British Journal of Obstetrics and Gynaecology July 1991, Vol. 98, pp. 648-655
ADONIS 030654569100169Y
Placental bed spiral arteries in the hypertensive disorders of pregnancy ROBERT PIJNENBORG, JOHN ANTHONY, DENNIS A. DAVEY, ALEXANDRA REES, ANDREW TILTMAN, LISBETH VERCRUYSSE, ANDRE VAN ASSCHE Abstract Objective-The investigation of the histology of the placental bed spiral arteries in normal pregnancy and in pregnancies complicated by hypertension, with or without proteinura. Design-An observational study, bascd on women having caesarean sections for clinical reasons. Subjects-17 normal pregnant women, 43 with gestational hypertension, of whom 39 had proteinuria, 17 with chronic hypertension, of whom 6 had proteinuria, and 5 with unclassified hypertension. Interventions-Placental bed biopsies obtained during caesarean section. Main outcome measures-Histological appearance of sections stained with haematoxylin and eosin PAS and Lendrum’s MSB. Results-Biopsies containing spiral arteries were obtained from 6 normotensive and 44 hypertensive women. Trophoblastic invasion was prescnt in 5 of the 6 normotensive biopsies but absent in the majority of those with hypertension. Subintimal proliferation was seen in all the normotcnsive biopsies but in only 8 of 28 from those with gestational hypertension and proteinuria. Other features seen predominantly or only in the hypertensivc biopsies, in order of frequency, were medial hyperplasia, fibrin deposits, acute atherosis, endothelial vacuolation and thrombosis. Conclusion-Absence of physiological changes may not be peculiar to preeclampsia but may be associated or even a result of various forms of hypertension in pregnancy. Spiral arteries show a spectrum of changes in hypertensive prcgnancies that do not appear to bear a clear-cut relation to the clinical signs.
Hypertensive disorders are a major complication of pregnancy and lcsions of the spiral arteries play a key role in the pathophysiology of these disorders but the precise relation between
the histopathological changes in the placental bed and the different hypertensive disorders remains to be established. Until recently there was no agreed classification of the hypertensive
University of Cape Town, South Africa, Department of Obstetrics and Gynaecdogy J. ANTHONY D. A. DAVEY A. REES
University of Leuven, Belgium, Department of Obstetrics and Gynaecdogy R. PIJNENBORG L. VERCRUYSSE A. VAN ASSCHE
Department of Patholqy A. TILTMAN
Correspondence: Dr R. Pijncnborg, Department of Obstctrin and Gynaecology, UZ Gasthuisberg, University of Leuven. Bclgium
648
Placental bed spiral arteries disorders of pregnancy mainly due to the lack of knowledge of the nature of the underlying disease. Davey & MacGillivray (1988) introduced a new classification which groups patients with hypertension andor proteinuria in pregnancy in clearly defined clinical categories. In this study we have attempted to relate the changes in the spiral arteries to the clinical condition of the patients. The conversion of spiral arteries into uteroplacental arteries depends upon two waves of endovascular invasion by trophoblast in the first two trimesters of pregnancy. At term the trophoblastic cells are characteristically buried in the vessel walls and wrapped in fibrinoid material (Brosens el al. 1967; De Wolf et al. 1980; Pijnenborg et al. 1983). These changes are an essential part of placentation and the establishment of an adequate choriodecidual blood flow in normal pregnancy. In pre-eclampsia the second wave of trophoblastic invasion into the myometrial segments of the spiral arteries is believed to be inhibited and the normal physiological changes are absent (Brosens et al. 1972). The failure of the trophoblast invasion in the spiral arteries and the absence of the physiological changes has been regarded as responsible for the pathological changes in the placenta (Fox 1978) and the reduced uteroplacental blood flow in ‘pre-eclampsia’ (Browne & Veal1 1953; McParland & Pearce 1988). However, a similar absence of physiological changes has been described in the spiral arteries of women with fetuses that were small for gestational age, both with and without ‘pre-eclampsia’ (Sheppard & Bonnar 1976; 1981; Brosens etal. 1977;Khong et al. 1986). In the other hypertensive disorders of pregnancy the changes in the spiral arteries have been less well studied, although there have been reports of a small number of different hypertensive patients (Robertson et al. 1975; Brosens 1977; Sheppard & Bonnar 1981; Hustin et al. 1983; Khong et al. 1986; Frusca et al. 1989). Investigators have, however, used different terminology and classifications and have not adequately defined the clinical condition of the different patients from whom placental bed biopsies were obtained. The publication of the clinical classification developed by Davey & MacGillivray (1988) has presented a fresh opportunity to assess the placental bed changes and to relate to the clinical condition of the patient.
