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The Epidemiology of Perinatal Mortality
Symposium on Recent Clinical Advances
The Epidemiology of Perinatal Mortality The Power of the Autopsy
Richard L. Naeye, MD.*
Deaths just before or after birth are often unexplained because in many hospitals only a small proportion of such deaths are investigated by autopsy and those that are investigated are not analyzed in enough detail to identify all the disease processes that may be present. In addition, in many institutions, placentas are sold or discarded without detailed examination and important socioeconomic, racial, ethnic, and nutritional information is not utilized in case analysis. One consequence of these deficiencies is that much of the perinatal disease data on death certificates is unreliable. 52 The value of good autopsies in understanding the mechanisms of perinatal death is demonstrated in recent analyses of 1044 consecutive perinatal autopsies at aNew York City hospital. lB • :17-44. 46 Patients Material was examined from 1044 consecutive autopsies on 361 stillborn and 683 newborn infants whose tissues were well preserved at Babies Hospital, New York City. lB. 37-44. 46 Gestational ages ranged from 20 to 44 weeks. None of the liveborn infants lived longer than 72 hours. Seven hundred and ninety-three of the mothers received their gestational care at Sloane Hospital, which is associated with Babies Hospital, while the other 251 infants mostly reached Babies Hospital via transport incubators from nearby institutions. Three hundred and seventy-one infants were classified as black, 480 white, and 193 Puerto Rican, according to the mother's self-identification. Income data were available on 608 of the ward cases and they were divided into subgroups by representation of their family incomes in percentage of poverty-line values recorded in tables developed by the United States Social Security Administration. 38 Taking 1966 as a base line, the Social Security index was corrected for earlier and later changes in the economy by means of the consumer price ':'Professor and Chairman, Department of Pathology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania Supported by U.S. Public Health Service Grant HE 11688-04, and Grant No. 698 from the Council for Tobacco Research.
Pediatric Clinics of North America- Vol. 19, No.2, May 1972
295
296
RICHARD
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index. At the poverty line the index allowed 75 cents a day per person for food in 1966.38 For the subproject dealing with sex ratios, 1007 consecutive additional stillborn and newborn autopsies were included from the Los Angeles County Hospital and 684 from the Chicago Lying-in Hospital. 40 The Effects of Poverty and Race on Prenatal Nutrition42 ,
43
Perinatal infant mortality rates in the United States are far higher than rates in a number of other economically developed nations. 21 Most of the excess United States mortality appears related to lower birth weights in poor and nonwhites, a reflection of either premature delivery or of antenatal growth retardation. 3 , 8, 19, 21, 49, 50 Both factors appeared to contribute to low birth weights in infants born to poor and nonwhite mothers at Babies Hospital, undernutrition being operative in growth retardation and antenatal bacterial infections a likely explanation for many of the premature labors. . In the analysis 449 infants were excluded from further consideration because of .fetal or maternal disorders which might have affected fetal growth. With these exclusions, body weight for infants from families with income below the poverty line was 13 to 17 per cent less than the mean value for infants from nonpoor families (Table 1). Body length and all organ weights were also smaller in the infants from poor families. In these latter infants, weights of thymus, spleen, liver and adrenal glands were disproportionately small, whereas brain weights were near those in infants of non poor mothers (Table 1). When matched for gestational age, neonates of poor mothers had less subcutaneous fat and a smaller cytoplasmic mass in individual cells of several organs than infants of nonpoor mothers (Fig. 1). There were almost no differences in body and organ growth between blacks, whites, and Puerto Ricans when the comparisons were between families of similar economic statuS. 42 • 4:1 Table 1. Weight and Length Data by Income* INCOME (PERCENTAGE OF POVERTY LINE)
<100%
100-149%
150-199%
98 ±9
104 ± 9'
104 ± 9"
102 ± 10'
Weight§ Body Brain Heart Liver Spleen Thymus Kidney Adrenal
94± 17 102 ± 17 91 ±24 88 ±24 83 ±44 74 ±36 92±35 84 ±39
110±21* 114 ± 28' 114 ± 55* 110 ± 32* 106 ± 52' 103 ± 50" 102 ± 34" 100 ± 37*
111 ± 111 ± 109 ± 106 ± 105 ± 111 ± 108 ± 108 ±
107 ± 21" 110 ± 25" 107 ± 29" 101 ± 32* 98 ± 51" 98 ± 48" 96±38 94 ± 45"
No. of cases
83
102
Length§ Body
25* 23* 28* 29' 51" 51* 37* 45*
Over 200%
79
§Values are given in mean ± SD. *P <0.05 comparing each of the nonpoor groups with the poor group. Group measurements are in per cent of published "normal" control values·'
205
297
EPIDEMIOLOGY OF PERINATAL MORTALITY
o
INFANTS OF NON POOR MOTHERS , [] INFANTS OF POOR MOTHERS
±42
100
90r--
I-
z w
SOr-±40
-22
u
5 a.
701-601--
50::
~T~H~IC~K~NE~S=S~--A~V=E~RA~G=E~---S=K~E~L~Er.=~~L--~L~I~VE~R~----~A~D~RE~N~A~L--~W~H~A~R~TO=N7.'S~
SUBC~ltNEOUS o'¥25Pp~E CELLS
~YJi~~ CYTOPLASM/CELL ~~r:EL CYTO~I~l.,ICELL CYTOPLASM/CELL CYTOPLASM/CELL
Figure 1. When matched for gestational age, neonates of poor mothers had less subcutaneous fat and a smaller cytoplasmic mass in individual cells of several organs than infants of mothers who were not poor.
If one considers organ structure in the infants of non poor mothers to be normal, organs were abnormal in the infants from poor families, the abnormalities being characteristic of undernutrition. 42 , 4:l These organ abnormalities are observed in a number of placental and uterine disorders that restrict the flow of nutrients to the growing fetus. 15. :l0, :1:1. 45 This growth pattern also has frequently been reported in both children and young animals with chronic postnatal undernutrition.:l 4,:35 In virtually all non-nutritional fetal growth disorders studied to date organs are small because they have a subnormal number of cells, while cell size is normal or increased. 45 Only when fetal undernutrition is severe is cell number reduced in various organs of the neonate. 33 • 45 Infants of poor mothers in the current study had a normal number of cells in several organs, indicating that as a group, their undernutrition was not severe. 42 . 4:3 The undernutrition in newborn infants of the poor might be related to abnormalities that restrict nutrient flow to the fetus or to inadequate maternal nutrition during pregnancy. Since cases with recognized uterine or placental abnormalities were specifically excluded from the analysis, maternal malnutrition provides the most likely explanation. Although lay opinion easily relates maternal diet to fetal nutrition, critical scientific data is surprisingly sparse. Several clinical studies designed to analyze the influence of maternal nutritional intake on fetal nutrition and growth are now under way in the United States.
Antenatal Bacterial Infections and Premature Deliverf8.
41
Another analysis of the 1044 Babies Hospital cases suggests that antenatal bacterial infections might be an important cause of prematurity
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ANTENATAL AND INTRAPARTUM INFECTIONS
60 50 en w en
a
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• 40 30
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Salary
100-149'1'.
