticals, which funded the GWPCARE4 and GWPCARE3 trials and manufacturers the oral cannabidiol solution. Several authors in each study were employees of GW Pharmaceuticals.

sworcester@frontlinemedcom.com

BOSTON – Cannabidiol add-on treatment significantly reduces the frequency of drop seizures in patients with Lennox-Gastaut syndrome, according to findings from the randomized, double-blind, placebo-controlled GWPCARE4 and GWPCARE3 trials.

In GWPCARE4 – the first controlled trial of cannabidiol in Lennox-Gastaut syndrome (LGS) – 171 patients were randomized to receive either placebo or cannabidiol oral solution at a dose of 20 mg/kg per day for 14 weeks, including 2 weeks of titration and 12 weeks of maintenance therapy. The drop seizure frequency decreased by a median of 44% in the cannabidiol group vs. 22% in the placebo group. The difference between the groups was statistically significant and was apparent within the first 4 weeks of the maintenance period, Jacqueline French, MD, director of translational research and clinical trials in epilepsy at New York University Langone Medical Center reported at the annual meeting of the American Academy of Neurology.

Study participants had a mean age of 15 years, and 34% were aged 18 years or older. The median drop seizure frequency was 74 per month at baseline.

“That is a very high seizure burden,” Dr. French said, noting that the median total drop and non-drop seizure frequency was in the mid to high 100s. “So you can see that these children were very afflicted by seizures.”

Interestingly, there was a “very substantial drop” in non-drop seizures, as well, she said.

“And that’s really hard to demonstrate, so that’s impressive to me, at least,” she added.

Patients had taken a median of six antiepileptic drugs (AEDs) in their past and were taking a median of three AEDs in addition to the cannabidiol throughout the study period.

Adverse events were common, occurring in 86% of cannabidiol patients and 69% of placebo patients. The most common were diarrhea, somnolence, pyrexia, decreased appetite, and vomiting, but most were mild or moderate. Treatment-related serious adverse events were reported in nine cannabidiol patients and one placebo patient. All patients who completed the trial entered an open-label extension study, Dr. French said.

GWPCARE4 was followed by GWPCARE3, which compared both 20 mg/kg per day and 10 mg/kg per day doses of cannabidiol with placebo.

In that study, 225 patients with a mean age of 16 years (30% were aged 18 years or older) were randomized, and the median drop in seizure frequency was 42% with 20 mg/kg of cannabidiol and 37% with 10 mg/kg of cannabidiol versus 17% with placebo, Anup D. Patel, MD, reported at the meeting.

Approximately 40% and 36% of patients in the 20 mg/kg and 10 mg/kg groups, respectively, achieved the secondary outcome of a 50% or greater drop in seizure frequency, compared with 15% of placebo patients.

“Overall, 5 patients in the 20 mg/kg per day arm, 3 in the 10 [mg/kg per day arm], and 1 in the placebo arm achieved drop seizure freedom during the maintenance period of our study,” said Dr. Patel, a pediatric neurologist at Nationwide Children’s Hospital, Columbus, Ohio.

The median monthly drop seizure frequency at baseline was 80-87 in the three groups, and patients had previously failed a median of six to seven AEDs. They took a median of three AEDs during the study.

Adverse events occurred in 94% of patients in the 20-mg/kg cannabidiol group, 84% of those in the 10-mg/kg group, and 72% of placebo patients, and most were mild or moderate. The most common were somnolence and decreased appetite.

Treatment-related serious adverse events were reported in 5, 2, and 0 patients in the groups, respectively. Some elevations in transaminases were seen (in 11 patients in the 20-mg/kg dose group, and 2 in the 10-mg/kg dose group), but no patients met criteria for drug-induced liver injury with concurrent elevated bilirubin, and all cases resolved, Dr. Patel said.

Similar findings were noted in GWPCARE4, and both Dr. Patel and Dr. French noted that most patients with elevated transaminases were also taking valproic acid.

No deaths occurred in either GWPCARE4 or GWPCARE3.

“We feel both doses... produce significantly greater reductions in drop seizures as compared to placebo,” Dr. Patel said.

In an interview, he noted that the two cannabidiol doses were not compared directly to determine if the differences in response rates and adverse events were statistically significant, but said that the rates appeared comparable, and that the adverse event rates were high in all of the groups, reflecting a very sick patient population.

