Atrial natriuretic factor concentration in normal, growth-retarded, anemic, and hydropic fetuses

7
Volume 171, Number 3 Am J Obstet Gynecol 8. Ploton D, Menager M, ]eanneson P, Himber G, Adnet]J. Improvement in the staining and in the visualization of the argyrophilic proteins of the nucleolar organizer region at the optical level. Histochem] 1986;18:5-14. 9. Quinn CM, Wright NA. The usefulness of clinical measure- ments of cell proliferation in gynecological cancer. Int] Gynecol Pathol 1992;2:131-43. 10. Crocker], Maccartney]C, Smith PJ. Correlation between DNA flow cytometric and nucleolar organizer regions in non-Hodgkin's limphoma.] Pathol 1988;154:151-6. 11. Crocker], Skillbeck N. Nucleolar organizer region associ- ated proteins in melanotic lesions: a quantitative study. ] Clin Pathol 1987;40:885-9. 12. Tosi P, Cintorino M, Santopietro R, et al. Prognostic factors in invasive cervical carcinomas associated with human papillomavirus (HPV). Quantitative data and cyto- keratin expression. Pathol Res Pract 1992;188:866-73. 13. Dame JF, Polacarz SV, Sheridan E, Anderson D, Ginsberg R, Sharp F. Nucleolar organizer regions in adenocarci- noma in situ and invasive adenocarcinoma of the cervix. ] Clin Pathol 1990;43:657-60. 14. Armitage P. Statistical methods in medical research. New York: John Wiley, 1971. 15. Centers for Disease Control and Prevention. 1993 revised classification system for HIV infection and expanded sur- veillance case definition for AIDS among adolescents and adults. Morb Mortal Wkly Rep MMWR 1992;41:1-15. 16. Maiman M, Tarricone N, Vieira], SuarezJ, Serur E, Boyce ]. Colposcopic evaluation of human immunodeficiency virus-seropositive women. Obstet Gynecol 1991;78:84-8. Ville et al. 17. Maiman M, Fruchter R, Serur E, Levine PA, Arrastia CD, Sedlis A. Recurrent cervical intraepithelial neoplasia in human immunodeficiency virus-seropositive women. Ob- stet Gynecol 1993;82: 170-4. 18. Bleiweiss I], Heller D, Dottino P, Cass I, Deligdish L. IdentifYing human papillomavirus subtypes in cervical biopsies with in situ DNA hybridization with biotinylated probes. J Reprod Med 1992;37:151-6. 19. Carlson Jw, Twiggs LB. Clinical applications of molecular biologic screening for human papillomavirus: diagnostic techniques. Clin Obstet Gynecol 1992;35: 13-21. 20. Trere D, Cancellieri A, Perrone A, et al. Ag-NOR protein distribution correlates with patient survival in stage I endometrial adenocarcinoma. Virchows Arch A Pathol Anat Histopathol 1992;421 :203-7. 21. Thickett KM, Griffin NR, Griffiths AP, Wells M. A study of nucleolar organizer regions in cervical intraepithelial neo- plasia and human papillomavirus infection. Int] Gynecol Pathol 1989;8:331-9. 22. Husseinzadek N, Shbaro I, Wessler T. Predictive value of cone margin and post-cone endocervical curettage with residual disease in subsequent hysterectomy. Gynecol On- col 1989;33: 198-200. 23. Spinillo A, Tenti P, Zappatore R, De Seta F, Silini E, Guaschino S. Langerhans' cell counts and cervical in- traepithelial neoplasia in women with human immunode- ficiency virus infection. Gynecol Oncol 1993;48:210-3. 24. Forrest BD. Women, HIV, and mucosal immunity. Lancet 1991;337:835-7. Atrial natriuretic factor concentration in normal, growth-retarded, anemic, and hydropic fetuses Yves Ville, MD, Antony Proudler, PhD, Antony Abbas, MD, and Kypros Nicolaides, MD London, United Kingdom OBJECTIVE: Our purpose was to establish a reference range with gestation for plasma concentrations of atrial natriuretic factor in fetal blood and to examine whether the concentration is altered in fetal anemia, acidemia, or hydrops. STUDY DESIGN: Atrial natriuretic factor was measured in umbilical venous blood taken by cordocentesis from pregnancies complicated by red blood cell isoimmunization (n = 17), intrauterine growth retardation (n = 12), and hydrops fetalis (n = 20) and from controls (n = 66). Additionally, maternal blood atrial natriuretic factor concentration was measured in 40 uncomplicated pregnancies. RESULTS: In the control group detectable levels were found from 16 weeks onward, and the fetal plasma atrial natriuretic factor concentration did not change with gestation. In anemic, acidemic, and hydropic fetuses the concentration was higher than in controls. CONCLUSION: Fetuses are capable of producing atrial natriuretic factor under physiologic conditions, and the concentration is increased appropriately in pathologic states. (AM J OBSTET GYNECOL 1994;171 :777-83.) Key words: Fetal blood atrial natriuretic factor, cordocentesis, intrauterine growth retardation, red blood cell isoimmunization, hydrops fetalis From the Harris Birthright Research Centre for Fetal Medicine, King's College Hospital Medical School, and WYNN Institute for Metabolic Research. Reprint requests: Kypros H. Nicolaides, MD,. Department of Obstet- rics and Gynaecology, Harris Birthright Research Centre, King's College Hospital, London, England EE5. Received for publication August 4, 1993; revised September 30,1993; accepted March 11,1994. Copyright © 1994 by Mosby-Year Book, Inc. 0002-9378/94 $3.00 + 0 6/1/55806 777