Salary
150%
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Semiprivate
and
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WARD CASES
Figure 2. Anatomic evidences of antenatal infections were more common in the poor than in the non poor and more common in blacks than in whites and Puerto Ricans. The salary is related to the "poverty line," which allowed 75 cents per day per person for food in 1966. "Poor" refers to cases in which the family income was at or less than "poverty-line" v.alues.
and consequent perinatal deaths in poor urban whites and nonwhites in the United States. More than 45 per cent of the infants of the poorest families had congenital pneumonia or chorioamnionitis, most often the result of amniotic fluid infections (Fig. 2). The rate of infections in the poor was about double that in the most prosperous, and blacks had about double the rate encountered in whites and Puerto Ricans (Fig. 2).:18 Pathogenic bacteria, in moderate or large numbers, were demonstrated by culture in 351 of the 755 neonates from whom cultures were taken. Such pathogenic bacteria were recovered in 63 per cent of the neonates who had congenital pneumonia.38 , 41 Two thirds of the positive cultures contained common gram-negative organisms, the remainder being grampositive.:1 8 , 41 There were no positive correlations between congenital pneumonia and abnormalities in the neonate that are usually ascribed to hypoxia.:18 One or more late gestational maternal abnormalities were recorded in 95 per cent of the mothers whose infants had congenital pneumonia. 41 These abnormalities included: premature rupture of the membranes, pre delivery abnormal bleeding, fever, pyuria and leukocytosis. By contrast, one or more of these late gestational abnormalities were recorded in only 24 per cent of mothers whose neonates had no congenital pneumonia. All these maternal disorders were more common in blacks and Puerto Ricans than in whites, and more common in the poor than in the nonpoor, but there were no significant differences in their incidence between racial and economic groups when only cases associated with congenital pneumonia were considered. 41
299
EPIDEMIOLOGY OF PERINATAL MORTALITY
Maternal fever, leukocytosis, and pyuria were more common in culture-positive cases of congenital pneumonia than in those from whom no pathogenic bacteria were recovered (Table 2). Although bacterial cultures were not taken routinely, pathogenic bacteria were recovered from one or more sites in 180 of the mothers. Recovery of such bacteria from maternal reproductive and urinary tracts was significantly associq,ted with congenital pneumoniaY An even stronger association was found between congenital pneumonia and the recovery of pathogenic bacteria when the analysis was for the same predominant organism in a mother and her ofi'spring.41 The mean duration of labor for infants with congenital pneumonia was 9.2 ±7.5 hours and for those without pneumonia, 8.5 ±7.8 hours (P>.I). Many investigations of inflammation of the umbilical cord, placenta, and membranes have been published in recent years. 5 - 7, 10, 23, 27, a8, 47, 48, 5:l Some have attributed these disorders and their often associated antenatal aspiration pneumonia to bacterial infection, while others have related them to acidosis, hypoxia, or the irritant properties of meconium. Our data suggest that common bacteria are most often involved in the pathogenesis of these disorders, especially in the poor and in nonwhites. However, the nonbacterial origin of some cases of chorioamnionitis and pneumonia are suggested by the finding that 37 per cent of the congenital pneumonia cases showed no pathogenic organisms. A viral or mycoplasma etiology has not been excluded from these cases but it is noteworthy that common pathogenic bacteria were cultured from almost every neonate with pneumonia of apparent postnatal onset.41 By contrast, chorioamnionitis without associated congenital pneumonia seems mainly nonbacterial in origin, pathogenic bacteria being recovered from only 9 per cent of such cases. 41 Since bacterial-related congenital pneumonia is most common in neonates of nonwhite and poor white urban families, it might be asked if such infections are responsible for any significant proportion of their ex-
Table 2. Late Gestational Maternal Disorders and the Recovery of Pathogenic Bacteria from Their Neonates' Lungs CHORIOAMNIONITIS WITHOUT CONGENITAL PNEUMONIA
Culture Premature rupture of membranes Fever Leukocytosis Pyuria Abnormal bleeding All cases
25 25 43 25 33 89
+
(28%) (28%) (48%) (28%) (37%)
CONGENITAL PNEUMONIA
+
Culture-
Culture
9 4 12 4 23 53
0 0 3 (100%) 0 0 3
(17%) (8%),,' (24%)" (8%)'" (43%)
Culture -
8 3 8 3 16 29
(28%) (10%) (28%) (10%) (55%)
':'P <0.05 by comparison with congenital pneumonia, culture positive. Values in parentheses represent percent of total cases in each category. Organ culture data were complete in 441 infants born at Babies Hospital. This table includes information on the 174 infants who had congenital pneumonia and chorioamnionitis without pneumonia.
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cessive premature deliveries. There have been some reports that bacterial products have oxytocic activity, but the evidence is not strong for such a mechanism in human beings. 22 , 54 Certain corticosteroids have oxytocic activity, and plasma levels of such steroids are increased in a variety of experimental infectionsP' 29 In the Babies Hospital cases, adrenal glands were 19 per cent heavier in infected than in noninfected neonates of the same gestational age, owing to increased cytoplasm in individual cells of the gland's permanent zone in the infected infants.3s Liggins and others have given recent evidence that corticosteroids of fetal adrenal origin may play an important role in the initiation of labor.4, 26 Hyperfunction of permanent zone adrenal cells in the human fetus offers a possible mechanism by which bacterial infections may initiate labor.3s
Sex Ratios as a Clue to the Roles of Infection and Other Disorders in Perinatal Death40 Male infants born in the United States have an excessive risk of neonatal death in comparison to females.1. 17,20 In an analysis of2735 consecutive autopsies in newborn infants at Babies Hospital, Los Angeles County, and Chicago Lying-in Hospitals, the 0.95:1 male to female ratio (sex ratio) for all stillborn infants did not differ significantly from the 1.05: 1 ratio recorded for alllivebirths in the United States (Table 3).40. ;;1 By contrast, almost all the ratios for infants dying after birth were far greater than the stillbirth or all United States livebirth ratios (Table 3). In fact, the sex ratios for most disorders in liveborn infants were greater than ratios for the same disorders in stillborn infants, many of the differences being statistically significant (Table 3). An exception was the value for infants with congenital pneumonia (prenatal infection). dying soon after birth (1.15:1) which was much smaller than the ratio for comparable non-infected infants (1.56: 1) (P<.02). The sex ratio for liveborn whites who died soon after birth was significantly greater than the ratio for nonwhites, and the nonpoor had a significantly greater ratio than the poor (Table 4). When all liveborn infants with prenatal infections are excluded from the analysis, half or more of the differences in mean sex ratios between liveborn blacks and whites and between the poor and nonpoor disappear, raising the possibility that antenatal bacterial infections might make a significant contribution to the excessive perinatal death rates of urban blacks and poor whites in the United States. Other inferences can be drawn from the sex ratio study. Sex ratios in the stillborns were close to the 1.05: 1 ratio for all U.S.livebirths, suggesting that males and females were affected in proportion to their relative numbers in utero and that maternal rather than fetal factors were responsible for antenatal death. By contrast, the much higher sex ratios encountered in virtually all disorders of liveborn infants reflect a basic biologic disadvantage for males, not specifically related to any single disease process.
Cerebral Intraventricular Hemorrhagel8 Although cerebral intraventricular hemorrhage is a common cause of neonatal death in premature infants, its epidemiologic features have
301
EPIDEMIOLOGY OF PERINATAL MORTALITY
Table 3.
