J. Inher. Metab. Dis. 13 (1990) 641-650 © SSIEM and Kluwer AcademicPublishers. Printed in the Netherlands
Maternal PKU Workshop
A Preliminary Report of the Collaborative Study of Maternal Phenylketonuria in the United States and Canada R. KOCH 1, W. HANLEY2, H. LEVY3, R. MATALON4, B. ROUSE5, F. DELA CRUZ6, C. AZEN 1 and E. GRoss FRIEDMANl 1PKU Program, Division of Medical Genetics, Children's Hospital of Los Angeles, 4650 Sunset Boulevard, Los Angeles, CA 90027, USA 2pKU Programme, Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8 3Biochemical Genetics, Children's Hospital Medical Center, 300 Longwood Avenue, Gardner 648, Boston, MA 02115, USA 4Division of Genetics and Metabolism, University of Illinois Hospital, 840 S. Wood St., Chicago, IL 60612, USA 5Child Development Division, University of Texas Medical Branch, 301 University Blvd., Galveston, TX 77550, USA 6Mental Retardation and Developmental Disabilities Branch, 6130 Executive Blvd. North, Rockville, MD 20892, USA
Summary: The Maternal Phenylketonuria Collaborative Study (MPKUCS), encompassing all the United States and provinces of Canada, is a prospective, longitudinal investigation designed to ascertain the efficacy of phenylalaninerestricted therapy in protecting the fetus from high maternal phenylalanine concentrations in women with hyperphenylalaninaemia. Preliminary findings are reported for 147 pregnancies for whom the recommended therapeutic range of blood phenylalanine was 120-360#mol/L. Sixty-three pregnancies had complete data for analysis. Dietary control was attempted prior to conception in 10 out of 63 women. Significant negative correlations were noted in length, weight and head circumference and blood phenylalanine concentrations during pregnancy. Average reported phenylalanine levels by trimester for 63 hyperphenylalaninaemic pregnancies resulting in live births revealed that no group requiring treatment achieved levels below 360/tmol/L until the third trimester. Median birth measurement percentiles revealed that all groups studied generally had smaller head size compared with birth length and weight. Those started on diet after the first trimester achieved a head circumference below the t0th percentile. The implication of small head circumference for subsequent intellectual 641
642
K o c h et al.
development is unclear at this time. Furthermore, the study must evaluate more offspring of women having optimal preconception and pregnancy restriction of phenylalanine.
The Maternal Phenylketonuria Collaborative Study has been previously described (Koch et al., 1986, 1987). It is an ongoing longitudinal prospective study of pregnant women with hyperphenylataninaemia and their offspring. The risk to these offspring of classical phenylketonuria (PKU) (McKusick 26160) and its milder forms has been well documented (Table 1) (Lenke and Levy, 1980, 1982; Lipson et al., 1984; Drogari et al., 1987; Koch et al., 1988). The objective of this investigation is to determine how best to reduce the morbidity associated with maternal hyperphenylalaninaemia. The study has completed its fourth year and is in the process of collecting data on the 147 pregnancies followed to date. Study design includes outcome data on the medical, nutritional and biochemical parameters gathered prospectively during the pregnancy and developmental course of the offspring (Table 2). All PKU centres in the United States and Canada are included in this study which is supported by the National Institute of Child Health and Human Development (USA) and the National Health Research and Development Programme (Canada). The study organization is outlined in Table 3 and Figure 1, with one Coordinating and four Contributing Centers Table 1 Effects of maternal phenylketonuria or hyperphenylalaninaemia on pregnancy outcome a
Maternal phenylaIanine levels (/tmol/L) _> 1200 960-1140 6 6 0 - 9 0 0 180-600 Percentage affected in each group