Transcript of Atrial natriuretic factor concentration in normal, growth-retarded, anemic, and hydropic fetuses

Volume 171, Number 3 Am J Obstet Gynecol

8. Ploton D, Menager M, ]eanneson P, Himber G, Adnet]J. Improvement in the staining and in the visualization of the argyrophilic proteins of the nucleolar organizer region at the optical level. Histochem] 1986;18:5-14.

9. Quinn CM, Wright NA. The usefulness of clinical measure­ments of cell proliferation in gynecological cancer. Int] Gynecol Pathol 1992;2:131-43.

10. Crocker], Maccartney]C, Smith PJ. Correlation between DNA flow cytometric and nucleolar organizer regions in non-Hodgkin's limphoma.] Pathol 1988;154:151-6.

11. Crocker], Skillbeck N. Nucleolar organizer region associ­ated proteins in melanotic lesions: a quantitative study. ] Clin Pathol 1987;40:885-9.

12. Tosi P, Cintorino M, Santopietro R, et al. Prognostic factors in invasive cervical carcinomas associated with human papillomavirus (HPV). Quantitative data and cyto­keratin expression. Pathol Res Pract 1992;188:866-73.

13. Dame JF, Polacarz SV, Sheridan E, Anderson D, Ginsberg R, Sharp F. Nucleolar organizer regions in adenocarci­noma in situ and invasive adenocarcinoma of the cervix. ] Clin Pathol 1990;43:657-60.

14. Armitage P. Statistical methods in medical research. New York: John Wiley, 1971.

15. Centers for Disease Control and Prevention. 1993 revised classification system for HIV infection and expanded sur­veillance case definition for AIDS among adolescents and adults. Morb Mortal Wkly Rep MMWR 1992;41:1-15.

16. Maiman M, Tarricone N, Vieira], SuarezJ, Serur E, Boyce ]. Colposcopic evaluation of human immunodeficiency virus-seropositive women. Obstet Gynecol 1991;78:84-8.

Ville et al.

17. Maiman M, Fruchter R, Serur E, Levine PA, Arrastia CD, Sedlis A. Recurrent cervical intraepithelial neoplasia in human immunodeficiency virus-seropositive women. Ob­stet Gynecol 1993;82: 170-4.

18. Bleiweiss I], Heller D, Dottino P, Cass I, Deligdish L. IdentifYing human papillomavirus subtypes in cervical biopsies with in situ DNA hybridization with biotinylated probes. J Reprod Med 1992;37:151-6.

19. Carlson Jw, Twiggs LB. Clinical applications of molecular biologic screening for human papillomavirus: diagnostic techniques. Clin Obstet Gynecol 1992;35: 13-21.

20. Trere D, Cancellieri A, Perrone A, et al. Ag-NOR protein distribution correlates with patient survival in stage I endometrial adenocarcinoma. Virchows Arch A Pathol Anat Histopathol 1992;421 :203-7.

21. Thickett KM, Griffin NR, Griffiths AP, Wells M. A study of nucleolar organizer regions in cervical intraepithelial neo­plasia and human papillomavirus infection. Int] Gynecol Pathol 1989;8:331-9.