Ratios of Male to Female Infants STILLBORN
All cases Major congenital malformations Hyaline membrane disease Pulmonary hemorrhage Subarachnoid hemorrhage Subependymal hemorrhage Intraventricular hemorrhage Subdural hemorrhage Erythroblastosis fetalis Toxemia of pregnancy Diabetic mothers Prenatal infection Postnatal infection Noninfected Antenatal aspiration
0.95:1 (396:419) 0.57:1 (28:49) 1.07:1 1.04:1 0.71:1 1.50:1 0.88:1 0.67:1 0.95:1 0.91:1 0.98:1
(30:28) (27:26) (5:7) (18: 12) (7:8) (24:36) (53:56) (20:22) (95:97)
0.94: 1 (301 :322) 0.97: 1 (237:244)
LIVEBORN
1.45:1 1.36:1 1. 71: 1 1.55: 1 1.29: 1 1.50: 1 1.54: 1 1.67: 1 1.48: 1 1.81: 1 1.48: 1 1.15:1 1.58: 1 1.56: 1 1.04: 1
(1137:783) (171 :126) (466:273) (155:100) (269:208) (135:90) (237:154) (35:21) (59:40) (65:36) (40:27) (248:215) (115:73) (774:495) (128: 123)
P VALUE':'
<0.005 <0.005 >0.1 >0.1 >0.1 >0.1 >0.1 <0.05 <0.05 >0.1 >0.1 <0.005 >0.1
,:.p values compare stillborn with liveborn infants.
received scant attention. Bleeding, which may extend through the entire ventricular system, is thought to originate from the choroid plexus or the terminal subependymal veins in the wall of the lateral ventricles. There is controversy concerning the etiology of the disorder, trauma, hypoxia, infection, and blood coagulation defects all having been suggested as stressors of immature cerebral vessels. 2 • 14. 16. 28 Babies Hospital cases were excluded from this study if they had congenital abnormalities, chromosomal defects or maternal diseases known to affect growth and development. 18 Only 6 per cent of the stillborn infants had cerebral intraventricular hemorrhage whereas the incidence was 18 per cent for liveborn infants who survived less than 24 hours and 38 per cent for those who survived for 27 to 72 hours. The peak incidence was at the earlier gestational ages. 18 The incidence of cerebral intraventricular hemorrhage in various groups was: (a) whites 10 per cent, blacks Table 4. Ratios of Male to Female Infants STILLBORN
Whites Blacks Puerto Ricans Mexican-Americans
0.87: 1 1.04:1 1.38: 1 0.93:1
Poor Non-Poor
1.06: 1 (95:90) 1.01:1 (122:121)
All births in United States
(195:223) (158:152) (22:16) (26:28)
LIVEBORN
1.71:1 1.30: 1 1.19:1 1.34: 1
(583:311) (400:306Y' (83:70)" (111 :83)
1.20:1 (245:204) 1.62:1 (420:259)", 1.05: 1
':'p <0.02 comparing non-whites with whites or non-poor with poor. ""'P <0.05 same comparisons.
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16 per cent, Puerto Ricans 14 per cent; (b) infants from poor families 20 per cent, nonpoor families 12 per cent; (c) infants with congenital pneumonia 14 per cent and without such pneumonia 8 per cent. The nonwhites, the poor, and the group with congenital pneumonia all had lower mean gestational ages than the groups with which they were compared so that none of the differences between the groups proved significant when corrected for gestational age. 18 There was a strong association between cerebral intraventricular hemorrhage and hyaline membrane disease, especially after 29 weeks of gestation, suggesting that hypoxia may playa role in the development of the cerebral hemorrhage. Neither maternal bleeding prior to delivery, duration of labor, nor breech delivery was found to be associated with cerebral intraventricular hemorrhage when corrections were made for gestational age. IS Infants with cerebral intraventricular hemorrhage weighed a mean 14 per cent less than infants without cerebral intraventricular hemorrhage when compensated for gestational age (Table 5). Adrenal glands, thymus, spleen, and liver were disproportionately small in infants with cerebral intraventricular hemorrhage, while brains, heart, and kidneys were near normal size (Table 5). Adrenals were small in infants with cerebral intraventricular hemorrhage because individual adrenal cortical fetal zone cells had a 25 per cent deficiency of cytoplasm. 18 As shown for the infants of poor mothers, these organ and cellular abnormalities are characteristic of antenatal undernutrition. 4:J, 45 From these data it is clear that neonates who are liveborn, premature, somewhat undernourished, and subject to sustained neonatal hypoxia (hyaline membrane disease) are most vulnerable to cerebral intraventricular hemorrhage. Hypoxia in a variety of clinical and experimental circumstances is known to alter vascular permeability and immature subependymal vessels might be particularly susceptible to hypoxic damage. Small arteries in undernourished neonates have been found to have both a subnormal number and a reduced cytoplasmic mass of smooth Table 5. Mean Body and Organ Weights':' in Neonates with and without Intraventricular Hemorrhage (IVH) IVH PRESENT
Body weight Adrenal weights (all cases) Adrenal weights (infection cases excluded) Thymus weight Brain weight Liver weight Kidney weights Heart weight Spleen weight
IVH ABSENT
95::+: 18 94 ::+:40
109::+: 22''':' 101 ::+: 46
76::+: 35
94::+: 29':'"
76 ::+:42 106::+: 22 88 ::+:26 91 ::+: 36 103::+: 57 87±44
104 ::+: 107::+: 104::+: 101 ::+: 109::+: 103 ±
50':":' 21 30':":' 36 35 51"':'
':'Expressed in per cent of normal for gestational age, mean ± SDM. "':'p <0.05 comparing IVH present and absent cases. Infants with hyaline membrane disease and stillborn infants excluded.
r
303
EPIDEMIOLOGY OF PERINATAL MORTALITY
muscle cells, but it is not clear how such structural abnormalities, if present in the cerebral circulation, might predispose to cerebral intraventricular hemorrhage. IS. :11
Hyaline Membrane Disease: Influences of the Adrenal Glands and Antenatal Infection 44 Hyaline membrane disease is a well known and common cause of neonatal death in premature infants. The administration of corticosteroids or ACTH to rabbits and lamb fetuses accelerates lung maturation as measured by surface tension properties of lung extracts and pulmonary pressure volume curves. 9 ,24 Since surfactant deficiency is responsible for many features of hyaline membrane disease in human neonates, an inquiry into human fetal corticosteroid metabolism before the disease develops would be of interest. The problem has been approached indirectly by studying the relationship between adrenal gland structure and the development of the pulmonary disorder. Detailed study was undertaken on the 387 infants of the Babies Hospital series who lived from 7 to 72 hours, 7 hours being chosen because the anatomic features of hyaline membrane disease are usually well developed by this time. Excluded were infants with disorders known to influence prenatal growth of the adrenal glands, i.e., chromosomal disorders, congenital malformations associated with retarded fetal growth, severe antenatal undernutrition, congenital rubella, cytomegalovirus disease, and diabetic mothers.45 The adrenal glands of infants with hyaline membrane disease were 19 per cent lighter than those of infants without the pulmonary disorder, owing to a greater number of adrenal cortical cells in the latter infants.44 The smallest glands for body size were found in infants over 35 weeks of gestation who developed the pulmonary disorder (Table 6). It is possible that these underdeveloped adrenals produced inadequate corticosteroids to induce needed surfactant production. Bacterial infections stimulate corticosteroid production and a correlation was found between evidences of antenatal bacterial infection and the absence of hyaline membrane disease. 44 The infected infants also had significantly larger adrenal adult zone cells, cells that produce corticosteroids. 44 Anencephaly is a useful model for study of the possible influence of adrenal function on surfactant production. Fourteen anencephalic neonates, with very subnormal sized adrenal glands had about one half the mass of osmiophilic granules in pulmonary Type II alveolar cells as did same gestational age "normal" control infants.44 The osmiophilic granules are reportedly the anatomic representation of surfactant. 13
Hydramnios and Oligohydramnios36 ,
37. 39, 46
Various reports cite an incidence of hydramnios in pregnancy varying from 0.13 to 3.20 per cent. 25 In almost half of such cases the fetus or newborn infant dies, either as a consequence of early delivery induced by the hydramnios or as the result of congenital malformationsY It has been difficult to devise therapy for hydramnios because the origin of the excess fluid is usually obscure. Current techniques do not permit exact measure-
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Table 6. Mean Adrenal Gland Weights in Infants with and without Hyaline Membrane Disease Dying Between 7 and 72 Hours of Age GESTATIONAL
HYALINE MEMBRANE
NO HYALINE
AGE IN WEEKS
DISEASE PRESENT
MEMBRANE DISEASE
20-23 24-27 28-31 32-35 36-39 40 and above
63.6 83.5 93.0 99.9 72.6 63.7
± ± ± ± ± ±
26.7 32.2 32.8 17.6 28.4 32.6
(6) (59) (70) (53) (27) (7)
117.3 104.5 110.3 118.3 104.9 103.5
± ± ± ± ± ±
38.6 34.6 46.4 27.8 46.4 37.5
(11)", (70)" (33)" (7) (17)* (27)'"
Values are in per cent of normal published values. "p value of 0.05 or less in comparison of the two groups. Number of cases are found in parentheses.