649
Subjects and methods The study population consisted of women attending the Groote Schuur Hospital, Cape Town for antenatal and intrapartum care who were delivered by elective caesarean section. The women were recruited after informed consent was obtained. Two groups were studied (a) patients with non-proteinuric and proteinuric hypertension and (b) normotensive patients who acted as controls. Patients with underlying disorders were excluded. No attempt was made to match the patients in the hypertensive and control groups. Each of the patients was classified according to the criteria of Davey & MacGillivray (1988). Urinary protein estimations, platelet counts and renal function tests were performed on all the hypertensive patients.
Placental bed biopsy technique A standardized technique for placental bed biopsies was used by all the surgeons. Immediately after the birth of the fetus the centre of the placenta was identified by inserting a hand into the uterus and palpating the placental site. The uterus was then delivcred into the wound and, with the hand as a guide, a 22 gauge needle was inserted from the serosal surface through the uterus into the centre of the placental bed. The protruding end of the needle was identified and the accessibility of the placental bed assessed by the surgeon. In patients with an accessible placental bed, a second 22 gauge needle was inserted from the decidual surface into the uterus alongside the first marking needle which was then removed. Using a sharp scalpel a cone of decidual and myometrial tissues was excised around the second needle approximately 1-2 cm diameter and 1cm deep. If necessary a pair of scissors was used to undercut the base of the cone and the freed specimen was placed in buffered formalin. The needle was left in thc biopsy specimen to facilitate orientation and handling by the pathologist. The placental bed biopsy site was inspected for bleeding and if necessary a figure of eight suture inserted to secure haemostasis.
Histological techniques and assessment After initial fixation the specimens were cut into thin slices of about 1mm thickness in a direction perpendicular to the placental floor. After further fixation and embedding in paraffin wax, step-serial sectioning and staining of the speci-
650
R. Pijnenborg et al.
mens (haematoxylin and eosin, PAS, and Lendrum's MSB) was performed using standard Table 1. Clinical classification of disorders of pregnancy
hypertensive
A. Gestational hypertension and/or proteinuria Hypcrtension and/or proteinuria developing during pregnancy, labour, or the puerperium in a previously normotcnsivc nonproteinuric woman subdividcd into 1, Gestational hypcrtcnsion (without protcinuria) a. Developing antepartum b. Developing intrapartum c. Developing postpartum 2. Gestational proteinura (without hypertension) a. Devcloping anteparturn b. Developing intrapartum c. Developing postparturn 3. Gestational proteinuric hypertension (preeclampsia) a. Developing antepartum b. Developing intrapartum c. Developing postpartum
B. Chronic hypertension and chronic renal disease Hypertension andor proteinuria in pregnancy in a woman with chronic hypertension or chronic renal disease diagnosed before, during, or aftcr pregnancy subdivided into 1. Chronic hypertension (without proteinuria) 2. Chronic renal disease (proteinuria with or without hypertension) 3. Chronic hypcrtcnsion with superimposed preeclampsia (protcinuria dcveloping during pregnancy in known chronic hypertension) C. Unclassificd hypertension and/or proteinuria Hypertension and/or protcinuria found either (a) At first examination after 20 weeks (140 days) in a woman without known chronic hypertension or chronic renal disease or (b) during pregnancy, labour, or the puerperium where information is insufficient to permit classification and subdivided into 1. Unclassified hypertension (without proteinuria) 2. Unclassificd proteinuria (without hypertension) 3. Unclassified proteinuric hypcrtcnsion D. Eclampsia The Occurrence of generalized convulsions during pregnancy, during labour, or within 7 days of dclivcry and not caused by epilepsy or othcr convulsive disorders.
histological techniques. Biopsies of the placental bed were considered adequate when interstitial trophoblastic giant cells and at least one spiral artery were present. Biopsies from the marginal areas of the placental bed, as indicated by accumulated glands in the decidua, were regarded as unrepresentative and inadequate, even if trophoblastic giant cells were present. Attention was concentrated on the myometrial portion of the placental bed as the most important changes occur at this site and decidual tissue was often limited.