22. Husseinzadek N, Shbaro I, Wessler T. Predictive value of cone margin and post-cone endocervical curettage with residual disease in subsequent hysterectomy. Gynecol On­col 1989;33: 198-200.

23. Spinillo A, Tenti P, Zappatore R, De Seta F, Silini E, Guaschino S. Langerhans' cell counts and cervical in­traepithelial neoplasia in women with human immunode­ficiency virus infection. Gynecol Oncol 1993;48:210-3.

24. Forrest BD. Women, HIV, and mucosal immunity. Lancet 1991;337:835-7.

Atrial natriuretic factor concentration in normal, growth-retarded, anemic, and hydropic fetuses

Yves Ville, MD, Antony Proudler, PhD, Antony Abbas, MD, and Kypros Nicolaides, MD

London, United Kingdom

OBJECTIVE: Our purpose was to establish a reference range with gestation for plasma concentrations of atrial natriuretic factor in fetal blood and to examine whether the concentration is altered in fetal anemia, acidemia, or hydrops. STUDY DESIGN: Atrial natriuretic factor was measured in umbilical venous blood taken by cordocentesis from pregnancies complicated by red blood cell isoimmunization (n = 17), intrauterine growth retardation (n = 12), and hydrops fetalis (n = 20) and from controls (n = 66). Additionally, maternal blood atrial natriuretic factor concentration was measured in 40 uncomplicated pregnancies. RESULTS: In the control group detectable levels were found from 16 weeks onward, and the fetal plasma atrial natriuretic factor concentration did not change with gestation. In anemic, acidemic, and hydropic fetuses the concentration was higher than in controls. CONCLUSION: Fetuses are capable of producing atrial natriuretic factor under physiologic conditions, and the concentration is increased appropriately in pathologic states. (AM J OBSTET GYNECOL

1994;171 :777-83.)

Key words: Fetal blood atrial natriuretic factor, cordocentesis, intrauterine growth retardation, red blood cell isoimmunization, hydrops fetalis

From the Harris Birthright Research Centre for Fetal Medicine, King's College Hospital Medical School, and WYNN Institute for Metabolic Research.

Reprint requests: Kypros H. Nicolaides, MD,. Department of Obstet­rics and Gynaecology, Harris Birthright Research Centre, King's College Hospital, London, England EE5.

Received for publication August 4, 1993; revised September 30,1993; accepted March 11,1994.

Copyright © 1994 by Mosby-Year Book, Inc. 0002-9378/94 $3.00 + 0 6/1/55806

777

778 Ville et al.

In postnatal life atrial natriuretic factor (ANF), also known as atrial natriuretic peptide, is released from specific granules in atrial myocytes in response to atrial distention and hypervolemia. I ANF enhances diuresis and natriuresis and produces a decrease in plasma volume with a shift of fluids from the intravascular to the extravascular compartment, leading to hemocon­centration and hypotension. 2• 3

In fetal life ANF has been demonstrated in blood from late-second-trimester human fetuses, and in vitro studies have shown that ANF is produced by both auricles and ventricles. 2 , 4. 5 Fetal human and animal studies have shown that a rise in atrial pressure, related to expansion of blood volume, is associated with an increase in plasma ANF concentration.6 . s Furthermore, in fetal lambs the effects of systemic administration of exogenous ANF are similar to those in the adult. 2

The aim of this study was to establish a reference range with gestation for fetal plasma ANF concentra­tion and to examine possible changes in association with three situations where cardiovascular function and fluid homeostasis in the fetus are impaired: fetal ane­mia in red blood cell isoimmunization, acidemia in intrautrine growth retard31tion (lUGR), and presence of nonimmune hydrops fetalis.

Patients and methods

ANF was measured in fetal blood samples taken by cordocentesis in pregnancies complicated by red blood cell isoimmunization (n = 17), IUGR (n = 12), and nonimmune hydrops fetalis (n = 20). The values were compared with a reference range constructed from the study of 66 singleton pregnancies undergoing prenatal diagnosis at 16 to 40 (mean 25) weeks of gestation. Additonally, maternal plasma ANF levels were mea­sured in 40 women with uncomplicated singleton preg­nancies at 10 to 40 weeks' gestation.

Indications for cordocentesis in the control group were fetal karyotyping for minor defects such as choroid plexus cysts, prenatal diagnosis of blood disorders or infection such as hemophilia or toxoplasmosis, assess­ment of fetal platelets in maternal alloimmune throm­bocytopenia, and assessment of fetal hemoglobin in red blood cell isoimmunization. Criteria for inclusion in this study were (I) normal amniotic fluid volume as subjec­tively assessed by ultrasonography, (2) fetuses appropri­ately grown for gestation without chromosomal abnor­malities or major malformations, (3) blood hemoglobin concentration and pH within the appropriate reference range for gestation, and (4) absence of the blood disorder or infection under investigation and in the red blood cell isoimmunization group fetal Coombs' test negative.

Patients with red blood cell isoimmunization were referred for diagnosis and, if necessary, treatment of

September 1994 Am J Obstet Gynecol

fetal anemia by intravascular blood transfusion. For this study 17 fetuses (12 nonhydropic and five hydropic) that had not undergone previous transfusions were selected; cordocentesis was performed at 18 to 35 (mean 25) weeks' gestation.

Patients with pregnancies complicated by IUGR were referred to our unit for further assessment at 24 to 37 (mean 30) weeks' gestation. Ultrasonographic examina­tion had demonstrated that the fetal abdominal circum­ference was < 5th percentile for gestation and continu­ous-wave Doppler ultrasonographic studies (Doptek, Chichester, U.K.) were suggestive of placental insuffi­ciency with absent end-diastolic frequencies in the wave­form from an umbilical artery, In five cases there was anhydramnios, and in six cases the amniotic fluid vol­ume was reduced. In all cases included in this study the fetuses were chromosomally and anatomically normal and at delivery the infants had a birth weight < 5th percentile for gestation.

There were 20 pregnancies with nonimmune hydrops fetalis; in all cases ultrasonographic examination dem­onstrated the presence of effusion in at least two dis­tinct anatomic cavities or generalized edema. Fetal blood was obtained for karyotyping, infection screen including immunoglobulin M and deoxyribonucleic acid analysis for B 19 parvovirus infection, and measure­ment of blood gases and hematologic index values.

Gestation at cordocentesis was determined from the maternal menstrual history or an ultrasonographic scan performed in early pregnancy. Cordocentesis was car­ried out with a 20-gauge needle by a free-hand tech­nique without maternal sedation or fetal paralysis. Blood pH (Radiometer ABL 330, Copenhaen, Den­mark) and hematologic index values (Coulter Electron­ics, Luton, U.K.) were determined.

Fetal blood (I ml) was collected into heparinized syringes, centrifuged at 5000 revolutions/min for 10 minutes and the plasma was frozen at - 20° C until the sample was defrosted for the assay. ANF was meausred by radioimmunoassay on 50 fLI of unextracted plasma (Nichols Institute, Diagnostic B.Y, Wijchen, The Neth­erlands). All samples were analyzed in one batch, and the intraassay coefficient of variation was II %. The lower limit for detection by the assay was 10 pg/ml; values below this level were assigned 10 pg/ml.

Statistical analysis. Regression analysis was used to establish the reference range (mean and individual 90% confidence intervals) for fetal plasma ANF concentra­tion with gestation. Unpaired Student t test was applied to examine whether measurements in fetal blood from pregnancies complicated by red blood cell isoimmuni­zation, IUGR, and nonimmune hydrops fetalis differed significantly from the appropriate normal mean for gestation. Because pH and hemoglobin concentration change with gestation, individual values in the patho-

Volume 171 , Number 3 Am.J Obstet Gynecol

pg/I 1000

. · . · 100 ·

10 _.

1

· · I · . • . • · · 0 · .

. . . . . · . · • 0 o. 0

t . . · 0 ••

16 20 24 28 32 36 40

Gestation (wk)

pg/I 1000

100 ~. ·0· .

10

1

· . . 0 · • . · 0

. .. .. . . 0 .. .. . . . .

10 15 20 25 30 35 40

Gestation (wk)

Ville et al. 779

Fig. 1. Individual values and reference range (mean and individual 90% confidence intervals) offetal plasma ANF concentration with gestation in control pregnancies (left). Maternal levels are plotted on fetal reference range on right.

g/dl pg/l 18 10000

16

14 1000

12 · 0

10 . 100 o . •

8

6 00 10

4

2 8 0

0 1 16 20 24 28 32 36 40 16 20 24 28 32 36 40

Gestation (wk) Gestation (wk)

Fig. 2. Hemoglobin concentration (left) and plasma ANF levels (right) in hydropic (0) and nonhy­dropic (e) fetuses from red blood cell-isoimmunized pregnancies plotted on appropriate reference range (mean and individual 90% conftdence intervals) with gestation.

logic groups were expressed as the number of SDs by which the measurements differed from the appropriate normal mean for gestation (d values).