ments of the individual contributions of the placenta, fetal membranes, and fetal micturition to the increased amniotic volume. Analysis of the Babies Hospital cases gives evidence that fetal micturition may sometimes be an important contributor to hydramnios.:16 • 37. 39. 46 Autopsy material was examined from 31 anencephalic and 20 control infants from the Babies Hospital series who were stillborn or died in the immediate neonatal period. None had gross renal or gastrointestinal malformations which might explain an amniotic fluid disorder. Eight of the 31 anencephalic gestations were associated with hydramnios. 39 • 46 Also studied was a newborn anencephalic twin with no pituitary who had a completely normal monovular parabiotic partner who survived. Finally, members of 7 twin pairs with the parabiotic transplacental transfusion syndrome were studied.:l2 None of these latter infants was anencephalic. In every instance severe hydramnios was associated with the polycythemic, recipient member of the parabiotic pair while oligohydramnios was reported with the anemic donor memberY2 The anencephalic newborns had very small adrenals, the single ex- . ception being the parabiotic anencephalic twin who had adrenals of near normal size. 46 Glomeruli and renal tubular cells were subnormal in number in most of the anencephalic infants.39. 46 In addition, cytoplasmic mass was subnormal in cells of various parts of the nephron, especially at those sites beyond the proximal convoluted tubule (Table 7). By contrast, such tubular values were normal or near normal in the anencephalic twin who presumably received ACTH from her normal parabiotic partner during fetal life. Whereas renal collecting tubular lumina were almost closed in the anencephalic infants without hydramnios, these lumina were half the normal size in the group with hydramnios (Table 7). Luminal area of these collecting tubules was a mean 138 per cent of control values in recipient twins (hydramnios) and only 8 per cent in donor members (oligohydramnios) of the 7 parabiotic pairs (Figs. 3,4). A pituitary gland was found in all of the anencephalic infants without hydramnios but in only one such infant with hydramnios. 46
305
EPIDEMIOLOGY OF PERINATAL MORTALITY
Table 7. Nephron Measurements in Newborn Infants in Percentages of Control Values Derived from 20 Term and Post-Term Infants ANENCEPHALY
WITHOUT
HYDRAMNIOS
HYDRAMNIOS
(8 Glomeruli Mean diameter Proximal convoluted tubules Diameter of nuclei Cytoplasm per cell Thin segment of Henle's loop Diameter of nuclei Cytoplasm per cell Distal convoluted tubules Diameter of nuclei Cytoplasm per cell Collecting tubules in outer zone of medulla Diameter of nuclei Cytoplasm per cell Collecting tubules in inner zone of medulla Diameter of nuclei Cytoplasm per cell Luminal area of tubules
CASES)
(23
CASES)
96
93
96 74'"
95 76'"
96 55'"
101 59"
92 44*
101 70"
105 53"
98 64*
105 47* 50'"
95 58* 12"
*Indicates a P value of 0.05 or less in comparison with controls.
Figure 3. The luminal areas of renal collecting and other tubules are normal or increased in size in recipient members of the parabiotic, transplacental, twin transfusion syndrome. (Verhoeff and van Gieson stains, X 780.)
ANENCEPHALY
WITH
306
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Figure 4. The lumina of renal tubules are almost closed in this donor partner of a parabiotic, twin transfusion pair. Tubules of the recipient partner are seen in Figure 3. (Verhoeff and van Gieson stains, x 780).
The aforementioned renal abnormalities offer clues to the origin of hydramnios and oligohydramnios. Pituitary posterior lobe function in the fetus appears to influence development of the more distal portions of the renal tubule. 3g • 46 Parabiotic recipient twins with hydramnios have enlarged renal tubular lumina, while donor twins with oligohydramnios have almost closed tubular lumina. These latter donor members of transplacental transfusion pairs have small bladders at birth, with scanty urine, while their polycythemic recipient partners have enlarged full bladders and increased urinary output during the early postnatal period. These findings strongly suggest that increased fetal urinary output contributes to hydramnios in recipient twins and that a reduced renal output is at least partially responsible for oligohydramnios in the donor members. A similar relationship between renal tubular luminal size and fetal urine flow is likely for the anencephalic infants since collecting tubules in those with hydramnios have much larger lumina than do collecting tubules in the infants with a normal or reduced amniotic volume. After a relationship between renal tubular structure and amniotic fluid volume in parabiotic twins and in anencephaly was found, other examples of unexplained hydramnios and oligohydramnios were sought among the cases from Babies Hospital. After exclusion of infants with gross renal or gastrointestinal malformations, there remained 21 cases of hydramnios and 8 of oligohydramnios. The infants with hydramnios were heterogenous in their clinical background and neonatal findings; 4 had congenital heart disease, 4 hydrops, 7 malformations which might have interfered with fetal swallowing, 2 diabetic mothers, and 4 other conditions. as All 8 cases of olighohydramnios had a chronic leak of amniotic
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Table 8.
Nephron Measurements in Newborn Infants Whose Gestations Were Associated with Hydramnios
Glomeruli Mean diameter
CONGENITAL
IDIOPATHIC
RH
SWALLOWING
DIABETIC
PLACENTAL
HEARTt
HYDROPS
HYDROPS
DEFECTS
MOTHERS
ANGIOMATOSIS
HEPATITIS
l>j
OTHER
82 ±21
101
126 ± 10'
104
94
91
95
100 ±9 78 ±31
100± 13 87 ±32
104 90
101 ±9 90 ± 16
107 109
99 97
98 87
92 91
89 ± 17 127 ±45
99 92
100 ±9 115 ±43
99 101
106 100
99 94
101 108
Collecting tubules, outer zone of medulla Diameter nuclei 99 ± 12 Cytoplasm/cell 72 ±30 Luminal area 323 ± 138"
110 ± 12 109 ± 29 228 ±69*
98 68 103
100 ± 12 133 ± 57 145 ± 49*
102 83 156
92 123 68
99 55 163
103 141 79
Thin segment of Henle's loop Luminal area
268 ± 124*
104
222 ± 101'"
117
64
205
69
Distal convoluted tubules Diameter nuclei Cytoplasm! cell
~ 2!
:» >-l :» 82 ± 16
Proximal convoluted tubules Diameter nuclei Cytoplasm/cell
><
'"0"
&
CIRRHOSIS
C1
o
96 ± 16 61 ± 22"
195 ± 58*
t-<
~ o
":» >-l
t-<
::; ><
*P value of 0.05 or less in comparison with controls. t All figures are in per cent of control values as defined in the text.
1.>:1 Q
'-l
308
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fluid for 3 or more weeks prior to delivery as a basis for their reducE;ld amniotic volume. Renal tubular lumina were abnormally enlarged in all but two of the subgroups with hydramnios (Table 8). Most other nephron measurements were normal or near normal (Table 8). If dilated renal tubules reflect increased micturition as a contributor to hydramnios it is likely that a substantial fetal urine flow contributed to the hydramnios in many of these cases. Nephron measurements, including tubular luminal areas, were normal in the infants with chronic amniotic fluid leak. 36 SUMMARY A recent study has shown that epidemiologic studies of perinatal mortality based on death certificates are unreliable. Use of the autopsy instead of the death certificate for epidemiologic investigations offers the possibility of new and useful data about common perinatal disorders. The current study illustrates the value of conducting careful autopsies on every infant dying just before or after birth. ACKNOWLEDGMENT
We are greatly indebted to Dr. William Blanc, Babies Hospital, New York City, who directly aided the projects. Dr. Douglas Shanklin, The Chicago Lying-in Hospital, and Dr. Dorothy Tatter, The Los Angeles County Hospital, provided valuable autopsy material.