Results General observations
The clinical classification, demographic characteristics and perinatal outcome of the patients are set out in Tables 1, 2 and 3. Biopsies were obtained from 65 hypertensive patients of which 44 (68%) were adequate and 17 from normotensive patients of which 6 (35%) were adequate (Table 4). The number of spiral arteries found was 1in 20,2 in 22 and 3 in 8 biopsies. The occurrence and degree of the trophoblastic invasion and of the physiological changcs of the spiral arteries was carefully assessed The presence of perivascular trophoblastic cclls (interstitial trophoblastic giant cells in the direct vicinity of the arteries) was also recorded. The Occurrence and degree of thc physiological changes was confirmed using PAS and Lendrum's MSB staining to reveal fibrinoid material more clearly (Fig. 1). Physiological changes may be present in the whole circumference or may be restricted to one sector of a vessel. Sometimes only a few isolated trophoblastic cells can be seen (Fig. 2). Vessels where physiological changes were restricted to lcss than 50% of the circumference were referred to as arteries with partial physiological changes. Cushions of fibrous tissue were often found in the intima and, notably, in arteries with only partial physiological changes, the cushions were invariably found in the intima overlying the fibrinoid material and the trophoblastic cells buried in the vessel wall. In the absence of trophoblast and physiological changes any abcrrations from normal histology were carefully noted. One such feature was the occurrence of endothelial vacuolation in a number of biopsies. Furthermore, apart from intimal thickening, the media often showed disorganization and sometimes a marked hyper-
Table 2. Demographic data Classification N
GH
GPH
CH
CH+GPH
UH
UPH
39
11
6
34 (28-37)
29 (2635)
35
28 (21-35)
2 (1-3)
3
2 (0-5)
~
Numbcr of patients Age ycars Modc (Range) Parity Mode (Range)
17
4
28 (19-36)
33 (22-39)
20 (1645)
2 (0-7)
3 (14)
0
1
(0-10)
(0-5)
1
4
Key: N = normotensive, GH = gestational hypertension, GPH = gestational proteinuric hypertension, CH = chronic hypertension, CH+GPH = chronic hypertension with superimposed gestational proteinuric hypcrtension, UH = unclassified hypertension, UPH = unclassified proteinuric hypertension.
plasia, leading to a narrowing or even a virtual obliteration of the arterial lumen (Fig. 3). Two other vasculopathies of the spiral arteries were encountered, namely, acute atherosis and arterial thrombosis. Acute atherosis, which is characterized by fibrinoid necrosis and infiltration of the media with foam cells and leucocytes (Robertson etal. 1967), only occurred in arteries in which trophoblastic invasion and physiological changes were absent (Fig. 4). Acute atherosis was, howcver, sometimes associated with
subintimal and medial hyperplasia. Arterial thrombosis was only found in two biopsies. Histological characterization of the spiral arteries The characteristic histological features of the rnyometrial segments of the spiral arteries in the different clinical categories are summarised in Tables 4,5 and 6. The number of biopsies in each category that show either partial or complete
Table 3. Clinical data at delivery and perinatal outcome Classification N Number of patients Diastolic blood pressure (mmHg) Proteinuria (mgn4 h) Serum uratc (mmolll) Serum creatinine (mmoV1) Platclct count Gestational age at delivery (wecks) Birthweight (8) Placental weight (9) No. of SGA babies*
GH
GPH
CH
CH+GPH
UH
UPH
11 92.7 (8.2) 0-34 (0.07) 70.3 (11.0) 273 (108)
6 105.0 (8.4) 2215 (1842) 0.34
1 110
0.28 (0.02) 74.7 (8.5) 240 (53)
39 103-0 (11.6) 5263 (4243) 0.41 (0.12) 78-5 (16.6) 234 (70)
4 97.5 (9.6) 7075 (3382) 0.37 (0.08) 88.0 (25.8) 248 (102)
34.2 (3.4) 2065 (913) 390 (179) 1
31.4 (3.0) 1503 (578) 340 (114) 22
34.6 (3.9) 2385 (893) 522 (155) 3
4 102.5 (17.1) -
0.24
(045)
73.5 (19.7) 289 (134)
70.0
32.0 (3.9) 1753 (764) 425 (112) 3
32
Results are expressed as means (SD). See Table 2 for key to abbreviations. * Small for gestational age:
ADONIS 030654569100169Y
