- Email: [email protected]
Maternal and Neonatal Vitamin B12 Deficiency Detected through Expanded Newborn Screening—United States, 2003–2007
Maternal and Neonatal Vitamin B12 Deficiency Detected through Expanded Newborn Screening—United States, 2003–2007 Cynthia F. Hinton, PhD, MS, MPH, Jelili A. Ojodu, MPH, Paul M. Fernhoff, MD, Sonja A. Rasmussen, MD, MS, Kelley S. Scanlon, PhD, and W. Harry Hannon, PhD The incidence of neonatal vitamin B12 (cobalamin) deficiency because of maternal deficiency was determined by surveying state newborn screening programs. Thirty-two infants with nutritional vitamin B12 deficiency were identified (0.88/100 000 newborns). Pregnant women should be assessed for their risk of inadequate intake/malabsorption of vitamin B12. (J Pediatr 2010;157:162-3)
C
auses of maternal vitamin B12 deficiency include adherence to a diet that excludes or has limited amounts of animal products, pernicious anemia, and previous gastric bypass.1 Unrecognized neonatal vitamin B12 deficiency worsens if the infant is breastfed without vitamin B12 supplementation. Clinical presentation of vitamin B12 deficiency is often nonspecific (eg, developmental delay and failure to thrive), which can lead to a delay in diagnosis and treatment.1,2 Irreversible neurologic damage results from prolonged vitamin B12 deficiency; however, the extent and degree of disability depends on the severity and duration of the deficiency.1 Thus early detection and intervention is critical. In newborn screening (NBS), tandem mass spectrometry (MS/MS) detects many metabolic disorders including those that result in methylmalonic acidemia (indicated by elevations of the acylcarnitines, propionylcarnitine [C3] or methylmalonylcarnitine [C4DC]).3 All 50 states and the District of Columbia currently include MS/MS in their NBS panels.4 Recent case reports show that NBS with MS/MS has the potential to identify vitamin B12 deficiency, an important and treatable condition.5,6 NBS programs refer newborns with elevated levels of C3 or C4DC to a metabolic center for testing and treatment.7 Maternal nutritional deficiency may be diagnosed consequent to the diagnosis of the infant.7 Because nutritional vitamin B12 deficiency is not a genetic metabolic disorder, it is not explicitly included in NBS panels nor screened by methylmalonic acid, a sensitive and specific indicator of infant B12 deficiency. Infants subsequently diagnosed with nutritional vitamin B12 deficiency are not routinely recorded in NBS records. Therefore the incidence of neonatal vitamin B12 deficiency resulting from maternal deficiency is unknown.1,7
through a web-based survey collection tool. Reminder e-mails were sent to nonresponders at 3 and 6 weeks after the survey was launched in September 2008. Calls were made when no response was received. Programs were asked about their use of MS/MS during the study period (January 1, 2003, through December 31, 2007), whether they measured levels of C3 or C4DC acylcarnitines, and whether newborns with increased levels had been identified during this time period. The survey also collected information on confirmation of nutritional vitamin B12 deficiency among the infants with increased levels of C3 or C4DC and whether the mothers of infants with nutritional deficiency adhered to a strict vegetarian (vegan) diet, had undergone gastric bypass surgery, had autoimmune pernicious anemia, or had nutritional deficiency resulting from an unknown, or other, cause. Information on how cases were confirmed was beyond the scope of the survey.
Results Thirty-one programs responded. This represents a response rate of 67% among the 46 programs that used MS/MS during all or at least part of the study period.3 Of these, 12 state programs were able to provide data on detection of nutritional vitamin B12 deficiency among newborns. In these 12 states, 32 newborns with increased levels of C3 or C4DC acylcarnitines because of nutritional vitamin B12 deficiency were detected. Seven infants were born to women who adhered to a vegan or strict vegetarian diet, 3 were born to women who previously had undergone gastric bypass, and 3 were born to women identified with autoimmune pernicious anemia. Nineteen cases were identified as nutritional in origin
Methods A 10-question survey was distributed to each NBS follow-up program in 50 states and 2 territories. Respondents replied
C3 C4DC MS/MS NBS
Propionylcarnitine Methylmalonylcarnitine Tandem mass spectrometry Newborn screening
From the National Center on Birth Defects and Developmental Disabilities (C.H., S.R.), the National Center for Environmental Health (P.F., W.H.), and the National Center for Chronic Disease Prevention and Health Promotion (K.S.), Centers for Disease Control and Prevention, and the Division of Medical Genetics, Department of Human Genetics, Emory University School of Medicine (P.F.), Atlanta, GA; and the Association of Public Health Laboratories (J.O.), Silver Spring, MD The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention. The authors declare no conflicts of interest. 0022-3476/$ - see front matter. Copyright ª 2010 Mosby Inc. All rights reserved. 10.1016/j.jpeds.2010.03.006
162
Vol. 157, No. 1 July 2010
but of unknown cause. To estimate the rate of nutritional vitamin B12 deficiency from 2003–2007, the number of live births was obtained for the reporting 12 states for the study period.8 Confidence intervals were calculated with a Poisson distribution. The rate of nutritional vitamin B12 deficiency was 0.88/100 000 births (95% CI = 0.60-1.26).