Mental retardation Microcephaly Congenital heart disease Birth weight < 2500g Spontaneous abortion
92 73 12 40 24
73 68 15 52 30
22 35 6 56 0
21 24 0 13 8
Adopted from Lenke and Levy (1980) aOffspring with PKU or hyperphenylalaninaemia are excluded Table 2
Maternal Phenyiketonuria Collaborative Study outcome measures
Rate of spontaneous abortion Rates of major complications of pregnancy and delivery on offspring: Growth retardation Intrauterine growth by ultrasound Birth length, weight and head circumference Pediatric evaluation of gestational age Congenital heart defect Microcephaly Congenital malformations Cognitive/behavioural development
J. Inher. Metab. Dis. 13 (1990)
643
Maternal P K U in North America
Table 3
Maternal PKU Collaborative Study Centers
C O O R D I N A T I N G CENTER
Principal Investigator: Richard Koch, MD Associate Director: Eva Gross Friedman Coordinator, Biostatistics: Colleen Azen, MS Maternal PKU Collaborative Study Children's Hospital of Los Angeles, 4650 Sunset Blvd., Los Angeles, CA 90027 Telephone: 213-669-2152 NICHD Project Officer: Felix de la Cruz, MD, MPH Chief, Mental Retardation and Developmental Disabilities Branch, NICHD, NIH Executive Plaza North, Rm 631, 6130 Executive Blvd. North, Rockvilte, MD 20892 Telephone: 301-496-1383 NICHD Contracting Officer: Harvey Shifrin Coniracts Management Section, NICHD, NIH Executive Plaza North, Rm 515, 6130 Executive Blvd. North, Rockville, MD 20892 Telephone: 301-496-4611 CONTRIBUTING CENTERS
NORTHEAST REGION: Connecticut, Delaware, Maine, Maryland, Massachusetts, New Hampshire, New Jersey, New York, Vermont, Pennsylvania, Rhode Island, Virginia, West Virginia, District of Columbia Principal Investigator: Harvey Levy, MD Project Coordinator: Deborah Lobbregt Biochemical Genetics Children's Hospital Medical Center 300 Longwood Ave., Gardner 648, Boston, MA 02115 Telephone: 617-735-7945
SOUTHEAST REGION: Alabama, Arkansas, Georgia, Florida, Texas, Mississippi, North Carolina, Louisiana, South Carolina, Tennessee, Puerto Rico Principal Investigator: Bobbye Rouse, MD Project Coordinator: Lois Castiglioni, MS, RD Department of Pediatrics, C19 University of Texas Medical Branch, 301 University Blvd., Galveston, TX 77550 Telephone: 409-761-2355 MIDWEST REGION: Illinois, Iowa, Ohio, Kentucky, Michigan, Kansas, Wisconsin, Missouri, Nebraska, North Dakota, South Dakota, Indiana, Minnesota, Oklahoma Principal Investigator: Reuben Matalon, MD, PhD Project Coordinator: Barbara Swift, RDMS Department of Pediatrics, RM 1311-N-CSB, University of Illinois Hospital, 840 S. Wood St., Chicago, IL 60612 Telephone: 312-996-5326 WESTERN REGION: Alaska, Utah, Idaho, Arizona, California, Montana, Nevada, Colorado, Hawaii, New Mexico, Oregon, Washington, Wyoming Principal Investigator: Richard Koch, MD Project Coordinator: Cindy Bauman, MPH Maternal PKU Collaborative Study, Children's Hospital of Los Angeles, 4650 Sunset Blvd., Los Angeles, CA 90027 Telephone: 213-669-2152
CANADA
Principal Investigator William B. Hanley, MD Project Coordinator: Wanda Schoonheyt, RN
The Hospital for Sick Children, 555 University Ave., Toronto, Ontario, Canada M5G 1X8 Telephone: 416-597-1500
J. Inher. Metab. Dis. 13 (1990)
~igure I
.EGEND:
PARTICIPATING CLINICS I
,"
//Liil
Untv. of Texas Medical Branch Galveston, TX
B, Rouse
SOUTHEAST
H. Shlfrtn
Advisory
I~
Administ ~,dministrative
CLINICS
m
WESTERN
....
It::i
I PARTICIPATING CLINICS
Los Angeles, CA
R. Koch Chiidrena Hospital of Los Angeles
B, Rouse W. Hanley F. dela Cruz
R. Koch It, Levy R, Matalon
)OLICY COMMITTEE
F. dela Cruz H. Shifrin
)ARTICIPATING ~ARTICIPATINGcLINICS I PARTICI
Iliil .................
R. Matalon Univ. of Illinois Medical Center Chicago, IL
MIDWEST
R. Koch ~hlldrens Hospital of Los Angeles Staff/Consultants
;OORDINATING CENTER
)rganization of the Maternal PKU Collaborative Study
~ARTICIPATING CLINICS
H, Levy The Children's Hospital Boston, MA
L
I
W.B, Henley Hospital for ~ick Children "oronto, ONT.