Placental bed spiral arteries in the hypertensive disorders of pregnancy ROBERT PIJNENBORG, JOHN ANTHONY, DENNIS A. DAVEY, ALEXANDRA REES, ANDREW TILTMAN, LISBETH VERCRUYSSE, ANDRE VAN ASSCHE Abstract Objective-The investigation of the histology of the placental bed spiral arteries in normal pregnancy and in pregnancies complicated by hypertension, with or without proteinura. Design-An observational study, bascd on women having caesarean sections for clinical reasons. Subjects-17 normal pregnant women, 43 with gestational hypertension, of whom 39 had proteinuria, 17 with chronic hypertension, of whom 6 had proteinuria, and 5 with unclassified hypertension. Interventions-Placental bed biopsies obtained during caesarean section. Main outcome measures-Histological appearance of sections stained with haematoxylin and eosin PAS and Lendrum’s MSB. Results-Biopsies containing spiral arteries were obtained from 6 normotensive and 44 hypertensive women. Trophoblastic invasion was prescnt in 5 of the 6 normotensive biopsies but absent in the majority of those with hypertension. Subintimal proliferation was seen in all the normotcnsive biopsies but in only 8 of 28 from those with gestational hypertension and proteinuria. Other features seen predominantly or only in the hypertensivc biopsies, in order of frequency, were medial hyperplasia, fibrin deposits, acute atherosis, endothelial vacuolation and thrombosis. Conclusion-Absence of physiological changes may not be peculiar to preeclampsia but may be associated or even a result of various forms of hypertension in pregnancy. Spiral arteries show a spectrum of changes in hypertensive prcgnancies that do not appear to bear a clear-cut relation to the clinical signs.
Hypertensive disorders are a major complication of pregnancy and lcsions of the spiral arteries play a key role in the pathophysiology of these disorders but the precise relation between
the histopathological changes in the placental bed and the different hypertensive disorders remains to be established. Until recently there was no agreed classification of the hypertensive
University of Cape Town, South Africa, Department of Obstetrics and Gynaecdogy J. ANTHONY D. A. DAVEY A. REES
University of Leuven, Belgium, Department of Obstetrics and Gynaecdogy R. PIJNENBORG L. VERCRUYSSE A. VAN ASSCHE
Department of Patholqy A. TILTMAN
Correspondence: Dr R. Pijncnborg, Department of Obstctrin and Gynaecology, UZ Gasthuisberg, University of Leuven. Bclgium
648
Placental bed spiral arteries disorders of pregnancy mainly due to the lack of knowledge of the nature of the underlying disease. Davey & MacGillivray (1988) introduced a new classification which groups patients with hypertension andor proteinuria in pregnancy in clearly defined clinical categories. In this study we have attempted to relate the changes in the spiral arteries to the clinical condition of the patients. The conversion of spiral arteries into uteroplacental arteries depends upon two waves of endovascular invasion by trophoblast in the first two trimesters of pregnancy. At term the trophoblastic cells are characteristically buried in the vessel walls and wrapped in fibrinoid material (Brosens el al. 1967; De Wolf et al. 1980; Pijnenborg et al. 1983). These changes are an essential part of placentation and the establishment of an adequate choriodecidual blood flow in normal pregnancy. In pre-eclampsia the second wave of trophoblastic invasion into the myometrial segments of the spiral arteries is believed to be inhibited and the normal physiological changes are absent (Brosens et al. 1972). The failure of the trophoblast invasion in the spiral arteries and the absence of the physiological changes has been regarded as responsible for the pathological changes in the placenta (Fox 1978) and the reduced uteroplacental blood flow in ‘pre-eclampsia’ (Browne & Veal1 1953; McParland & Pearce 1988). However, a similar absence of physiological changes has been described in the spiral arteries of women with fetuses that were small for gestational age, both with and without ‘pre-eclampsia’ (Sheppard & Bonnar 1976; 1981; Brosens etal. 1977;Khong et al. 1986). In the other hypertensive disorders of pregnancy the changes in the spiral arteries have been less well studied, although there have been reports of a small number of different hypertensive patients (Robertson et al. 1975; Brosens 1977; Sheppard & Bonnar 1981; Hustin et al. 1983; Khong et al. 1986; Frusca et al. 1989). Investigators have, however, used different terminology and classifications and have not adequately defined the clinical condition of the different patients from whom placental bed biopsies were obtained. The publication of the clinical classification developed by Davey & MacGillivray (1988) has presented a fresh opportunity to assess the placental bed changes and to relate to the clinical condition of the patient.