Results

In the control pregnancies the mean fetal plasma ANF concentration did not change significantly with gestation (Fig. 1, mean 108.7 pg/ml, range 10 to 526 pg/ml, SEM 15.4) and was significantly lower than mean maternal concentration (Fig. 1, mean 145.8 pg/ml, range 67 to 326 pg/ml, SEM 9.6, t = 4.43, P < 0.0001).

In the red blood cell isoimmunization group the mean ANF concentration was significantly higher and

the hemoglobin concentration significantly lower than the appropriate normal mean for gestation (Fig. 2, mean difference 0.841 SD, SEM 0.137, t = 6.14, P < 0.0001 and mean difference 6.239 SD, SEM 0.671, t = 9.30, P < 0.0001). There was no significant associa­tion between d values for ANF and hemoglobin con­centration (r = 0.39).

In all IVCR fetuses the abdominal circumference and the umbilical venous blood pH were < 5th percentile for gestation (Fig. 3). The mean plasma ANF concen­tration was significantly higher than in the control group (Fig. 4, mean difference 0.675 SD, SEM 0.298, t = 2.27), and there was a nonsignificant trend for an

780 Ville et al.

mm 400.-------------------.

300

200

100

O+--.--'--.---'--r-~ 16 20 24 28 32 36 40

Gestation (wk)

7.5

-7.4 f- -. . .: .-. 7.3 . . . . . 7.2

7.1

7.0 16 20 24 28 32 36 40

Gestation (wk)

Scptcmber 1994 Am J ObSlet Gynecol

Fig. 3. Abdominal circumference (left) and umbilical venous blood pH (right) in growth-retarded fetuses plotted on appropriate reference range (mean and individual 90% confidence intervals) with gestation .

pg/I 10000.------------------,

1000

100' . .

10+-------------L---~

1 +--,--,-----,--r~

16 20 24 28 32 36 40

Gestation (wk)

delta ANF (80s) 3.---------------------,

2

o

·1

·2 +-.--,-.--,-.--,-.~

·8 ·7 ·6 ·5 ·4 ·3 ·2 ·1 0

delta pH (80s)

Fig. 4. Plasma ANF concentration (left) in growth-retarded fe tuses plotted on appropriate reference range (mean and individual 90% confidence intervals) with gestation (left) . On right is relationship between M NF and ~pH .

mcrease m ANF with mcreasmg degrees of acidemia (Fig. 4, r = 0.55).

In the nonimmune hydrops fetalis group plasma ANF levels were significantly higher than in controls (Fig. 5, mean difference 1.164 SD, SEM 0.257, t = 4.53, P < 0.01). There were five cases of B19 par­vovirus infection, two cases of multiple pterygium syn­drome, one case of mucopolysaccharidosis, one cardiac defect, one recipient twin in a pregnancy with twin-to­twin transfusion syndrome, and in the 10 remaining cases no possible cause was identified . High levels of ANF were found in every case of B 19 parovovirus infection, in the recipient twin, in the case with muco­polysaccharidosis, and in four cases of unknown cause, including two that were anemic. There was no correla-

tion between the concentration of ANF and the degree or site of effusion or edema Cfable I) .

Comment

This study has demonstrated that ANF is detectable in the fe tal circulation from at least 16 weeks' gestation and the mean plasma concentration does not change with gestation. These findings are compatible with those of previous studies and suggest that in fetal life there is early maturation of ANF-secreting myocytes and, by implication, involvement of ANF in cardiovas­cular regulation.2 Although fetal cardiac output in­creases with gestation, parallel fetal heart growth may prevent atrial distention and increase in ANF secretion.