REFERENCES 1. Abramowicz, M., and Barnett, H. L.: Sex ratio of infant mortality, trends of change. Amer. J. Dis. Child., 119:314, 1970. 2. Arey, J. B., and Anderson, D. W.: Pathology of the newborn in obstetrics. In Greenhill, J. P., ed.: Obstetrics. Philadelphia, W. B. Saunders, 1965. 3. Baird, D.: Preventive medicine in obstetrics. New Eng. J. Med., 246:561,1952. 4. Bassett, J. M., and Thorburn, G. D.: Foetal plasma corticosteroids and the initiation of parturition in sheep. J. Endocrinol., 44:285, 1969. 5. Benirschke, K.: Routes and types of infection in the fetus and the newborn. Amer. J. Dis. Child., 99:714, 1960. 6. Benirschke, K., and Driscoll, S. G.: The Pathology of the Human Placenta, New York, Springer-Verlag, 1967. 7. Blanc, W. A.: Amniotic infection syndrome. Pathogenesis, morphology, and circumnatal mortality. Clin. Obstet. Gynec., 2:705, 1959. 8. Chase, H. C.: The Relationship of Certain Biologic and Socio-economic Factors to Fetal, Infant, and Early Childhood Mortality. Albany, New York, New York State Health Department, Vol. 2, 1962. 9. DeLemos, R. A., Shermeta, D. W., Knelson, J. H., Kotas, R. V., and Avery, M. E.: Acceleration of appearance of pulmonary surfactant in the fetal lamb's lung by administration of corticosteroids. Amer. Rev. Resp. Dis., 102:459,1970. 10. Dominguez, R., Segal, A. J., and O'Sullivan, J. A.: Leukocyte infiltration of umbilical cord: manifestation of fetal hypoxia due to reduction of blood flow in the cord. J.A.M.A., 173:346,1960. 11. Eastman, J. J., and Hellman, L. M.: Williams' Obstetrics. New York, Appleton-CenturyCrofts, 1961. 12. Friedman, S. B., Glasgow, L. A., and Grota, I. J.: Plasma adrenocorticosteroid levels during experimental infections. Presented at the Eightieth Annual Meeting of the American Pediatric Society, Atlantic City, New Jersey, April 30, 1970.
EPIDEMIOLOGY OF PERINATAL MORTALITY
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13. Gandy, G., Jacobson, W., and Gairdner, D.: Hyaline membrane disease. Arch. Dis. Child., 45:289,1970. 14. Gray, O. P., Ackerman, A., and Fraser, A. J.: Intracranial hemorrhage and clotting defects in low-birth weight infants. Lancet, 8:545, 1968. 15. Gruenwald, P.: Chronic fetal distress and placental insufficiency. BioI. Neonatorum, 5:215,1963. 16. Gruenwald, P.: Subependymal cerebral hemorrhage in premature infants and its relation to various injurious influences at birth. Amer. J. Obstet. Gynec., 61 :1285,1951. 17. Hammound, E. I.: Studies in fetal and infant mortality. II. Differentials in mortality by sex and race. Amer. J. Pub. Health, 55:1152,1964. 18. Harcke, H. T., Jr., Naeye, R. L., Storch, A., and Blanc, W. A.: Perinatal cerebral intraventricular hemorrhage. J. Pediat., 80:37,1972. 19. Hendricks, C. H.: Delivery patterns and reproductive efficiency among groups of differing socioeconomic status and ethnic origins. Amer. J. Obstet. Gynec., 97:608,1967. 20. Infant, fetal and maternal mortality, United States -1963. National Center for Health Statistics, Vital and Health Statistics, Series 20, No.3. 21. International Comparison of Perinatal and Infant Mortality: The United States and six west European countries. Washington, D.C., Government Printing Office, U.S. PHS Publication No. 1000, Series 3, No.6, 1967. 22. Kass, E. H.: Bacteriuria and the prevention of prematurity and perinatal death. Transactions of the Fifth Conference on the Physiology of Prematurity, Princeton, New Jersey, March 16, 17 and 18,1960, Vol. 5. Edited by M. Kowlessar, New York, Josiah Macy, Jr., Foundation, 1961, pp. 119-137. 23. Kelsall, G. R. H., Barter, R. A., and Manessis, C.: Prospective bacteriological studies in inflammation of the placenta, cord, and membranes. J. Obstet. Gynaec. Brit. Comm., 74:401, 1967. 24. Kotas, R. V., and Avery, M. E.: Effects of corticosteroids on elastic properties of fetal rabbit lungs. Fed. Proc., 29:776,1970. 25. Kramer, E. E.: Hydramnios, oligohydramnios and fetal malformations. Clin. Obstet. Gynec., 9:508, 1966. 26. Liggins, G. C.: Premature parturition after infusion of corticotrophin or cortisol into foetal lambs. J. Endocrinol., 42:323, 1968. 27. Maudsley, R. F., Brix, G. A., Hinton, N. A., Robertson, E. M., Bryans, A. M., and Haust, M. D.: Placental inflammation and infection: A prospective bacteriologic and histologic study. Amer. J. Obstet. Gynec., 95:648,1966. 28. Morison, J. E.: Foetal and Neonatal Pathology. London, Butterworths, 2nd ed., 1963. 29. Mossman, R. G., and Conrad, J. T.: Oxytocic and modulating effects of water-soluble hydrocortisone and methylprednisolone upon in vitro contractions of myometrium. Amer. J. Obstet. Gynec., 105:897, 1969. 30. Naeye, R. L.: Abnormalities in infants of mothers with toxemia of pregnancy. Amer. J. Obstet. Gynec., 95:276,1966. 31. Naeye, R. L.: Cardiovascular abnormalities in infants malnourished before birth. BioI. Neonat., 8:104,1965. 32. Naeye, R. L.: Human intrauterine parabiotic syndrome and its complications. New Eng. J. Med., 268:804, 1963. 33. Naeye, R. L.: Malnutrition, a probable cause of fetal growth retardation. Arch. Path., 79:284, 1965. 34. Naeye, R. L.: Organ and cellular development in congenital heart disease and in alimentary malnutrition. J. Pediat., 67:447,1965. 35. Naeye, R. L.: Organ and cellular development in mice growing at simulated high altitude. Lab. Invest., 15:700,1966. 36. Naeye, R. L., and Blanc, W. A.: Fetal renal structure and the genesis of amniotic fluid disorders. (Submitted for publication.) 37. Naeye, R. L., and Blanc, W. A.: Organ and body growth in anencephaly. Arch. Path., 91 :140,1971. 38. Naeye, R. L., and Blanc, W. A.: Relation of Poverty and Race to Antenatal Infection. New Eng. J. Med., 283:555,1970. 39. Naeye, R. L., Blanc, W. A., and Milic, A. M.: Renal Development in Dysplasia of the Fetal Pituitary. Pediat. Res., 4:257, 1970. 40. Naeye, R. L., Burt, L. S., Wright, D. L., Blanc, W. A., and Tatter, D.: Neonatal mortality, the male disadvantage. Pediatrics, 48:902,1971. 41. Naeye, R. L., Dellinger, W. S., and Blanc, W. A.: Fetal and maternal features of antenatal bacterial infections. J. Pediat., 79:773,1970. 42. Naeye, R. L., Diener, M. M., and Dellinger, W. S.: Urban poverty: Effects on prenatal nutrition. Science, 166: 1026, 1969. 43. Naeye, R. L., Diener, M. M., Harcke, H. T., Jr., and Blanc, W. A.: Relation of poverty and race to birth weight and organ and cell structure in the newborn. Pediat. Res., 5: 17, 1971.
