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Elevated maternal serum human chorionic gonadotropin increases the chance of adverse pregnancy outcome
Letters 1359
Volume 169. Number 5 Am J Obstet Gynecol
in use in parts of Great Britain," becau se it requires that tho se who counsel couples withhold some information some of the time . Cultural differen ces in attitudes toward paternalism and reproductive choice probably explain d ifferent degrees of acce p tance of this strategy across the Atlan tic. If the se concern s share a theme, perhaps it is that th e provision of information is not nec essarily neutral and ben ign . The idea that providin g all available options in som e way insulates counselors, or prevents them from becoming moral participants in th ese de cisions, may not be su p port able.' If the line betwee n communicating op tions and making rec ommendati on s is indeed a false on e, then we may need to reconsider what options should be presented. At th e same time, those who are now accustomed to providing gene tic counseling in a nondirective way should recognize that as the availability of genetic screening tests increa ses, so will the settings in which these test s are used . Physicians and other health care prov iders may not be so accustomed to providing nondirective informati on . And in the new settings in which these exc ha nges may occur, patients may not be accustomed to provide rs who are un willing to make suggestions or in othe r ways lead the way. David A. Asch, MD, M BA, J ames P. Patton, M D, MBA, J ohn C. Hershey, PhD, and Michael T. Mennuti, MD Univ ersity of Penn sylvania, 36 /5 Chestnut St., Philadelphia, PA / 9104-2676
REFERENCES I. Asch DA, Patton JP, Hershey J C. Knowing for the sake of
knowing: the value of prognostic information. Med Decis Making 1990;10:47 -57. 2. Asch DA, Patton JP, Hershey J C. Prognostic information versus accuracy: once more with meaning. Med Decis Making 1991 ;1l :45-7. 3. Wald NJ. Couple screening for cystic fibrosis . Lancet 1991; 338:1318-9. 4. Clarke A. Is non-directive genetic counseling possible?
Lancet 1991;338:998-1001.
Elevated maternal serum human chorionic gonadotropin increases the chance of adverse pregnancy outcome To the Editors: Elevated seco nd -trimester maternal serum o-fetoprotein (AFP) levels ar e associated with increased risk for prematurity and lat e pregnancy complication s. I It has been hypothesized th at this association is caused by placental ano malies that allow increased diffusion of AFP from th e fetal blood into the mother's circulation. These abno rmalities also increase the risk of prematurity or pregnancy com plications. I The use of human cho rionic go na do tro pin (hCG) in multiple-mark er protocols for fetal Down syndrome scree ning is becoming wides pread. Increased levels of hCG, a pla cental protein , in the first tr imester are associate d with increased risk for spontan eous abortion and trophoblastic disease." We were con cerned whether elevated second-trimester hCG levels, not associated with a fetal chromosome abnormality, might predict an abno rmal pregnancy outcome. We report the results of a coho rt study addressing th is question.
We compared pregnancy outcome in 874 patients with normal AFP and hCG valu es, 268 patients with elevated hCG values and normal AFP values, and nine patien ts with elevated hCG and AFP. The con trol group was collected prospectively for an other study. Pre gnan cy outcome data were requested for all patients who re quested prenatal testing from Aug. 17, 1988, to Jan. 17, 1989. The group with elevated hCG included patients in the 1988 study gro up and patients from our Down syndro me screening program who se hCG multiple s of the median was > 2.00 . We had nine patients whose AFP and hCG levels were both elevated. The risk for specific adverse ou tcomes and the p valu e are listed in Table I. T he p value for the risks of prematurity and all adverse outcom es were calculated by X2 analysis. Fisher exact te st was used for all other outcome categories because of the small number of cases. The relative risk gives th e risk for a patient with hCG > 2.00 multiples of the median and normal AFP relat ive to a patient with normal hC G and AFP. Possible d iffer ences in groups were contro lled by stratified analyses. These an alyses showed th at race but not age affected th e average