Discussion Identification of newborns with nutritional vitamin B12 deficiency is an additional benefit of NBS programs. However, the finding that several states were unable to provide details on the nutritional causes of methylmalonic acidemia suggests that feedback to state NBS programs about these conditions could be strengthened. Moreover, some states might consider identification of infants with nongenetic causes of methylmalonic acidemia to be ‘‘false-positive’’ results or outside the realm of their program’s intent. Timely detection of nutritional vitamin B12 deficiency and intervention can reduce or prevent morbidity and mortality rates associated with this condition. This study is subject to several limitations. Not all state NBS programs responded to the survey or to the question related to detection of acylcarnitines. Programs that did not respond might have been less likely to detect infants with this deficiency, resulting in an overestimate of the incidence. The sensitivity of MS/MS for NBS screening nutritional vitamin B12 deficiency is unknown6; these results could be overestimates or underestimates. We lack information on how maternal conditions were determined, which might affect the number of cases of unknown nutritional cause. The use of live births as the denominator assumes that 100% of newborns were screened, but the actual number of screened newborns may be slightly less. This limitation is unlikely to have a significant effect on our estimated incidence. Vitamin B12 deficiency should be considered in infants who exhibit failure to thrive, developmental delay, neurologic or behavioral disorders, and who were born to mothers at risk for this deficiency.1 NBS programs should consider newborns diagnosed with confirmed nutritional vitamin B12 deficiency to be true-positive, not false-positive, cases.9
Future improvements in the feedback from metabolic centers that are responsible for ultimate diagnosis of these conditions to NBS follow-up programs will result in a better estimate of the incidence of this preventable nutritional disorder. Finally, health-care providers should ask pregnant and lactating women about their diet and medical history to identify those who are at risk for an inadequate intake or malabsorption of vitamin B12. Providers should not rely solely on measurement of serum vitamin B12 levels but should measure plasma methylmalonic acid and total homocysteine to diagnose vitamin B12 deficiency in at-risk women.9 If a deficiency is suspected, then both the mother and the infant should be promptly evaluated for vitamin B12 deficiency.1 n Submitted for publication Oct 6, 2009; last revision received Dec 23, 2009; accepted Mar 9, 2010. Reprint requests: Cynthia F. Hinton, PhD, MS, MPH, Centers for Disease Control and Prevention, 1600 Clifton Rd, NE, MS E-86, Atlanta, GA 30333. Email: [email protected].
References 1. Rasmussen SA, Fernhoff PM, Scanlon KS. Vitamin B12 deficiency in children and adolescents. J Pediatr 2001;138:10-7. 2. Grattan-Smith PJ, Wilcken B, Procopis PG, Wise GA. The neurological syndrome of infantile cobalamin deficiency: developmental regression and involuntary movements. Mov Disord 1997;12:39-46. 3. CDC. Impact of expanded newborn screening—United States, 2006. MMWR Morb Mortal Wkly Rep 2008;57:1012-5. 4. National Newborn Screening Information Center. Available from: http:// www2.uthscsa.edu/nnsis/. [cited January 7, 2009]. 5. Marble M, Copeland S, Khanfar N, Rosenblatt DS. Neonatal vitamin B12 deficiency secondary to maternal subclinical pernicious anemia: identification by expanded newborn screening. J Pediatr 2008;152:731-3. 6. Campbell CD, Ganesh J, Ficicioglu C. Two newborns with nutritional vitamin B12 deficiency: challenges in newborn screening for vitamin B12 deficiency. Haematologica 2005;90(Suppl):ECR45. 7. CDC. Neurologic impairment in children associated with maternal dietary deficiency of cobalamin—Georgia, 2001. MMWR Morb Mortal Wkly Rep 2003;52:61-4. 8. National Center for Health Statistics. Available from: http://www.cdc. gov/nchs/births.htm. [cited March 17, 2009]. 9. Carmel R, Sarrai M. Diagnosis and management of clinical and subclinical cobalamin deficiency: advances and controversies. Curr Hematol Rep 2006;5:23-33.
163
C
auses of maternal vitamin B12 deficiency include adherence to a diet that excludes or has limited amounts of animal products, pernicious anemia, and previous gastric bypass.1 Unrecognized neonatal vitamin B12 deficiency worsens if the infant is breastfed without vitamin B12 supplementation. Clinical presentation of vitamin B12 deficiency is often nonspecific (eg, developmental delay and failure to thrive), which can lead to a delay in diagnosis and treatment.1,2 Irreversible neurologic damage results from prolonged vitamin B12 deficiency; however, the extent and degree of disability depends on the severity and duration of the deficiency.1 Thus early detection and intervention is critical. In newborn screening (NBS), tandem mass spectrometry (MS/MS) detects many metabolic disorders including those that result in methylmalonic acidemia (indicated by elevations of the acylcarnitines, propionylcarnitine [C3] or methylmalonylcarnitine [C4DC]).3 All 50 states and the District of Columbia currently include MS/MS in their NBS panels.4 Recent case reports show that NBS with MS/MS has the potential to identify vitamin B12 deficiency, an important and treatable condition.5,6 NBS programs refer newborns with elevated levels of C3 or C4DC to a metabolic center for testing and treatment.7 Maternal nutritional deficiency may be diagnosed consequent to the diagnosis of the infant.7 Because nutritional vitamin B12 deficiency is not a genetic metabolic disorder, it is not explicitly included in NBS panels nor screened by methylmalonic acid, a sensitive and specific indicator of infant B12 deficiency. Infants subsequently diagnosed with nutritional vitamin B12 deficiency are not routinely recorded in NBS records. Therefore the incidence of neonatal vitamin B12 deficiency resulting from maternal deficiency is unknown.1,7
through a web-based survey collection tool. Reminder e-mails were sent to nonresponders at 3 and 6 weeks after the survey was launched in September 2008. Calls were made when no response was received. Programs were asked about their use of MS/MS during the study period (January 1, 2003, through December 31, 2007), whether they measured levels of C3 or C4DC acylcarnitines, and whether newborns with increased levels had been identified during this time period. The survey also collected information on confirmation of nutritional vitamin B12 deficiency among the infants with increased levels of C3 or C4DC and whether the mothers of infants with nutritional deficiency adhered to a strict vegetarian (vegan) diet, had undergone gastric bypass surgery, had autoimmune pernicious anemia, or had nutritional deficiency resulting from an unknown, or other, cause. Information on how cases were confirmed was beyond the scope of the survey.
Results Thirty-one programs responded. This represents a response rate of 67% among the 46 programs that used MS/MS during all or at least part of the study period.3 Of these, 12 state programs were able to provide data on detection of nutritional vitamin B12 deficiency among newborns. In these 12 states, 32 newborns with increased levels of C3 or C4DC acylcarnitines because of nutritional vitamin B12 deficiency were detected. Seven infants were born to women who adhered to a vegan or strict vegetarian diet, 3 were born to women who previously had undergone gastric bypass, and 3 were born to women identified with autoimmune pernicious anemia. Nineteen cases were identified as nutritional in origin
Methods A 10-question survey was distributed to each NBS follow-up program in 50 states and 2 territories. Respondents replied
C3 C4DC MS/MS NBS
Propionylcarnitine Methylmalonylcarnitine Tandem mass spectrometry Newborn screening
From the National Center on Birth Defects and Developmental Disabilities (C.H., S.R.), the National Center for Environmental Health (P.F., W.H.), and the National Center for Chronic Disease Prevention and Health Promotion (K.S.), Centers for Disease Control and Prevention, and the Division of Medical Genetics, Department of Human Genetics, Emory University School of Medicine (P.F.), Atlanta, GA; and the Association of Public Health Laboratories (J.O.), Silver Spring, MD The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention. The authors declare no conflicts of interest. 0022-3476/$ - see front matter. Copyright ª 2010 Mosby Inc. All rights reserved. 10.1016/j.jpeds.2010.03.006
162
Vol. 157, No. 1 July 2010
but of unknown cause. To estimate the rate of nutritional vitamin B12 deficiency from 2003–2007, the number of live births was obtained for the reporting 12 states for the study period.8 Confidence intervals were calculated with a Poisson distribution. The rate of nutritional vitamin B12 deficiency was 0.88/100 000 births (95% CI = 0.60-1.26).
Discussion Identification of newborns with nutritional vitamin B12 deficiency is an additional benefit of NBS programs. However, the finding that several states were unable to provide details on the nutritional causes of methylmalonic acidemia suggests that feedback to state NBS programs about these conditions could be strengthened. Moreover, some states might consider identification of infants with nongenetic causes of methylmalonic acidemia to be ‘‘false-positive’’ results or outside the realm of their program’s intent. Timely detection of nutritional vitamin B12 deficiency and intervention can reduce or prevent morbidity and mortality rates associated with this condition. This study is subject to several limitations. Not all state NBS programs responded to the survey or to the question related to detection of acylcarnitines. Programs that did not respond might have been less likely to detect infants with this deficiency, resulting in an overestimate of the incidence. The sensitivity of MS/MS for NBS screening nutritional vitamin B12 deficiency is unknown6; these results could be overestimates or underestimates. We lack information on how maternal conditions were determined, which might affect the number of cases of unknown nutritional cause. The use of live births as the denominator assumes that 100% of newborns were screened, but the actual number of screened newborns may be slightly less. This limitation is unlikely to have a significant effect on our estimated incidence. Vitamin B12 deficiency should be considered in infants who exhibit failure to thrive, developmental delay, neurologic or behavioral disorders, and who were born to mothers at risk for this deficiency.1 NBS programs should consider newborns diagnosed with confirmed nutritional vitamin B12 deficiency to be true-positive, not false-positive, cases.9
Future improvements in the feedback from metabolic centers that are responsible for ultimate diagnosis of these conditions to NBS follow-up programs will result in a better estimate of the incidence of this preventable nutritional disorder. Finally, health-care providers should ask pregnant and lactating women about their diet and medical history to identify those who are at risk for an inadequate intake or malabsorption of vitamin B12. Providers should not rely solely on measurement of serum vitamin B12 levels but should measure plasma methylmalonic acid and total homocysteine to diagnose vitamin B12 deficiency in at-risk women.9 If a deficiency is suspected, then both the mother and the infant should be promptly evaluated for vitamin B12 deficiency.1 n Submitted for publication Oct 6, 2009; last revision received Dec 23, 2009; accepted Mar 9, 2010. Reprint requests: Cynthia F. Hinton, PhD, MS, MPH, Centers for Disease Control and Prevention, 1600 Clifton Rd, NE, MS E-86, Atlanta, GA 30333. Email: [email protected].
References 1. Rasmussen SA, Fernhoff PM, Scanlon KS. Vitamin B12 deficiency in children and adolescents. J Pediatr 2001;138:10-7. 2. Grattan-Smith PJ, Wilcken B, Procopis PG, Wise GA. The neurological syndrome of infantile cobalamin deficiency: developmental regression and involuntary movements. Mov Disord 1997;12:39-46. 3. CDC. Impact of expanded newborn screening—United States, 2006. MMWR Morb Mortal Wkly Rep 2008;57:1012-5. 4. National Newborn Screening Information Center. Available from: http:// www2.uthscsa.edu/nnsis/. [cited January 7, 2009]. 5. Marble M, Copeland S, Khanfar N, Rosenblatt DS. Neonatal vitamin B12 deficiency secondary to maternal subclinical pernicious anemia: identification by expanded newborn screening. J Pediatr 2008;152:731-3. 6. Campbell CD, Ganesh J, Ficicioglu C. Two newborns with nutritional vitamin B12 deficiency: challenges in newborn screening for vitamin B12 deficiency. Haematologica 2005;90(Suppl):ECR45. 7. CDC. Neurologic impairment in children associated with maternal dietary deficiency of cobalamin—Georgia, 2001. MMWR Morb Mortal Wkly Rep 2003;52:61-4. 8. National Center for Health Statistics. Available from: http://www.cdc. gov/nchs/births.htm. [cited March 17, 2009]. 9. Carmel R, Sarrai M. Diagnosis and management of clinical and subclinical cobalamin deficiency: advances and controversies. Curr Hematol Rep 2006;5:23-33.
163