In our study maternal concentrations of ANF were

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Ville et al. 781

Table I. Data of 21 pregnancies complicated by nonimmune fetal hydrops including gestational age,

amniotic fluid volume, degree of ascites, skin edema, pleural effusion, pericardial effusion, cystic

hygroma, fetal plasma ANF concentration, ~ values for hemoglobin concentration and ANF, other

findings, and outcome

Gestational Amniotic Degree age fluid ot Skin Pleural Pericardial Cystic Other (wk) volume ascites edema effusion effusion hygroma MIemoglohin ANF LlANF findings Outcome

16 Oligohy- + ++ + + +++ -2.5 86 0.5 Multiple ptery- Termination of dramnios glUm syn- pregnancy,

drome 16 wk 18 Normal ++ + -3.5 278 1.5 Mucopoly- Interuterine

saccharidosis death, 23 wk 19 Normal ++ +++ + 0.7 290 1.5 Talipes, over- Termination of

lapping fin- pregnancy, gers, hyperte- 20wk lorism, narrow colon

19 Normal ++ ++ -8.4 1102 2.6 Parvovirus, Live birth, 37 wk blood trans-fusion

19 Normal + + +++ 0.4 81 0.5 Multiple ptery- Termination of gium syn- pregnancy, drome 19wk

20 Normal +++ + 0.7 605 2.1 Unexplained, Live birth, 37 wk spontaneous resolution af-ter 23 wk

20 Normal +++ + 1.7 99 0.6 Cardiac defect Termination of pregnancy, 21 wk

20 Normal +++ -8.0 979 2.5 Parvovirus, Spontaneous blood trans- abortion, 22 wk fusion

20 Normal +++ +++ +++ 1.0 54 0.1 Unexplained Neonatal death, 29 wk

22 Oligohy- ++ ++ ++ ++ -3.0 740 2.3 Parvovirus, Termination of dramnios ventriculo- pregnancy,

megaly 22 wk 24 Normal ++ ++ -3.0 1113 2.6 Hydrocephalus, Termination of

twin-twin trans- pregnancy, fusion syn- 24 wk drome

25 Polyhy- + +++ +++ -2.8 12 1.2 Unexplained, Neonatal death, dramnios one prevIOus 32 wk

hydrops 25 Normal ++ ++ -3.0 92 0.5 Unexplained Intrauterine

death, 26 wk 27 Polyhy- ++ +++ ++ ++ -2.3 355 1.7 Unexplained, Intrauterine

dramnios two previous death, 29 wk hydrops

31 Polyhy- + + ++ 1.3 49 0 Unexplained, Neonatal death, dramnios pulmonary 32 wk

hypoplasia 32 Normal ++ 5.1 315 1.6 Parvovirus, Live birth, 37 wk

rebound poly-cythemia

24 Oligohy- +++ +++ ++ + 0.65 26 0.5 Unexplained Intrauterine dramnios death, 27 wk

22 Normal +++ +++ -3.3 273 1.5 Parvovirus Live birth, 36 wk blood trans-fusion

21 Normal +++ ++ ++ -4.5 221 1.3 Unexplained Intrauterine death, 25 wk

higher than fetal levels. However, because we did not et al. IO measured ANF in umbilial cord blood at delivery

measure ANF III maternal-fetal paired samples, we and reported higher levels in the umbilical artery but

cannot draw conclusions as to the interrelationship of similar levels in the umbilical vein compared with ma-

the two compartments. Ervin et al.a reported that in ternal concentrations.

fetal lambs plasma ANF is higher than in adults. Yamaji In growth-retarded fetuses plasma ANF concentra-

782 Ville et al.

g/dl 20 .---------------------,

5

o~----_.--,_------~

16 20 24 28 32 36 40

Gestation (wk)

pg/l 10000.----------------,

1000 00

o. . . 100 0 00

10'+-----~~--------~

16 20 24 28 32 36 40

Gestation (wk)

Seplember 1994 Am J Obslel Gynecol

Fig. 5. Fetal hemoglobin (left) and plasma ANF concentrations (right) in hydropic fetuses plotted on appropriate reference range (mean and individual 90% confidence intervals) with gestation.

tions were increased. This has also been reported from studies of cord blood at delivery both in IUCR and in preeclampsia. I I. 12 These findings are compatible with asphyxial impairment of cellular metabolism; both in­creased vascular resistance in the placenta and hypoxic heart failure could lead to atrial distension or myocar­dial infarction and increased ANF secretion. Addition­ally, because the placenta is capable of degrading ANF,13 increased plasma ANF concentration may be the consequence of impaired placental function and clear­ance of ANF from the fetal circulation.

In IUCR there was a nonsignificant trend for in­creased ANF concentration with an increasing degree of acidemia. In sheep hypoxia elevates fetal levels of ANF.14 Furthermore, maternal injection of ANF in­creases blood flow in the placental vessels in growth­retarded, but not in normally grown, fetuses. 15 It is possible that the increase in ANF may represent an adaptive response by the fetuses to maximize fetopla­cental blood flow and oxygen transport under the stress of hypoxic conditions, and iatrogenic administration of ANF may find a therapeutic role in the management of IUCR.

In fetal hemolytic anemia there is a compensatory rise in cardiac output, presumably because of a de­crease in viscosity and an increase in venous return and cardiac filling. IG Atrial distention may explain the in­crease in plasma ANF concentration, which may cause shift of fluid from the intravascular to the extravascular compartment and contribute to the development of hydrops.

The increase in plasma AN F concentration in hydrops fetalis is compatible with the observation that in postna­tal life there is a fivefold elevation of ANF levels in adults who have edema with congestive heart failure, irrespec­tive of the primary condition. 17 In our cases the highest

levels of ANF were observed in the recipient of twin transfusion syndrome that was in severe congestive heart failure I" and in association with B19 parvovirus infection, where viral myocarditis may exacerbate anemic heart failure . 19 Elevated ANF concentration in hydrops result­ing from other mechanisms was a less constant feature unless it was associated with fetal anemia.

The findings of this study demonstrate that produc­tion of ANF matures early in human life. Furthermore, the data suggest that fetuses can increase plasma ANF concentration, which may have both beneficial and detrimental consequences.

REFERENCES I. Goetz KL. Physiology and pathophysiology of the atrial

peptides. Am J Physiol 1988;254:EI-15. 2. Smith FG, Sato T, Varille VA, Robillard E. Atrial natri­

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3. Almeida FA, Suzuki M, Maack T. Atrial natriuetric factor increases hematocrit and decreases plasma volume in nephrectomized rats. Life Sci 1986;39; 1193-9.

4. Cheung CY, Gibs OM, Brace RA. Atrial natriuretic factor in maternal and fetal sheep. Am J Physiol 1987;252:E279-82.

5. Kikuchi K, Nakao K, Hayashi K, et al. Ontogeny of atrial natriuretic peptide in human heart. Acta Endocrinol (Copen h) 1987; 115:211-7.

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7. Robillard J E, Weiner C. Atrial natriuretic factor in the human fetus: effect of volume expansion. J Pediatr 1988; 113:552-4.

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9. Ervin MG, Ross MG, Castro R, et al. Ovine fetal and adult natriuretic factor metabolism. Am J Physiol 1986;254: R40-6.

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10. Yamaji T, Hirai N, Ishibashi M, Takaku F, Yanaihara 'C Nakayama T. Atrial natriuretic peptide in umbilical cord blood: evidence for a circulating hormone in human fetus. .I Clin Endocrinol Metab 1986;63: 1414-7.

11. Kingdom JCP, McQueen .I, Connell JMC, Whittle MJ. Maternal and fetal atrial natriuretic peptide levels at delivery' from normal and growth retarded pregnancies. BrJ Obstet Gynaecol 1992;99:845-9.

12. Hatjis CG, Greelish JP, Kofinas AD, Stroud A, Hashimoto K, Rose JC. Atrial natriuretic factor maternal and fetal concentrations in severe preeclampsia. AM .I OBSTET GVNECOL 1989;61: 1015-9.

13. Inglish GC, Kingdom JCP, Nelson M, Lindop GB, Whittle MJ, ConnellJMC. Atrial natriuretic hormone: a paracrine or endocrine role within the human placenta? .I Clin EndocrinoI1993;76:1014-8.

14. Castro LC, Arora CP, Roll KE, Sassoon DA, Hobel C.J. Perinatal factors influencing atrial natriuretic peptide lev-

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els in umbilical arterial plasma at the time of delivery. AM .I OBSTET GVNECOI. 1989; 161 :623-7.

15. Jansson TB. Low-dose infusion of atrial natriuretic pep­tide in the conscious guinea pig increases blood flow to the placenta of growth-retarded fetuses. AM.J OBSTFT GYKECOI. 1992;66:213-8.

16. Nicolaides KH. Studies on fetal physiology and patho­physiology in rhesus disease. Semin Perinatol 1989;56:28-37.

17. Shinker Y, Sider RS, Ostagin EA. Plasma levels of immu­noreactive atrial natriuretic factor in healthy subjects and in patients with edema . .I Clin Invest 1985;76:1684-7.

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