risk. Becau se hCG levels and the risk for adverse pregnancy outcom e are increased in black patients, th e number of black patients in th e study affect s th e calculated relative risk. This problem is addressed by using a weigh ted average of the relat ive risk for wh ite and black pati ents. The relative ri sks given are weighted by th e Mantel-Haenszel pr ocedure unl ess otherwise noted ." Fetal d efects associated with elevated hCG included neural tub e and vent ral wall defects, oligohydramnios, skin defects, and diaphragm ati c hernia. Pregnancy complications included hypertensi on , preeclampsia, eclampsia, and gestational diabetes. Our results agree with thos e of Goren et al.," who found an association with hyperten sion, fetal growth restriction, and prematurity. In addition, we found an increased risk of nonchromosom al fetal defects. Women with fetal abnormalities were excl ude d fro m their study. Beekhuis et al." found h igh levels of both AFP and hCG ar e associated with a high risk for adverse pregnan cy outcome but not for neur al tub e defects or Down syndrome. We found an increased risk of neural tub e and ven tra l wall defects and pregnan cy complications in the se cases . Alth ou gh the disparity be tween stud ies indicate the need for further investigati on , we believe th at elevated levels of maternal seru m hCG indicate an increased risk for pregnancy complication s, p rematurity, and fetal defe cts. These pregnancies sho uld be man aged accordingly. Nedra Whitehead, M S, Wendy MacMahon, BS, and Paul M . Fernhoff, MD Department of Pediatrics, Emory Genetics Laboratory, 27// Irvin Way, Suite 1//. Decatur, GA 30030
REFERENCES I. Katz V, Chescheir N, Cefalo R. Unexplained elevations of maternal serum a-fetoprotein. Obstet Gynecol SUTY 1990; 45:719-26 .
1360 Letters
November 1993 Am
J Obstet Gynecol
Table I. Adverse pregnancy outcome by hCG and AFP level Outcome
Prematurity Fetal defects (nonchromosomal) Pregnancy complications Spontaneous abortions and fetal death All adverse outcomes rorxr.
AFPand hCG elevated
Relative risk hCG elevated
Significance
0 4
10
17 7 15 4
4.54 3.28* 53.78* 1.52*
P < 0.0001 P = 0.0230 P < 0.0001 P = 0.5062
36 874
43 268
6 9
4.14
P < 0.0001
hCG normal
hCG elevated
17 8 1
I I
*r.;ot weighted. too few cases for stratification.
2. Dcutchman M. Advances in the diagnosis of first-trimester pregnancy problems. Am Fam Physician 1991;11(suppl 5):15-305. 3. Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. .I Natl Cancer Inst 1959;28:719-47. 1. Goren R. Perez R, David '.1, Dar H. The association hetween unexplained levels of second-trimester maternal serum hCG elevation and pregnancy complications. Obstet Gynecol 1992;80:83-6. 5. Beekhuis JR, Van Lith '.1M, De Wolf BTHM, Mantingh A. Increased maternal serum a-fetoprotein and human chorionic gonadotropin in compromised pregnancies other than for neural tube defects and Down syndrome. Prenat Diagn 1992;12:643-7.
Does tertiary center perinatal care lower mortality In Infants < 1500 gm? More data needed To the Editors: Advances in neonatology and regionalization of perinatal care have been credited by Copper et al. (Copper RI., Goldenberg RI., Creasy RK, et al. A multicenter study of preterm birth weight and gestational age-specific neonatal mortality. AM J OBS'I ET GV:-;ECOI. 1993; 168:78-84). for lowering neonatal mortality rates in tertiary care centers. Neonatal mortality rates for infants at < 29 weeks' gestation, compared with the rates during the 1960s and 1970s from the University of Colorado, led the overall decline. I. " In addition, black premature infants were found, as many others have found, to have lower neonatal mortality rates than white premature infants. Then the authors ignored their own finding. They failed to connect a decrease in mortality with an increase in the number of black premature infants. Their population included 46% black births compared with 7% in the more recent Colorado study." The racial difference would be much greater for infants < 29 weeks' gestation, because births weights < 1500 gm occur three times more frequently among blacks than among whites. AJthough the numbers of births in various birth weight categories and weight stratifications by weight were not included in the study. one can estimate that approximately 70% of the newborns < 1500 gm were black.' More recent neonatal mortality rates from the National Institute of Child Health and Human Development Neonatal Network, another tertiary care
study that supplied birth weights, reported 62% black infants of this weight in their study.' When birth weight-specific and race-weight data for the tiniest births are left out of a study, selection bias and the extent of the bias can escape scrutiny or only be surmised. Lack of this information can help perpetuate the "high-risk fallacy," the notion that tertiary care centers invariably receive for treatment a majority of the high-risk mothers and newborns in a given population just because the centers were set up to do so.' Birth weights of extremely small newborns at the edge of viability are indispensable in studies of neonatal mortality, such as this one, for another reason. Gestational age estimates, when available (how many were not available in this study), can be ajourney into science fiction. Obstetric estimates derived from menstrual history, the best estimate available,'; become progressively worse as they deviate from term births." Biologic variation is probably the source of the error. Neonatal gestational estimates that might assess the accuracy of the obstetric estimates are also worse with premature infants." Finally, racial differences in neonatal gestational-age estimates have yet to be worked out." Black mothers may have shorter periods of gestation. \0
Samuel Sepkountz, MD Department of Pediatrics, University of Oklahoma Health Sciences Center. 5300 N. Meridian, Oklahoma City. OK 73112
REFERENCES I. Lubchenco LO, Searles DT, Brazie .IV. Neonatal mortality rate: relationship to birth weight and gestational age. .I Pediatr 1972;84:814-22. 2. Koops BL, Morgan L], Battaglia Fe. Neonatal mortality risk in relation to birth weight and gestational age: update. .I Pediatr 1982;10 1:969-77. 3. National Center for Health Statistics. Vital statistics of the United States. Volume I: natality. Hyattsville, Maryland: Public Health Service, 1982-1987. 4. Hack '.1, Hobar JD, Malloy MH, Tyson .IE, Wright E, Wright L. Very low birth weight outcomes of the National Institute of Child Health and Human Development Nconatal Network. Pediatrics 1991;87:587-92. 5. Lumley J. Does this work? Pediatrics 1987;79: I040-4. 6. Fetal extrauterine survivability, Report of the Committee on Fetal Extrauterine Survivability to The New York State Task Force on Life and the Law. Albany, New York: State of New York. 1988.
Volume 169. Number 5 Am J Obstet Gynecol
in use in parts of Great Britain," becau se it requires that tho se who counsel couples withhold some information some of the time . Cultural differen ces in attitudes toward paternalism and reproductive choice probably explain d ifferent degrees of acce p tance of this strategy across the Atlan tic. If the se concern s share a theme, perhaps it is that th e provision of information is not nec essarily neutral and ben ign . The idea that providin g all available options in som e way insulates counselors, or prevents them from becoming moral participants in th ese de cisions, may not be su p port able.' If the line betwee n communicating op tions and making rec ommendati on s is indeed a false on e, then we may need to reconsider what options should be presented. At th e same time, those who are now accustomed to providing gene tic counseling in a nondirective way should recognize that as the availability of genetic screening tests increa ses, so will the settings in which these test s are used . Physicians and other health care prov iders may not be so accustomed to providing nondirective informati on . And in the new settings in which these exc ha nges may occur, patients may not be accustomed to provide rs who are un willing to make suggestions or in othe r ways lead the way. David A. Asch, MD, M BA, J ames P. Patton, M D, MBA, J ohn C. Hershey, PhD, and Michael T. Mennuti, MD Univ ersity of Penn sylvania, 36 /5 Chestnut St., Philadelphia, PA / 9104-2676
REFERENCES I. Asch DA, Patton JP, Hershey J C. Knowing for the sake of
knowing: the value of prognostic information. Med Decis Making 1990;10:47 -57. 2. Asch DA, Patton JP, Hershey J C. Prognostic information versus accuracy: once more with meaning. Med Decis Making 1991 ;1l :45-7. 3. Wald NJ. Couple screening for cystic fibrosis . Lancet 1991; 338:1318-9. 4. Clarke A. Is non-directive genetic counseling possible?
Lancet 1991;338:998-1001.