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44. Naeye, R. L., Harcke, H. T., Jr., and Blanc, W. A.: Adrenal gland structure and the development of hyaline membrane disease. Pediatrics, 47:bOU, 1971. 45. Naeye, R. L., and Kelly, J. A.: Judgment of fetal age. III. The pathologist's evaluation. Pediat. Clin. N. Amer., 13:849, 1966. 46. Naeye, R. L., Milic, A. M. B., and Blanc, W. A.: Fetal endocrine disorders: Clues to the origin of hydramnios. Amer. J. Obstet. Gynec., 108:1251,1970. 47. Olding, L.: Value of placentitis as a sign of intrauterine infection in human subjects. Acta Path. Microbiol. Scand., Section A, 78:256, 1970. 48. Overbach, A. M., Daniel, S. J., and Cassidy, G.: The value of umbilical cord histology in the management of potential perinatal infection. J. Pediat., 76:22, 1970. 49. Perinatal Mortality and Survival, California, 1949-1959: A decade of experience, Sacramento, California, California Department of Public Health, 1962. 50. Scott, R. B., Jenkins, M. E., and Crawford, R. P.: Growth and development of Negro infants. I. Analysis of birth weights of 11,818 newly born infants. Pediatrics, 64:425,1950. 51. Statistical abstract of the United States, 1969, U.S. Department of Commerce, Bureau of the Census, 90th ed., Washington, D.C., 1969. 52. Valdes-Dapena, M. A., and Arey, J. B.: The Causes of Neonatal Mortality: An Analysis of 501 Autopsies on Newborn Infants. J. Pediat., 77:366, 1970. 53. Widholm, 0., Hjelt, M. L., and Cantell, K.: The birth canal as the origin of primary infections. Ann. Med. Fenn., 36:191, 1958. 54. Wren, B. G.: Subclinical renal infection and prematurity. Med. J. Aust., 2:596-600, 1969. Department of Pathology Milton S. Hershey Medical Center Hershey, Pennsylvania 17033
The Epidemiology of Perinatal Mortality The Power of the Autopsy
Richard L. Naeye, MD.*
Deaths just before or after birth are often unexplained because in many hospitals only a small proportion of such deaths are investigated by autopsy and those that are investigated are not analyzed in enough detail to identify all the disease processes that may be present. In addition, in many institutions, placentas are sold or discarded without detailed examination and important socioeconomic, racial, ethnic, and nutritional information is not utilized in case analysis. One consequence of these deficiencies is that much of the perinatal disease data on death certificates is unreliable. 52 The value of good autopsies in understanding the mechanisms of perinatal death is demonstrated in recent analyses of 1044 consecutive perinatal autopsies at aNew York City hospital. lB • :17-44. 46 Patients Material was examined from 1044 consecutive autopsies on 361 stillborn and 683 newborn infants whose tissues were well preserved at Babies Hospital, New York City. lB. 37-44. 46 Gestational ages ranged from 20 to 44 weeks. None of the liveborn infants lived longer than 72 hours. Seven hundred and ninety-three of the mothers received their gestational care at Sloane Hospital, which is associated with Babies Hospital, while the other 251 infants mostly reached Babies Hospital via transport incubators from nearby institutions. Three hundred and seventy-one infants were classified as black, 480 white, and 193 Puerto Rican, according to the mother's self-identification. Income data were available on 608 of the ward cases and they were divided into subgroups by representation of their family incomes in percentage of poverty-line values recorded in tables developed by the United States Social Security Administration. 38 Taking 1966 as a base line, the Social Security index was corrected for earlier and later changes in the economy by means of the consumer price ':'Professor and Chairman, Department of Pathology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania Supported by U.S. Public Health Service Grant HE 11688-04, and Grant No. 698 from the Council for Tobacco Research.
Pediatric Clinics of North America- Vol. 19, No.2, May 1972
295
296
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index. At the poverty line the index allowed 75 cents a day per person for food in 1966.38 For the subproject dealing with sex ratios, 1007 consecutive additional stillborn and newborn autopsies were included from the Los Angeles County Hospital and 684 from the Chicago Lying-in Hospital. 40 The Effects of Poverty and Race on Prenatal Nutrition42 ,
43
Perinatal infant mortality rates in the United States are far higher than rates in a number of other economically developed nations. 21 Most of the excess United States mortality appears related to lower birth weights in poor and nonwhites, a reflection of either premature delivery or of antenatal growth retardation. 3 , 8, 19, 21, 49, 50 Both factors appeared to contribute to low birth weights in infants born to poor and nonwhite mothers at Babies Hospital, undernutrition being operative in growth retardation and antenatal bacterial infections a likely explanation for many of the premature labors. . In the analysis 449 infants were excluded from further consideration because of .fetal or maternal disorders which might have affected fetal growth. With these exclusions, body weight for infants from families with income below the poverty line was 13 to 17 per cent less than the mean value for infants from nonpoor families (Table 1). Body length and all organ weights were also smaller in the infants from poor families. In these latter infants, weights of thymus, spleen, liver and adrenal glands were disproportionately small, whereas brain weights were near those in infants of non poor mothers (Table 1). When matched for gestational age, neonates of poor mothers had less subcutaneous fat and a smaller cytoplasmic mass in individual cells of several organs than infants of nonpoor mothers (Fig. 1). There were almost no differences in body and organ growth between blacks, whites, and Puerto Ricans when the comparisons were between families of similar economic statuS. 42 • 4:1 Table 1. Weight and Length Data by Income* INCOME (PERCENTAGE OF POVERTY LINE)
<100%
100-149%
150-199%
98 ±9
104 ± 9'
104 ± 9"
102 ± 10'
Weight§ Body Brain Heart Liver Spleen Thymus Kidney Adrenal
94± 17 102 ± 17 91 ±24 88 ±24 83 ±44 74 ±36 92±35 84 ±39
110±21* 114 ± 28' 114 ± 55* 110 ± 32* 106 ± 52' 103 ± 50" 102 ± 34" 100 ± 37*
111 ± 111 ± 109 ± 106 ± 105 ± 111 ± 108 ± 108 ±
107 ± 21" 110 ± 25" 107 ± 29" 101 ± 32* 98 ± 51" 98 ± 48" 96±38 94 ± 45"
No. of cases
83
102
Length§ Body
25* 23* 28* 29' 51" 51* 37* 45*
Over 200%
79
§Values are given in mean ± SD. *P <0.05 comparing each of the nonpoor groups with the poor group. Group measurements are in per cent of published "normal" control values·'
205
297
EPIDEMIOLOGY OF PERINATAL MORTALITY
o
INFANTS OF NON POOR MOTHERS , [] INFANTS OF POOR MOTHERS
±42
100
90r--
I-
z w
SOr-±40
-22
u
5 a.
701-601--
50::
~T~H~IC~K~NE~S=S~--A~V=E~RA~G=E~---S=K~E~L~Er.=~~L--~L~I~VE~R~----~A~D~RE~N~A~L--~W~H~A~R~TO=N7.'S~
SUBC~ltNEOUS o'¥25Pp~E CELLS
~YJi~~ CYTOPLASM/CELL ~~r:EL CYTO~I~l.,ICELL CYTOPLASM/CELL CYTOPLASM/CELL
Figure 1. When matched for gestational age, neonates of poor mothers had less subcutaneous fat and a smaller cytoplasmic mass in individual cells of several organs than infants of mothers who were not poor.
If one considers organ structure in the infants of non poor mothers to be normal, organs were abnormal in the infants from poor families, the abnormalities being characteristic of undernutrition. 42 , 4:l These organ abnormalities are observed in a number of placental and uterine disorders that restrict the flow of nutrients to the growing fetus. 15. :l0, :1:1. 45 This growth pattern also has frequently been reported in both children and young animals with chronic postnatal undernutrition.:l 4,:35 In virtually all non-nutritional fetal growth disorders studied to date organs are small because they have a subnormal number of cells, while cell size is normal or increased. 45 Only when fetal undernutrition is severe is cell number reduced in various organs of the neonate. 33 • 45 Infants of poor mothers in the current study had a normal number of cells in several organs, indicating that as a group, their undernutrition was not severe. 42 . 4:3 The undernutrition in newborn infants of the poor might be related to abnormalities that restrict nutrient flow to the fetus or to inadequate maternal nutrition during pregnancy. Since cases with recognized uterine or placental abnormalities were specifically excluded from the analysis, maternal malnutrition provides the most likely explanation. Although lay opinion easily relates maternal diet to fetal nutrition, critical scientific data is surprisingly sparse. Several clinical studies designed to analyze the influence of maternal nutritional intake on fetal nutrition and growth are now under way in the United States.
Antenatal Bacterial Infections and Premature Deliverf8.
41
Another analysis of the 1044 Babies Hospital cases suggests that antenatal bacterial infections might be an important cause of prematurity
298
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ANTENATAL AND INTRAPARTUM INFECTIONS
60 50 en w en
a
W
...-- ....-
..
"., "
". "" /BLACKS
"" .
"BLACKS
• 40 30
PUERTO RICANS
PUERTO .RICANS
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---
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Salary
100-149'1'.
Salary
150%
_'
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WARD CASES
Figure 2. Anatomic evidences of antenatal infections were more common in the poor than in the non poor and more common in blacks than in whites and Puerto Ricans. The salary is related to the "poverty line," which allowed 75 cents per day per person for food in 1966. "Poor" refers to cases in which the family income was at or less than "poverty-line" v.alues.
and consequent perinatal deaths in poor urban whites and nonwhites in the United States. More than 45 per cent of the infants of the poorest families had congenital pneumonia or chorioamnionitis, most often the result of amniotic fluid infections (Fig. 2). The rate of infections in the poor was about double that in the most prosperous, and blacks had about double the rate encountered in whites and Puerto Ricans (Fig. 2).:18 Pathogenic bacteria, in moderate or large numbers, were demonstrated by culture in 351 of the 755 neonates from whom cultures were taken. Such pathogenic bacteria were recovered in 63 per cent of the neonates who had congenital pneumonia.38 , 41 Two thirds of the positive cultures contained common gram-negative organisms, the remainder being grampositive.:1 8 , 41 There were no positive correlations between congenital pneumonia and abnormalities in the neonate that are usually ascribed to hypoxia.:18 One or more late gestational maternal abnormalities were recorded in 95 per cent of the mothers whose infants had congenital pneumonia. 41 These abnormalities included: premature rupture of the membranes, pre delivery abnormal bleeding, fever, pyuria and leukocytosis. By contrast, one or more of these late gestational abnormalities were recorded in only 24 per cent of mothers whose neonates had no congenital pneumonia. All these maternal disorders were more common in blacks and Puerto Ricans than in whites, and more common in the poor than in the nonpoor, but there were no significant differences in their incidence between racial and economic groups when only cases associated with congenital pneumonia were considered. 41
299
EPIDEMIOLOGY OF PERINATAL MORTALITY
Maternal fever, leukocytosis, and pyuria were more common in culture-positive cases of congenital pneumonia than in those from whom no pathogenic bacteria were recovered (Table 2). Although bacterial cultures were not taken routinely, pathogenic bacteria were recovered from one or more sites in 180 of the mothers. Recovery of such bacteria from maternal reproductive and urinary tracts was significantly associq,ted with congenital pneumoniaY An even stronger association was found between congenital pneumonia and the recovery of pathogenic bacteria when the analysis was for the same predominant organism in a mother and her ofi'spring.41 The mean duration of labor for infants with congenital pneumonia was 9.2 ±7.5 hours and for those without pneumonia, 8.5 ±7.8 hours (P>.I). Many investigations of inflammation of the umbilical cord, placenta, and membranes have been published in recent years. 5 - 7, 10, 23, 27, a8, 47, 48, 5:l Some have attributed these disorders and their often associated antenatal aspiration pneumonia to bacterial infection, while others have related them to acidosis, hypoxia, or the irritant properties of meconium. Our data suggest that common bacteria are most often involved in the pathogenesis of these disorders, especially in the poor and in nonwhites. However, the nonbacterial origin of some cases of chorioamnionitis and pneumonia are suggested by the finding that 37 per cent of the congenital pneumonia cases showed no pathogenic organisms. A viral or mycoplasma etiology has not been excluded from these cases but it is noteworthy that common pathogenic bacteria were cultured from almost every neonate with pneumonia of apparent postnatal onset.41 By contrast, chorioamnionitis without associated congenital pneumonia seems mainly nonbacterial in origin, pathogenic bacteria being recovered from only 9 per cent of such cases. 41 Since bacterial-related congenital pneumonia is most common in neonates of nonwhite and poor white urban families, it might be asked if such infections are responsible for any significant proportion of their ex-
Table 2. Late Gestational Maternal Disorders and the Recovery of Pathogenic Bacteria from Their Neonates' Lungs CHORIOAMNIONITIS WITHOUT CONGENITAL PNEUMONIA
Culture Premature rupture of membranes Fever Leukocytosis Pyuria Abnormal bleeding All cases
25 25 43 25 33 89
+
(28%) (28%) (48%) (28%) (37%)
CONGENITAL PNEUMONIA
+
Culture-
Culture
9 4 12 4 23 53
0 0 3 (100%) 0 0 3
(17%) (8%),,' (24%)" (8%)'" (43%)
Culture -
8 3 8 3 16 29
(28%) (10%) (28%) (10%) (55%)
':'P <0.05 by comparison with congenital pneumonia, culture positive. Values in parentheses represent percent of total cases in each category. Organ culture data were complete in 441 infants born at Babies Hospital. This table includes information on the 174 infants who had congenital pneumonia and chorioamnionitis without pneumonia.
300
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cessive premature deliveries. There have been some reports that bacterial products have oxytocic activity, but the evidence is not strong for such a mechanism in human beings. 22 , 54 Certain corticosteroids have oxytocic activity, and plasma levels of such steroids are increased in a variety of experimental infectionsP' 29 In the Babies Hospital cases, adrenal glands were 19 per cent heavier in infected than in noninfected neonates of the same gestational age, owing to increased cytoplasm in individual cells of the gland's permanent zone in the infected infants.3s Liggins and others have given recent evidence that corticosteroids of fetal adrenal origin may play an important role in the initiation of labor.4, 26 Hyperfunction of permanent zone adrenal cells in the human fetus offers a possible mechanism by which bacterial infections may initiate labor.3s
Sex Ratios as a Clue to the Roles of Infection and Other Disorders in Perinatal Death40 Male infants born in the United States have an excessive risk of neonatal death in comparison to females.1. 17,20 In an analysis of2735 consecutive autopsies in newborn infants at Babies Hospital, Los Angeles County, and Chicago Lying-in Hospitals, the 0.95:1 male to female ratio (sex ratio) for all stillborn infants did not differ significantly from the 1.05: 1 ratio recorded for alllivebirths in the United States (Table 3).40. ;;1 By contrast, almost all the ratios for infants dying after birth were far greater than the stillbirth or all United States livebirth ratios (Table 3). In fact, the sex ratios for most disorders in liveborn infants were greater than ratios for the same disorders in stillborn infants, many of the differences being statistically significant (Table 3). An exception was the value for infants with congenital pneumonia (prenatal infection). dying soon after birth (1.15:1) which was much smaller than the ratio for comparable non-infected infants (1.56: 1) (P<.02). The sex ratio for liveborn whites who died soon after birth was significantly greater than the ratio for nonwhites, and the nonpoor had a significantly greater ratio than the poor (Table 4). When all liveborn infants with prenatal infections are excluded from the analysis, half or more of the differences in mean sex ratios between liveborn blacks and whites and between the poor and nonpoor disappear, raising the possibility that antenatal bacterial infections might make a significant contribution to the excessive perinatal death rates of urban blacks and poor whites in the United States. Other inferences can be drawn from the sex ratio study. Sex ratios in the stillborns were close to the 1.05: 1 ratio for all U.S.livebirths, suggesting that males and females were affected in proportion to their relative numbers in utero and that maternal rather than fetal factors were responsible for antenatal death. By contrast, the much higher sex ratios encountered in virtually all disorders of liveborn infants reflect a basic biologic disadvantage for males, not specifically related to any single disease process.