Of the 212 patients who completed GWPCARE3, 99% entered an open-label extension study.

Eligible patients in both trials were children and adults aged 2-55 years with a clinical diagnosis of LGS, at least two drop seizures (including tonic, atonic, and tonic-clonic seizures) each week at baseline, and documented failures on at least one AED.

Patients and caregivers in both trials were more likely to report improvement in overall condition among treated vs. placebo patients, as measured using the Subject/Caregiver Global Impression of Change scale.

The findings provide class 1 evidence that cannabidiol as add-on therapy in LGS is efficacious for reducing seizure frequency, and is generally well tolerated, Dr. French and Dr. Patel said.

Dr. French noted that enthusiasm for the trials was high, with many study sites reporting waiting lists for patient enrollment.

Some of the authors in each study have consulted for, conducted studies funded by, or received honoraria from GW Pharmaceuticals, which funded the GWPCARE4 and GWPCARE3 trials and manufacturers the oral cannabidiol solution. Several authors in each study were employees of GW Pharmaceuticals.

sworcester@frontlinemedcom.com

BOSTON – Cannabidiol add-on treatment significantly reduces the frequency of drop seizures in patients with Lennox-Gastaut syndrome, according to findings from the randomized, double-blind, placebo-controlled GWPCARE4 and GWPCARE3 trials.

In GWPCARE4 – the first controlled trial of cannabidiol in Lennox-Gastaut syndrome (LGS) – 171 patients were randomized to receive either placebo or cannabidiol oral solution at a dose of 20 mg/kg per day for 14 weeks, including 2 weeks of titration and 12 weeks of maintenance therapy. The drop seizure frequency decreased by a median of 44% in the cannabidiol group vs. 22% in the placebo group. The difference between the groups was statistically significant and was apparent within the first 4 weeks of the maintenance period, Jacqueline French, MD, director of translational research and clinical trials in epilepsy at New York University Langone Medical Center reported at the annual meeting of the American Academy of Neurology.

Study participants had a mean age of 15 years, and 34% were aged 18 years or older. The median drop seizure frequency was 74 per month at baseline.

“That is a very high seizure burden,” Dr. French said, noting that the median total drop and non-drop seizure frequency was in the mid to high 100s. “So you can see that these children were very afflicted by seizures.”

Interestingly, there was a “very substantial drop” in non-drop seizures, as well, she said.

“And that’s really hard to demonstrate, so that’s impressive to me, at least,” she added.

Patients had taken a median of six antiepileptic drugs (AEDs) in their past and were taking a median of three AEDs in addition to the cannabidiol throughout the study period.

Adverse events were common, occurring in 86% of cannabidiol patients and 69% of placebo patients. The most common were diarrhea, somnolence, pyrexia, decreased appetite, and vomiting, but most were mild or moderate. Treatment-related serious adverse events were reported in nine cannabidiol patients and one placebo patient. All patients who completed the trial entered an open-label extension study, Dr. French said.

GWPCARE4 was followed by GWPCARE3, which compared both 20 mg/kg per day and 10 mg/kg per day doses of cannabidiol with placebo.

In that study, 225 patients with a mean age of 16 years (30% were aged 18 years or older) were randomized, and the median drop in seizure frequency was 42% with 20 mg/kg of cannabidiol and 37% with 10 mg/kg of cannabidiol versus 17% with placebo, Anup D. Patel, MD, reported at the meeting.

Approximately 40% and 36% of patients in the 20 mg/kg and 10 mg/kg groups, respectively, achieved the secondary outcome of a 50% or greater drop in seizure frequency, compared with 15% of placebo patients.

“Overall, 5 patients in the 20 mg/kg per day arm, 3 in the 10 [mg/kg per day arm], and 1 in the placebo arm achieved drop seizure freedom during the maintenance period of our study,” said Dr. Patel, a pediatric neurologist at Nationwide Children’s Hospital, Columbus, Ohio.

The median monthly drop seizure frequency at baseline was 80-87 in the three groups, and patients had previously failed a median of six to seven AEDs. They took a median of three AEDs during the study.

Adverse events occurred in 94% of patients in the 20-mg/kg cannabidiol group, 84% of those in the 10-mg/kg group, and 72% of placebo patients, and most were mild or moderate. The most common were somnolence and decreased appetite.