Elevated maternal serum human chorionic gonadotropin increases the chance of adverse pregnancy outcome To the Editors: Elevated seco nd -trimester maternal serum o-fetoprotein (AFP) levels ar e associated with increased risk for prematurity and lat e pregnancy complication s. I It has been hypothesized th at this association is caused by placental ano malies that allow increased diffusion of AFP from th e fetal blood into the mother's circulation. These abno rmalities also increase the risk of prematurity or pregnancy com plications. I The use of human cho rionic go na do tro pin (hCG) in multiple-mark er protocols for fetal Down syndrome scree ning is becoming wides pread. Increased levels of hCG, a pla cental protein , in the first tr imester are associate d with increased risk for spontan eous abortion and trophoblastic disease." We were con cerned whether elevated second-trimester hCG levels, not associated with a fetal chromosome abnormality, might predict an abno rmal pregnancy outcome. We report the results of a coho rt study addressing th is question.
We compared pregnancy outcome in 874 patients with normal AFP and hCG valu es, 268 patients with elevated hCG values and normal AFP values, and nine patien ts with elevated hCG and AFP. The con trol group was collected prospectively for an other study. Pre gnan cy outcome data were requested for all patients who re quested prenatal testing from Aug. 17, 1988, to Jan. 17, 1989. The group with elevated hCG included patients in the 1988 study gro up and patients from our Down syndro me screening program who se hCG multiple s of the median was > 2.00 . We had nine patients whose AFP and hCG levels were both elevated. The risk for specific adverse ou tcomes and the p valu e are listed in Table I. T he p value for the risks of prematurity and all adverse outcom es were calculated by X2 analysis. Fisher exact te st was used for all other outcome categories because of the small number of cases. The relative risk gives th e risk for a patient with hCG > 2.00 multiples of the median and normal AFP relat ive to a patient with normal hC G and AFP. Possible d iffer ences in groups were contro lled by stratified analyses. These an alyses showed th at race but not age affected th e average risk. Becau se hCG levels and the risk for adverse pregnancy outcom e are increased in black patients, th e number of black patients in th e study affect s th e calculated relative risk. This problem is addressed by using a weigh ted average of the relat ive risk for wh ite and black pati ents. The relative ri sks given are weighted by th e Mantel-Haenszel pr ocedure unl ess otherwise noted ." Fetal d efects associated with elevated hCG included neural tub e and vent ral wall defects, oligohydramnios, skin defects, and diaphragm ati c hernia. Pregnancy complications included hypertensi on , preeclampsia, eclampsia, and gestational diabetes. Our results agree with thos e of Goren et al.," who found an association with hyperten sion, fetal growth restriction, and prematurity. In addition, we found an increased risk of nonchromosom al fetal defects. Women with fetal abnormalities were excl ude d fro m their study. Beekhuis et al." found h igh levels of both AFP and hCG ar e associated with a high risk for adverse pregnan cy outcome but not for neur al tub e defects or Down syndrome. We found an increased risk of neural tub e and ven tra l wall defects and pregnan cy complications in the se cases . Alth ou gh the disparity be tween stud ies indicate the need for further investigati on , we believe th at elevated levels of maternal seru m hCG indicate an increased risk for pregnancy complication s, p rematurity, and fetal defe cts. These pregnancies sho uld be man aged accordingly. Nedra Whitehead, M S, Wendy MacMahon, BS, and Paul M . Fernhoff, MD Department of Pediatrics, Emory Genetics Laboratory, 27// Irvin Way, Suite 1//. Decatur, GA 30030
REFERENCES I. Katz V, Chescheir N, Cefalo R. Unexplained elevations of maternal serum a-fetoprotein. Obstet Gynecol SUTY 1990; 45:719-26 .
1360 Letters
November 1993 Am
J Obstet Gynecol
Table I. Adverse pregnancy outcome by hCG and AFP level Outcome
Prematurity Fetal defects (nonchromosomal) Pregnancy complications Spontaneous abortions and fetal death All adverse outcomes rorxr.
AFPand hCG elevated
Relative risk hCG elevated
Significance
0 4
10
17 7 15 4
4.54 3.28* 53.78* 1.52*
P < 0.0001 P = 0.0230 P < 0.0001 P = 0.5062
36 874
43 268
6 9
4.14
P < 0.0001
hCG normal
hCG elevated
17 8 1
I I
*r.;ot weighted. too few cases for stratification.