I
I
NORTHEAST
I
I
m
_=~-
Project Officer: Contracting Officer:
qATIONALINSTITUTE CHILD HEALTH& HUMANDEVELOPMENT
CANADA
Medicine Bloat atistlcs Nutrition Analysis Fetal Pathology Epldemiology
COORDINATING~ CONSULTANTS
Nutrition
~,DVISORYPERSONNEL
VIATERNAL PKU COLLABORATIVE STUDY ORGANIZATION AND ADMINISTRATION STRUCTURE
%
645
Maternal P K U in North America
located in different geographic regions across the continent. The purpose of this report is to provide a preliminary summary of the data collected as of January 1989. THE SAMPLE
Approximately 1500 women with hyperphenylalaninaemia have been identified by the project (Table 4). They range in age from 12 to over 35 years, but the majority are in the peak reproductive years of 18 to 30 years of age. An additional 206 are actively enrolled in the study at various participating clinics (Table 5). Fifty-nine percent were identified by newborn screening and are within the normal range of intelligence. Another 20% were identified by family screening and 13% by abnormal phenotype. Forty-eight percent of the pregnant women with hyperphenylalaninaemia were between 21 and 25 years of age at the time of conception; 36% were from 15 to 20 years of age at conception; and 16% were between 26 and 35 years of age. By 31 January 1989, 147 pregnancies had been followed, of which 20 were currently ongoing. Unfortunately, 80% of the pregnant women with hyperphenylalaninaemia in the study were enrolled with significantly elevated blood phenylalanine concentrations due to an unrestricted diet around the time of conception. Thus, only 20% of the pregnancies studied were planned with average blood phenylalanine concentrations within or close to the recommended therapeutic range of 120-360 ~mol/L (2-6 mg/dl). Table 4 Hyperphenylalaninaemic individuals identified in the United States and Canada a
Age (yrs)
Female
Male
Total
12-14 15-17 18-20 21-25 26-30 31-35 > 35 Unknown
223 309 269 324 199 88 66 22
155 160 148 140 84 32 26 4
378 469 417 464 283 120 92 26
1500
749
2249
Subtotal aExcludes enrollees
Table 5 Present age of 206 enrolled hyperphenylalaninaemic females
Age (yrs)
Number
Percentage
15-17 18-20 21-25 26-30 31-35 > 35
6 44 99 43 13 1
3 21 48 21 6
Maternal PKU Workshop
A Preliminary Report of the Collaborative Study of Maternal Phenylketonuria in the United States and Canada R. KOCH 1, W. HANLEY2, H. LEVY3, R. MATALON4, B. ROUSE5, F. DELA CRUZ6, C. AZEN 1 and E. GRoss FRIEDMANl 1PKU Program, Division of Medical Genetics, Children's Hospital of Los Angeles, 4650 Sunset Boulevard, Los Angeles, CA 90027, USA 2pKU Programme, Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8 3Biochemical Genetics, Children's Hospital Medical Center, 300 Longwood Avenue, Gardner 648, Boston, MA 02115, USA 4Division of Genetics and Metabolism, University of Illinois Hospital, 840 S. Wood St., Chicago, IL 60612, USA 5Child Development Division, University of Texas Medical Branch, 301 University Blvd., Galveston, TX 77550, USA 6Mental Retardation and Developmental Disabilities Branch, 6130 Executive Blvd. North, Rockville, MD 20892, USA
Summary: The Maternal Phenylketonuria Collaborative Study (MPKUCS), encompassing all the United States and provinces of Canada, is a prospective, longitudinal investigation designed to ascertain the efficacy of phenylalaninerestricted therapy in protecting the fetus from high maternal phenylalanine concentrations in women with hyperphenylalaninaemia. Preliminary findings are reported for 147 pregnancies for whom the recommended therapeutic range of blood phenylalanine was 120-360#mol/L. Sixty-three pregnancies had complete data for analysis. Dietary control was attempted prior to conception in 10 out of 63 women. Significant negative correlations were noted in length, weight and head circumference and blood phenylalanine concentrations during pregnancy. Average reported phenylalanine levels by trimester for 63 hyperphenylalaninaemic pregnancies resulting in live births revealed that no group requiring treatment achieved levels below 360/tmol/L until the third trimester. Median birth measurement percentiles revealed that all groups studied generally had smaller head size compared with birth length and weight. Those started on diet after the first trimester achieved a head circumference below the t0th percentile. The implication of small head circumference for subsequent intellectual 641
642
K o c h et al.
development is unclear at this time. Furthermore, the study must evaluate more offspring of women having optimal preconception and pregnancy restriction of phenylalanine.