649
Subjects and methods The study population consisted of women attending the Groote Schuur Hospital, Cape Town for antenatal and intrapartum care who were delivered by elective caesarean section. The women were recruited after informed consent was obtained. Two groups were studied (a) patients with non-proteinuric and proteinuric hypertension and (b) normotensive patients who acted as controls. Patients with underlying disorders were excluded. No attempt was made to match the patients in the hypertensive and control groups. Each of the patients was classified according to the criteria of Davey & MacGillivray (1988). Urinary protein estimations, platelet counts and renal function tests were performed on all the hypertensive patients.
Placental bed biopsy technique A standardized technique for placental bed biopsies was used by all the surgeons. Immediately after the birth of the fetus the centre of the placenta was identified by inserting a hand into the uterus and palpating the placental site. The uterus was then delivcred into the wound and, with the hand as a guide, a 22 gauge needle was inserted from the serosal surface through the uterus into the centre of the placental bed. The protruding end of the needle was identified and the accessibility of the placental bed assessed by the surgeon. In patients with an accessible placental bed, a second 22 gauge needle was inserted from the decidual surface into the uterus alongside the first marking needle which was then removed. Using a sharp scalpel a cone of decidual and myometrial tissues was excised around the second needle approximately 1-2 cm diameter and 1cm deep. If necessary a pair of scissors was used to undercut the base of the cone and the freed specimen was placed in buffered formalin. The needle was left in thc biopsy specimen to facilitate orientation and handling by the pathologist. The placental bed biopsy site was inspected for bleeding and if necessary a figure of eight suture inserted to secure haemostasis.
Histological techniques and assessment After initial fixation the specimens were cut into thin slices of about 1mm thickness in a direction perpendicular to the placental floor. After further fixation and embedding in paraffin wax, step-serial sectioning and staining of the speci-
650
R. Pijnenborg et al.
mens (haematoxylin and eosin, PAS, and Lendrum's MSB) was performed using standard Table 1. Clinical classification of disorders of pregnancy
hypertensive
A. Gestational hypertension and/or proteinuria Hypcrtension and/or proteinuria developing during pregnancy, labour, or the puerperium in a previously normotcnsivc nonproteinuric woman subdividcd into 1, Gestational hypcrtcnsion (without protcinuria) a. Developing antepartum b. Developing intrapartum c. Developing postpartum 2. Gestational proteinura (without hypertension) a. Devcloping anteparturn b. Developing intrapartum c. Developing postparturn 3. Gestational proteinuric hypertension (preeclampsia) a. Developing antepartum b. Developing intrapartum c. Developing postpartum
B. Chronic hypertension and chronic renal disease Hypertension andor proteinuria in pregnancy in a woman with chronic hypertension or chronic renal disease diagnosed before, during, or aftcr pregnancy subdivided into 1. Chronic hypertension (without proteinuria) 2. Chronic renal disease (proteinuria with or without hypertension) 3. Chronic hypcrtcnsion with superimposed preeclampsia (protcinuria dcveloping during pregnancy in known chronic hypertension) C. Unclassificd hypertension and/or proteinuria Hypertension and/or protcinuria found either (a) At first examination after 20 weeks (140 days) in a woman without known chronic hypertension or chronic renal disease or (b) during pregnancy, labour, or the puerperium where information is insufficient to permit classification and subdivided into 1. Unclassified hypertension (without proteinuria) 2. Unclassificd proteinuria (without hypertension) 3. Unclassified proteinuric hypcrtcnsion D. Eclampsia The Occurrence of generalized convulsions during pregnancy, during labour, or within 7 days of dclivcry and not caused by epilepsy or othcr convulsive disorders.
histological techniques. Biopsies of the placental bed were considered adequate when interstitial trophoblastic giant cells and at least one spiral artery were present. Biopsies from the marginal areas of the placental bed, as indicated by accumulated glands in the decidua, were regarded as unrepresentative and inadequate, even if trophoblastic giant cells were present. Attention was concentrated on the myometrial portion of the placental bed as the most important changes occur at this site and decidual tissue was often limited.