Treatment-related serious adverse events were reported in 5, 2, and 0 patients in the groups, respectively. Some elevations in transaminases were seen (in 11 patients in the 20-mg/kg dose group, and 2 in the 10-mg/kg dose group), but no patients met criteria for drug-induced liver injury with concurrent elevated bilirubin, and all cases resolved, Dr. Patel said.

Similar findings were noted in GWPCARE4, and both Dr. Patel and Dr. French noted that most patients with elevated transaminases were also taking valproic acid.

No deaths occurred in either GWPCARE4 or GWPCARE3.

“We feel both doses... produce significantly greater reductions in drop seizures as compared to placebo,” Dr. Patel said.

In an interview, he noted that the two cannabidiol doses were not compared directly to determine if the differences in response rates and adverse events were statistically significant, but said that the rates appeared comparable, and that the adverse event rates were high in all of the groups, reflecting a very sick patient population.

Of the 212 patients who completed GWPCARE3, 99% entered an open-label extension study.

Eligible patients in both trials were children and adults aged 2-55 years with a clinical diagnosis of LGS, at least two drop seizures (including tonic, atonic, and tonic-clonic seizures) each week at baseline, and documented failures on at least one AED.

Patients and caregivers in both trials were more likely to report improvement in overall condition among treated vs. placebo patients, as measured using the Subject/Caregiver Global Impression of Change scale.

The findings provide class 1 evidence that cannabidiol as add-on therapy in LGS is efficacious for reducing seizure frequency, and is generally well tolerated, Dr. French and Dr. Patel said.

Dr. French noted that enthusiasm for the trials was high, with many study sites reporting waiting lists for patient enrollment.

Some of the authors in each study have consulted for, conducted studies funded by, or received honoraria from GW Pharmaceuticals, which funded the GWPCARE4 and GWPCARE3 trials and manufacturers the oral cannabidiol solution. Several authors in each study were employees of GW Pharmaceuticals.

sworcester@frontlinemedcom.com

MONTREAL – Adding an immunostimulatory cytokine to chimeric antigen receptor–T cells (CAR-T) improved the adaptive immunotherapy’s activity against aggressive pediatric brain malignancies both in vitro and in animal models, an investigator reported.

CAR-T cells engineered to express interleukin-15 (IL-15), an inducer of T-cell proliferation and survival, were associated with significantly longer progression-free survival (PFS) and overall survival in mouse models of glioma, compared with regular CAR-T cells, said Giedre Krenciute, PhD, of Baylor College of Medicine in Houston.

MONTREAL – Adding an immunostimulatory cytokine to chimeric antigen receptor–T cells (CAR-T) improved the adaptive immunotherapy’s activity against aggressive pediatric brain malignancies both in vitro and in animal models, an investigator reported.

CAR-T cells engineered to express interleukin-15 (IL-15), an inducer of T-cell proliferation and survival, were associated with significantly longer progression-free survival (PFS) and overall survival in mouse models of glioma, compared with regular CAR-T cells, said Giedre Krenciute, PhD, of Baylor College of Medicine in Houston.

MONTREAL – Adding an immunostimulatory cytokine to chimeric antigen receptor–T cells (CAR-T) improved the adaptive immunotherapy’s activity against aggressive pediatric brain malignancies both in vitro and in animal models, an investigator reported.

CAR-T cells engineered to express interleukin-15 (IL-15), an inducer of T-cell proliferation and survival, were associated with significantly longer progression-free survival (PFS) and overall survival in mouse models of glioma, compared with regular CAR-T cells, said Giedre Krenciute, PhD, of Baylor College of Medicine in Houston.

There have been important reductions in hospitalization for acute gastroenteritis (AGE) and mortality since licensure of rotavirus vaccines 10 years ago, even in low-income countries with high child mortality, according to a new analysis of data from 27 countries.

In a search of articles published between Jan. 1, 2006, and Dec. 6, 2016, in the PubMed database, Eleanor Burnett of the division of viral diseases at the National Center for Immunization and Respiratory Diseases, Atlanta, and her associates identified 57 articles reporting on 59 data sources from 27 countries.

CDC/Dr. Erskine Palmer

cnellist@frontlinemedcom.com

There have been important reductions in hospitalization for acute gastroenteritis (AGE) and mortality since licensure of rotavirus vaccines 10 years ago, even in low-income countries with high child mortality, according to a new analysis of data from 27 countries.

In a search of articles published between Jan. 1, 2006, and Dec. 6, 2016, in the PubMed database, Eleanor Burnett of the division of viral diseases at the National Center for Immunization and Respiratory Diseases, Atlanta, and her associates identified 57 articles reporting on 59 data sources from 27 countries.

CDC/Dr. Erskine Palmer

cnellist@frontlinemedcom.com

There have been important reductions in hospitalization for acute gastroenteritis (AGE) and mortality since licensure of rotavirus vaccines 10 years ago, even in low-income countries with high child mortality, according to a new analysis of data from 27 countries.

In a search of articles published between Jan. 1, 2006, and Dec. 6, 2016, in the PubMed database, Eleanor Burnett of the division of viral diseases at the National Center for Immunization and Respiratory Diseases, Atlanta, and her associates identified 57 articles reporting on 59 data sources from 27 countries.

CDC/Dr. Erskine Palmer

cnellist@frontlinemedcom.com

The American Academy of Pediatrics’ new policy statement affirms that the medical home is the best location for nonemergency acute care but realizes that parents may take their children to other acute care services because of access, after-hours timing, or other reasons.

The AAP encourages its members to make the medical home available as “the first point of contact for acute care” by offering “enhanced access scheduling, extended hours, and telehealth incorporated inside the medical home.” Also, the AAP “supports innovation, peer-to-peer collaboration, and practice change to promote high-quality and accessible care for all children,” the policy states.

The policy, authored by Gregory P. Conners, MD, chairperson of the AAP Committee on Practice and Ambulatory Medicine, further outlines recommendations for acute care entities serving infants, children, and adolescents outside the medical home, such as maximizing continuity of care by quickly communicating information to the medical home, as well as referring the child for necessary follow-up.

Another recommendation is to have clearly defined scope-of-service limits that are transparent to families.

Other AAP entities involved in developing the policy were the Committee on Pediatric Emergency Medicine, the Section on Telehealth Care Executive Committee, the Task Force on Pediatric Practice Change, and the Section on Emergency Medicine Executive Committee.

Read more in the journal Pediatrics (2017;139[5]:e20170629).

cnellist@frontlinemedcom.com

The American Academy of Pediatrics’ new policy statement affirms that the medical home is the best location for nonemergency acute care but realizes that parents may take their children to other acute care services because of access, after-hours timing, or other reasons.

The AAP encourages its members to make the medical home available as “the first point of contact for acute care” by offering “enhanced access scheduling, extended hours, and telehealth incorporated inside the medical home.” Also, the AAP “supports innovation, peer-to-peer collaboration, and practice change to promote high-quality and accessible care for all children,” the policy states.

The policy, authored by Gregory P. Conners, MD, chairperson of the AAP Committee on Practice and Ambulatory Medicine, further outlines recommendations for acute care entities serving infants, children, and adolescents outside the medical home, such as maximizing continuity of care by quickly communicating information to the medical home, as well as referring the child for necessary follow-up.

Another recommendation is to have clearly defined scope-of-service limits that are transparent to families.

Other AAP entities involved in developing the policy were the Committee on Pediatric Emergency Medicine, the Section on Telehealth Care Executive Committee, the Task Force on Pediatric Practice Change, and the Section on Emergency Medicine Executive Committee.

Read more in the journal Pediatrics (2017;139[5]:e20170629).

cnellist@frontlinemedcom.com

The American Academy of Pediatrics’ new policy statement affirms that the medical home is the best location for nonemergency acute care but realizes that parents may take their children to other acute care services because of access, after-hours timing, or other reasons.

The AAP encourages its members to make the medical home available as “the first point of contact for acute care” by offering “enhanced access scheduling, extended hours, and telehealth incorporated inside the medical home.” Also, the AAP “supports innovation, peer-to-peer collaboration, and practice change to promote high-quality and accessible care for all children,” the policy states.

The policy, authored by Gregory P. Conners, MD, chairperson of the AAP Committee on Practice and Ambulatory Medicine, further outlines recommendations for acute care entities serving infants, children, and adolescents outside the medical home, such as maximizing continuity of care by quickly communicating information to the medical home, as well as referring the child for necessary follow-up.

Another recommendation is to have clearly defined scope-of-service limits that are transparent to families.

Other AAP entities involved in developing the policy were the Committee on Pediatric Emergency Medicine, the Section on Telehealth Care Executive Committee, the Task Force on Pediatric Practice Change, and the Section on Emergency Medicine Executive Committee.