The Maternal Phenylketonuria Collaborative Study has been previously described (Koch et al., 1986, 1987). It is an ongoing longitudinal prospective study of pregnant women with hyperphenylataninaemia and their offspring. The risk to these offspring of classical phenylketonuria (PKU) (McKusick 26160) and its milder forms has been well documented (Table 1) (Lenke and Levy, 1980, 1982; Lipson et al., 1984; Drogari et al., 1987; Koch et al., 1988). The objective of this investigation is to determine how best to reduce the morbidity associated with maternal hyperphenylalaninaemia. The study has completed its fourth year and is in the process of collecting data on the 147 pregnancies followed to date. Study design includes outcome data on the medical, nutritional and biochemical parameters gathered prospectively during the pregnancy and developmental course of the offspring (Table 2). All PKU centres in the United States and Canada are included in this study which is supported by the National Institute of Child Health and Human Development (USA) and the National Health Research and Development Programme (Canada). The study organization is outlined in Table 3 and Figure 1, with one Coordinating and four Contributing Centers Table 1 Effects of maternal phenylketonuria or hyperphenylalaninaemia on pregnancy outcome a
Maternal phenylaIanine levels (/tmol/L) _> 1200 960-1140 6 6 0 - 9 0 0 180-600 Percentage affected in each group
Mental retardation Microcephaly Congenital heart disease Birth weight < 2500g Spontaneous abortion
92 73 12 40 24
73 68 15 52 30
22 35 6 56 0
21 24 0 13 8
Adopted from Lenke and Levy (1980) aOffspring with PKU or hyperphenylalaninaemia are excluded Table 2
Maternal Phenyiketonuria Collaborative Study outcome measures
Rate of spontaneous abortion Rates of major complications of pregnancy and delivery on offspring: Growth retardation Intrauterine growth by ultrasound Birth length, weight and head circumference Pediatric evaluation of gestational age Congenital heart defect Microcephaly Congenital malformations Cognitive/behavioural development
J. Inher. Metab. Dis. 13 (1990)
643
Maternal P K U in North America
Table 3
Maternal PKU Collaborative Study Centers
C O O R D I N A T I N G CENTER
Principal Investigator: Richard Koch, MD Associate Director: Eva Gross Friedman Coordinator, Biostatistics: Colleen Azen, MS Maternal PKU Collaborative Study Children's Hospital of Los Angeles, 4650 Sunset Blvd., Los Angeles, CA 90027 Telephone: 213-669-2152 NICHD Project Officer: Felix de la Cruz, MD, MPH Chief, Mental Retardation and Developmental Disabilities Branch, NICHD, NIH Executive Plaza North, Rm 631, 6130 Executive Blvd. North, Rockvilte, MD 20892 Telephone: 301-496-1383 NICHD Contracting Officer: Harvey Shifrin Coniracts Management Section, NICHD, NIH Executive Plaza North, Rm 515, 6130 Executive Blvd. North, Rockville, MD 20892 Telephone: 301-496-4611 CONTRIBUTING CENTERS
NORTHEAST REGION: Connecticut, Delaware, Maine, Maryland, Massachusetts, New Hampshire, New Jersey, New York, Vermont, Pennsylvania, Rhode Island, Virginia, West Virginia, District of Columbia Principal Investigator: Harvey Levy, MD Project Coordinator: Deborah Lobbregt Biochemical Genetics Children's Hospital Medical Center 300 Longwood Ave., Gardner 648, Boston, MA 02115 Telephone: 617-735-7945
SOUTHEAST REGION: Alabama, Arkansas, Georgia, Florida, Texas, Mississippi, North Carolina, Louisiana, South Carolina, Tennessee, Puerto Rico Principal Investigator: Bobbye Rouse, MD Project Coordinator: Lois Castiglioni, MS, RD Department of Pediatrics, C19 University of Texas Medical Branch, 301 University Blvd., Galveston, TX 77550 Telephone: 409-761-2355 MIDWEST REGION: Illinois, Iowa, Ohio, Kentucky, Michigan, Kansas, Wisconsin, Missouri, Nebraska, North Dakota, South Dakota, Indiana, Minnesota, Oklahoma Principal Investigator: Reuben Matalon, MD, PhD Project Coordinator: Barbara Swift, RDMS Department of Pediatrics, RM 1311-N-CSB, University of Illinois Hospital, 840 S. Wood St., Chicago, IL 60612 Telephone: 312-996-5326 WESTERN REGION: Alaska, Utah, Idaho, Arizona, California, Montana, Nevada, Colorado, Hawaii, New Mexico, Oregon, Washington, Wyoming Principal Investigator: Richard Koch, MD Project Coordinator: Cindy Bauman, MPH Maternal PKU Collaborative Study, Children's Hospital of Los Angeles, 4650 Sunset Blvd., Los Angeles, CA 90027 Telephone: 213-669-2152
CANADA
Principal Investigator William B. Hanley, MD Project Coordinator: Wanda Schoonheyt, RN
The Hospital for Sick Children, 555 University Ave., Toronto, Ontario, Canada M5G 1X8 Telephone: 416-597-1500
J. Inher. Metab. Dis. 13 (1990)
~igure I
.EGEND:
PARTICIPATING CLINICS I
,"
//Liil
Untv. of Texas Medical Branch Galveston, TX
B, Rouse
SOUTHEAST
H. Shlfrtn
Advisory
I~
Administ ~,dministrative
CLINICS
m
WESTERN
....