Results General observations
The clinical classification, demographic characteristics and perinatal outcome of the patients are set out in Tables 1, 2 and 3. Biopsies were obtained from 65 hypertensive patients of which 44 (68%) were adequate and 17 from normotensive patients of which 6 (35%) were adequate (Table 4). The number of spiral arteries found was 1in 20,2 in 22 and 3 in 8 biopsies. The occurrence and degree of the trophoblastic invasion and of the physiological changcs of the spiral arteries was carefully assessed The presence of perivascular trophoblastic cclls (interstitial trophoblastic giant cells in the direct vicinity of the arteries) was also recorded. The Occurrence and degree of thc physiological changes was confirmed using PAS and Lendrum's MSB staining to reveal fibrinoid material more clearly (Fig. 1). Physiological changes may be present in the whole circumference or may be restricted to one sector of a vessel. Sometimes only a few isolated trophoblastic cells can be seen (Fig. 2). Vessels where physiological changes were restricted to lcss than 50% of the circumference were referred to as arteries with partial physiological changes. Cushions of fibrous tissue were often found in the intima and, notably, in arteries with only partial physiological changes, the cushions were invariably found in the intima overlying the fibrinoid material and the trophoblastic cells buried in the vessel wall. In the absence of trophoblast and physiological changes any abcrrations from normal histology were carefully noted. One such feature was the occurrence of endothelial vacuolation in a number of biopsies. Furthermore, apart from intimal thickening, the media often showed disorganization and sometimes a marked hyper-
Table 2. Demographic data Classification N
GH
GPH
CH
CH+GPH
UH
UPH
39
11
6
34 (28-37)
29 (2635)
35
28 (21-35)
2 (1-3)
3
2 (0-5)
~
Numbcr of patients Age ycars Modc (Range) Parity Mode (Range)
17
4
28 (19-36)
33 (22-39)
20 (1645)
2 (0-7)
3 (14)
0
1
(0-10)
(0-5)
1
4
Key: N = normotensive, GH = gestational hypertension, GPH = gestational proteinuric hypertension, CH = chronic hypertension, CH+GPH = chronic hypertension with superimposed gestational proteinuric hypcrtension, UH = unclassified hypertension, UPH = unclassified proteinuric hypertension.
plasia, leading to a narrowing or even a virtual obliteration of the arterial lumen (Fig. 3). Two other vasculopathies of the spiral arteries were encountered, namely, acute atherosis and arterial thrombosis. Acute atherosis, which is characterized by fibrinoid necrosis and infiltration of the media with foam cells and leucocytes (Robertson etal. 1967), only occurred in arteries in which trophoblastic invasion and physiological changes were absent (Fig. 4). Acute atherosis was, howcver, sometimes associated with
subintimal and medial hyperplasia. Arterial thrombosis was only found in two biopsies. Histological characterization of the spiral arteries The characteristic histological features of the rnyometrial segments of the spiral arteries in the different clinical categories are summarised in Tables 4,5 and 6. The number of biopsies in each category that show either partial or complete
Table 3. Clinical data at delivery and perinatal outcome Classification N Number of patients Diastolic blood pressure (mmHg) Proteinuria (mgn4 h) Serum uratc (mmolll) Serum creatinine (mmoV1) Platclct count Gestational age at delivery (wecks) Birthweight (8) Placental weight (9) No. of SGA babies*
GH
GPH
CH
CH+GPH
UH
UPH
11 92.7 (8.2) 0-34 (0.07) 70.3 (11.0) 273 (108)
6 105.0 (8.4) 2215 (1842) 0.34
1 110
0.28 (0.02) 74.7 (8.5) 240 (53)
39 103-0 (11.6) 5263 (4243) 0.41 (0.12) 78-5 (16.6) 234 (70)
4 97.5 (9.6) 7075 (3382) 0.37 (0.08) 88.0 (25.8) 248 (102)
34.2 (3.4) 2065 (913) 390 (179) 1
31.4 (3.0) 1503 (578) 340 (114) 22
34.6 (3.9) 2385 (893) 522 (155) 3
4 102.5 (17.1) -
0.24
(045)
73.5 (19.7) 289 (134)
70.0
32.0 (3.9) 1753 (764) 425 (112) 3
32
Results are expressed as means (SD). See Table 2 for key to abbreviations. * Small for gestational age:
