Atrial natriuretic factor concentration in normal, growth-retarded, anemic, and hydropic fetuses
Transcript of Atrial natriuretic factor concentration in normal, growth-retarded, anemic, and hydropic fetuses
Volume 171, Number 3 Am J Obstet Gynecol
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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.
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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
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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
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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-
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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)
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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
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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)
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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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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)
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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.
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19. Porter HJ, Quantrill AM, Fleming KA. B 19 parvovirus infection of myocardial cells. Lancet 1988; 1 :535-6.
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