It::i
I PARTICIPATING CLINICS
Los Angeles, CA
R. Koch Chiidrena Hospital of Los Angeles
B, Rouse W. Hanley F. dela Cruz
R. Koch It, Levy R, Matalon
)OLICY COMMITTEE
F. dela Cruz H. Shifrin
)ARTICIPATING ~ARTICIPATINGcLINICS I PARTICI
Iliil .................
R. Matalon Univ. of Illinois Medical Center Chicago, IL
MIDWEST
R. Koch ~hlldrens Hospital of Los Angeles Staff/Consultants
;OORDINATING CENTER
)rganization of the Maternal PKU Collaborative Study
~ARTICIPATING CLINICS
H, Levy The Children's Hospital Boston, MA
L
I
W.B, Henley Hospital for ~ick Children "oronto, ONT.
I
I
NORTHEAST
I
I
m
_=~-
Project Officer: Contracting Officer:
qATIONALINSTITUTE CHILD HEALTH& HUMANDEVELOPMENT
CANADA
Medicine Bloat atistlcs Nutrition Analysis Fetal Pathology Epldemiology
COORDINATING~ CONSULTANTS
Nutrition
~,DVISORYPERSONNEL
VIATERNAL PKU COLLABORATIVE STUDY ORGANIZATION AND ADMINISTRATION STRUCTURE
%
645
Maternal P K U in North America
located in different geographic regions across the continent. The purpose of this report is to provide a preliminary summary of the data collected as of January 1989. THE SAMPLE
Approximately 1500 women with hyperphenylalaninaemia have been identified by the project (Table 4). They range in age from 12 to over 35 years, but the majority are in the peak reproductive years of 18 to 30 years of age. An additional 206 are actively enrolled in the study at various participating clinics (Table 5). Fifty-nine percent were identified by newborn screening and are within the normal range of intelligence. Another 20% were identified by family screening and 13% by abnormal phenotype. Forty-eight percent of the pregnant women with hyperphenylalaninaemia were between 21 and 25 years of age at the time of conception; 36% were from 15 to 20 years of age at conception; and 16% were between 26 and 35 years of age. By 31 January 1989, 147 pregnancies had been followed, of which 20 were currently ongoing. Unfortunately, 80% of the pregnant women with hyperphenylalaninaemia in the study were enrolled with significantly elevated blood phenylalanine concentrations due to an unrestricted diet around the time of conception. Thus, only 20% of the pregnancies studied were planned with average blood phenylalanine concentrations within or close to the recommended therapeutic range of 120-360 ~mol/L (2-6 mg/dl). Table 4 Hyperphenylalaninaemic individuals identified in the United States and Canada a
Age (yrs)
Female
Male
Total
12-14 15-17 18-20 21-25 26-30 31-35 > 35 Unknown
223 309 269 324 199 88 66 22
155 160 148 140 84 32 26 4
378 469 417 464 283 120 92 26
1500
749
2249
Subtotal aExcludes enrollees
Table 5 Present age of 206 enrolled hyperphenylalaninaemic females
Age (yrs)
Number
Percentage
15-17 18-20 21-25 26-30 31-35 > 35
6 44 99 43 13 1
3 21 48 21 6