Read more in the journal Pediatrics (2017;139[5]:e20170629).

cnellist@frontlinemedcom.com

Image from NHS

Children born to mothers who underwent fertility treatments have an increased risk of developing pediatric neoplasms, according to research published in the American Journal of Obstetrics & Gynecology.

The study showed an increased risk of malignancies and benign tumors among children conceived after fertility treatments.

However, the risk of leukemias and lymphomas among these children was not significantly different from the risk among children who were conceived spontaneously.

The study was a population-based cohort analysis of babies born between 1991 and 2013 at Soroka University Medical Center in Beer-Sheva, Israel, with follow-up to age 18.

Of the 242,187 newborn infants in the study, 237,863 (98.3%) were conceived spontaneously, 2603 (1.1%) were conceived after in vitro fertilization (IVF), and 1721 (0.7%) were conceived after ovulation induction (OI) treatments.

During a median follow-up of 10.55 years, there were 1498 neoplasms reported, including 1074 benign tumors and 429 malignancies.

The rate of neoplasms per 10,000 children was 61.85 for the entire study cohort, 111.41 for the IVF group, 110.40 for the OI group, and 60.96 for the spontaneous conception group (P<0.001 for the comparison between spontaneous conception and both types of fertility treatments).

The rate of benign tumors per 10,000 children was 44.35 for the entire study cohort, 84.51 for the IVF group, 69.73 for the OI group, and 43.72 for the spontaneous conception group (P=0.002).

The rate of malignancies per 10,000 children was 17.71 for the entire study cohort, 26.89 for the IVF group, 40.67 for the OI group, and 17.44 for the spontaneous conception group (P=0.038).

The rate of leukemia per 10,000 children was 3.72 for the entire study cohort (n=90 leukemia cases total), 0 for the IVF group (n=0), 5.81 for the OI group (n=1), and 3.74 for the spontaneous conception group (n=89, P=0.56).

The rate of lymphoma per 10,000 children was 2.27 for the entire study cohort (n=55), 7.68 for the IVF group (n=2), 0 for the OI group (n=0), and 2.23 for the spontaneous conception group (n=53, P=0.15).

The researchers said the association between fertility treatments and total pediatric neoplasms or total malignancies remained significant in analyses controlled for confounders such as gestational diabetes mellitus, hypertensive disorders, preterm birth, and maternal age.

For any fertility treatment, the adjusted hazard ratio (aHR) for all neoplasms was 1.97, and the aHR for all malignancies was 1.96.

For IVF, the aHR was 2.48 for all neoplasms and 1.89 for all malignancies. For OI, the aHR was 1.51 for all neoplasms and 2.03 for all malignancies.

“The research concludes that the association between IVF and total pediatric neoplasms and malignancies is significant,” said study author Eyal Sheiner, MD, PhD, of Ben-Gurion University of the Negev in Beer-Sheva, Israel.

“With increasing numbers of offspring conceived after fertility treatments, it is important to follow up on their health.”

Image from NHS

Children born to mothers who underwent fertility treatments have an increased risk of developing pediatric neoplasms, according to research published in the American Journal of Obstetrics & Gynecology.

The study showed an increased risk of malignancies and benign tumors among children conceived after fertility treatments.

However, the risk of leukemias and lymphomas among these children was not significantly different from the risk among children who were conceived spontaneously.

The study was a population-based cohort analysis of babies born between 1991 and 2013 at Soroka University Medical Center in Beer-Sheva, Israel, with follow-up to age 18.

Of the 242,187 newborn infants in the study, 237,863 (98.3%) were conceived spontaneously, 2603 (1.1%) were conceived after in vitro fertilization (IVF), and 1721 (0.7%) were conceived after ovulation induction (OI) treatments.

During a median follow-up of 10.55 years, there were 1498 neoplasms reported, including 1074 benign tumors and 429 malignancies.

The rate of neoplasms per 10,000 children was 61.85 for the entire study cohort, 111.41 for the IVF group, 110.40 for the OI group, and 60.96 for the spontaneous conception group (P<0.001 for the comparison between spontaneous conception and both types of fertility treatments).

The rate of benign tumors per 10,000 children was 44.35 for the entire study cohort, 84.51 for the IVF group, 69.73 for the OI group, and 43.72 for the spontaneous conception group (P=0.002).

The rate of malignancies per 10,000 children was 17.71 for the entire study cohort, 26.89 for the IVF group, 40.67 for the OI group, and 17.44 for the spontaneous conception group (P=0.038).

The rate of leukemia per 10,000 children was 3.72 for the entire study cohort (n=90 leukemia cases total), 0 for the IVF group (n=0), 5.81 for the OI group (n=1), and 3.74 for the spontaneous conception group (n=89, P=0.56).

The rate of lymphoma per 10,000 children was 2.27 for the entire study cohort (n=55), 7.68 for the IVF group (n=2), 0 for the OI group (n=0), and 2.23 for the spontaneous conception group (n=53, P=0.15).

The researchers said the association between fertility treatments and total pediatric neoplasms or total malignancies remained significant in analyses controlled for confounders such as gestational diabetes mellitus, hypertensive disorders, preterm birth, and maternal age.

For any fertility treatment, the adjusted hazard ratio (aHR) for all neoplasms was 1.97, and the aHR for all malignancies was 1.96.

For IVF, the aHR was 2.48 for all neoplasms and 1.89 for all malignancies. For OI, the aHR was 1.51 for all neoplasms and 2.03 for all malignancies.

“The research concludes that the association between IVF and total pediatric neoplasms and malignancies is significant,” said study author Eyal Sheiner, MD, PhD, of Ben-Gurion University of the Negev in Beer-Sheva, Israel.

“With increasing numbers of offspring conceived after fertility treatments, it is important to follow up on their health.”

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Children born to mothers who underwent fertility treatments have an increased risk of developing pediatric neoplasms, according to research published in the American Journal of Obstetrics & Gynecology.

The study showed an increased risk of malignancies and benign tumors among children conceived after fertility treatments.

However, the risk of leukemias and lymphomas among these children was not significantly different from the risk among children who were conceived spontaneously.

The study was a population-based cohort analysis of babies born between 1991 and 2013 at Soroka University Medical Center in Beer-Sheva, Israel, with follow-up to age 18.

Of the 242,187 newborn infants in the study, 237,863 (98.3%) were conceived spontaneously, 2603 (1.1%) were conceived after in vitro fertilization (IVF), and 1721 (0.7%) were conceived after ovulation induction (OI) treatments.

During a median follow-up of 10.55 years, there were 1498 neoplasms reported, including 1074 benign tumors and 429 malignancies.

The rate of neoplasms per 10,000 children was 61.85 for the entire study cohort, 111.41 for the IVF group, 110.40 for the OI group, and 60.96 for the spontaneous conception group (P<0.001 for the comparison between spontaneous conception and both types of fertility treatments).

The rate of benign tumors per 10,000 children was 44.35 for the entire study cohort, 84.51 for the IVF group, 69.73 for the OI group, and 43.72 for the spontaneous conception group (P=0.002).

The rate of malignancies per 10,000 children was 17.71 for the entire study cohort, 26.89 for the IVF group, 40.67 for the OI group, and 17.44 for the spontaneous conception group (P=0.038).

The rate of leukemia per 10,000 children was 3.72 for the entire study cohort (n=90 leukemia cases total), 0 for the IVF group (n=0), 5.81 for the OI group (n=1), and 3.74 for the spontaneous conception group (n=89, P=0.56).

The rate of lymphoma per 10,000 children was 2.27 for the entire study cohort (n=55), 7.68 for the IVF group (n=2), 0 for the OI group (n=0), and 2.23 for the spontaneous conception group (n=53, P=0.15).

The researchers said the association between fertility treatments and total pediatric neoplasms or total malignancies remained significant in analyses controlled for confounders such as gestational diabetes mellitus, hypertensive disorders, preterm birth, and maternal age.

For any fertility treatment, the adjusted hazard ratio (aHR) for all neoplasms was 1.97, and the aHR for all malignancies was 1.96.

For IVF, the aHR was 2.48 for all neoplasms and 1.89 for all malignancies. For OI, the aHR was 1.51 for all neoplasms and 2.03 for all malignancies.

“The research concludes that the association between IVF and total pediatric neoplasms and malignancies is significant,” said study author Eyal Sheiner, MD, PhD, of Ben-Gurion University of the Negev in Beer-Sheva, Israel.

“With increasing numbers of offspring conceived after fertility treatments, it is important to follow up on their health.”