2. Dcutchman M. Advances in the diagnosis of first-trimester pregnancy problems. Am Fam Physician 1991;11(suppl 5):15-305. 3. Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. .I Natl Cancer Inst 1959;28:719-47. 1. Goren R. Perez R, David '.1, Dar H. The association hetween unexplained levels of second-trimester maternal serum hCG elevation and pregnancy complications. Obstet Gynecol 1992;80:83-6. 5. Beekhuis JR, Van Lith '.1M, De Wolf BTHM, Mantingh A. Increased maternal serum a-fetoprotein and human chorionic gonadotropin in compromised pregnancies other than for neural tube defects and Down syndrome. Prenat Diagn 1992;12:643-7.
Does tertiary center perinatal care lower mortality In Infants < 1500 gm? More data needed To the Editors: Advances in neonatology and regionalization of perinatal care have been credited by Copper et al. (Copper RI., Goldenberg RI., Creasy RK, et al. A multicenter study of preterm birth weight and gestational age-specific neonatal mortality. AM J OBS'I ET GV:-;ECOI. 1993; 168:78-84). for lowering neonatal mortality rates in tertiary care centers. Neonatal mortality rates for infants at < 29 weeks' gestation, compared with the rates during the 1960s and 1970s from the University of Colorado, led the overall decline. I. " In addition, black premature infants were found, as many others have found, to have lower neonatal mortality rates than white premature infants. Then the authors ignored their own finding. They failed to connect a decrease in mortality with an increase in the number of black premature infants. Their population included 46% black births compared with 7% in the more recent Colorado study." The racial difference would be much greater for infants < 29 weeks' gestation, because births weights < 1500 gm occur three times more frequently among blacks than among whites. AJthough the numbers of births in various birth weight categories and weight stratifications by weight were not included in the study. one can estimate that approximately 70% of the newborns < 1500 gm were black.' More recent neonatal mortality rates from the National Institute of Child Health and Human Development Neonatal Network, another tertiary care
study that supplied birth weights, reported 62% black infants of this weight in their study.' When birth weight-specific and race-weight data for the tiniest births are left out of a study, selection bias and the extent of the bias can escape scrutiny or only be surmised. Lack of this information can help perpetuate the "high-risk fallacy," the notion that tertiary care centers invariably receive for treatment a majority of the high-risk mothers and newborns in a given population just because the centers were set up to do so.' Birth weights of extremely small newborns at the edge of viability are indispensable in studies of neonatal mortality, such as this one, for another reason. Gestational age estimates, when available (how many were not available in this study), can be ajourney into science fiction. Obstetric estimates derived from menstrual history, the best estimate available,'; become progressively worse as they deviate from term births." Biologic variation is probably the source of the error. Neonatal gestational estimates that might assess the accuracy of the obstetric estimates are also worse with premature infants." Finally, racial differences in neonatal gestational-age estimates have yet to be worked out." Black mothers may have shorter periods of gestation. \0
Samuel Sepkountz, MD Department of Pediatrics, University of Oklahoma Health Sciences Center. 5300 N. Meridian, Oklahoma City. OK 73112
REFERENCES I. Lubchenco LO, Searles DT, Brazie .IV. Neonatal mortality rate: relationship to birth weight and gestational age. .I Pediatr 1972;84:814-22. 2. Koops BL, Morgan L], Battaglia Fe. Neonatal mortality risk in relation to birth weight and gestational age: update. .I Pediatr 1982;10 1:969-77. 3. National Center for Health Statistics. Vital statistics of the United States. Volume I: natality. Hyattsville, Maryland: Public Health Service, 1982-1987. 4. Hack '.1, Hobar JD, Malloy MH, Tyson .IE, Wright E, Wright L. Very low birth weight outcomes of the National Institute of Child Health and Human Development Nconatal Network. Pediatrics 1991;87:587-92. 5. Lumley J. Does this work? Pediatrics 1987;79: I040-4. 6. Fetal extrauterine survivability, Report of the Committee on Fetal Extrauterine Survivability to The New York State Task Force on Life and the Law. Albany, New York: State of New York. 1988.