Cerebral Intraventricular Hemorrhagel8 Although cerebral intraventricular hemorrhage is a common cause of neonatal death in premature infants, its epidemiologic features have
301
EPIDEMIOLOGY OF PERINATAL MORTALITY
Table 3.
Ratios of Male to Female Infants STILLBORN
All cases Major congenital malformations Hyaline membrane disease Pulmonary hemorrhage Subarachnoid hemorrhage Subependymal hemorrhage Intraventricular hemorrhage Subdural hemorrhage Erythroblastosis fetalis Toxemia of pregnancy Diabetic mothers Prenatal infection Postnatal infection Noninfected Antenatal aspiration
0.95:1 (396:419) 0.57:1 (28:49) 1.07:1 1.04:1 0.71:1 1.50:1 0.88:1 0.67:1 0.95:1 0.91:1 0.98:1
(30:28) (27:26) (5:7) (18: 12) (7:8) (24:36) (53:56) (20:22) (95:97)
0.94: 1 (301 :322) 0.97: 1 (237:244)
LIVEBORN
1.45:1 1.36:1 1. 71: 1 1.55: 1 1.29: 1 1.50: 1 1.54: 1 1.67: 1 1.48: 1 1.81: 1 1.48: 1 1.15:1 1.58: 1 1.56: 1 1.04: 1
(1137:783) (171 :126) (466:273) (155:100) (269:208) (135:90) (237:154) (35:21) (59:40) (65:36) (40:27) (248:215) (115:73) (774:495) (128: 123)
P VALUE':'
<0.005 <0.005 >0.1 >0.1 >0.1 >0.1 >0.1 <0.05 <0.05 >0.1 >0.1 <0.005 >0.1
,:.p values compare stillborn with liveborn infants.
received scant attention. Bleeding, which may extend through the entire ventricular system, is thought to originate from the choroid plexus or the terminal subependymal veins in the wall of the lateral ventricles. There is controversy concerning the etiology of the disorder, trauma, hypoxia, infection, and blood coagulation defects all having been suggested as stressors of immature cerebral vessels. 2 • 14. 16. 28 Babies Hospital cases were excluded from this study if they had congenital abnormalities, chromosomal defects or maternal diseases known to affect growth and development. 18 Only 6 per cent of the stillborn infants had cerebral intraventricular hemorrhage whereas the incidence was 18 per cent for liveborn infants who survived less than 24 hours and 38 per cent for those who survived for 27 to 72 hours. The peak incidence was at the earlier gestational ages. 18 The incidence of cerebral intraventricular hemorrhage in various groups was: (a) whites 10 per cent, blacks Table 4. Ratios of Male to Female Infants STILLBORN
Whites Blacks Puerto Ricans Mexican-Americans
0.87: 1 1.04:1 1.38: 1 0.93:1
Poor Non-Poor
1.06: 1 (95:90) 1.01:1 (122:121)
All births in United States
(195:223) (158:152) (22:16) (26:28)
LIVEBORN
1.71:1 1.30: 1 1.19:1 1.34: 1
(583:311) (400:306Y' (83:70)" (111 :83)
1.20:1 (245:204) 1.62:1 (420:259)", 1.05: 1
':'p <0.02 comparing non-whites with whites or non-poor with poor. ""'P <0.05 same comparisons.
302
RICHARD
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16 per cent, Puerto Ricans 14 per cent; (b) infants from poor families 20 per cent, nonpoor families 12 per cent; (c) infants with congenital pneumonia 14 per cent and without such pneumonia 8 per cent. The nonwhites, the poor, and the group with congenital pneumonia all had lower mean gestational ages than the groups with which they were compared so that none of the differences between the groups proved significant when corrected for gestational age. 18 There was a strong association between cerebral intraventricular hemorrhage and hyaline membrane disease, especially after 29 weeks of gestation, suggesting that hypoxia may playa role in the development of the cerebral hemorrhage. Neither maternal bleeding prior to delivery, duration of labor, nor breech delivery was found to be associated with cerebral intraventricular hemorrhage when corrections were made for gestational age. IS Infants with cerebral intraventricular hemorrhage weighed a mean 14 per cent less than infants without cerebral intraventricular hemorrhage when compensated for gestational age (Table 5). Adrenal glands, thymus, spleen, and liver were disproportionately small in infants with cerebral intraventricular hemorrhage, while brains, heart, and kidneys were near normal size (Table 5). Adrenals were small in infants with cerebral intraventricular hemorrhage because individual adrenal cortical fetal zone cells had a 25 per cent deficiency of cytoplasm. 18 As shown for the infants of poor mothers, these organ and cellular abnormalities are characteristic of antenatal undernutrition. 4:J, 45 From these data it is clear that neonates who are liveborn, premature, somewhat undernourished, and subject to sustained neonatal hypoxia (hyaline membrane disease) are most vulnerable to cerebral intraventricular hemorrhage. Hypoxia in a variety of clinical and experimental circumstances is known to alter vascular permeability and immature subependymal vessels might be particularly susceptible to hypoxic damage. Small arteries in undernourished neonates have been found to have both a subnormal number and a reduced cytoplasmic mass of smooth Table 5. Mean Body and Organ Weights':' in Neonates with and without Intraventricular Hemorrhage (IVH) IVH PRESENT
Body weight Adrenal weights (all cases) Adrenal weights (infection cases excluded) Thymus weight Brain weight Liver weight Kidney weights Heart weight Spleen weight
IVH ABSENT
95::+: 18 94 ::+:40
109::+: 22''':' 101 ::+: 46
76::+: 35
94::+: 29':'"
76 ::+:42 106::+: 22 88 ::+:26 91 ::+: 36 103::+: 57 87±44
104 ::+: 107::+: 104::+: 101 ::+: 109::+: 103 ±
50':":' 21 30':":' 36 35 51"':'
':'Expressed in per cent of normal for gestational age, mean ± SDM. "':'p <0.05 comparing IVH present and absent cases. Infants with hyaline membrane disease and stillborn infants excluded.
r
303
EPIDEMIOLOGY OF PERINATAL MORTALITY
muscle cells, but it is not clear how such structural abnormalities, if present in the cerebral circulation, might predispose to cerebral intraventricular hemorrhage. IS. :11
Hyaline Membrane Disease: Influences of the Adrenal Glands and Antenatal Infection 44 Hyaline membrane disease is a well known and common cause of neonatal death in premature infants. The administration of corticosteroids or ACTH to rabbits and lamb fetuses accelerates lung maturation as measured by surface tension properties of lung extracts and pulmonary pressure volume curves. 9 ,24 Since surfactant deficiency is responsible for many features of hyaline membrane disease in human neonates, an inquiry into human fetal corticosteroid metabolism before the disease develops would be of interest. The problem has been approached indirectly by studying the relationship between adrenal gland structure and the development of the pulmonary disorder. Detailed study was undertaken on the 387 infants of the Babies Hospital series who lived from 7 to 72 hours, 7 hours being chosen because the anatomic features of hyaline membrane disease are usually well developed by this time. Excluded were infants with disorders known to influence prenatal growth of the adrenal glands, i.e., chromosomal disorders, congenital malformations associated with retarded fetal growth, severe antenatal undernutrition, congenital rubella, cytomegalovirus disease, and diabetic mothers.45 The adrenal glands of infants with hyaline membrane disease were 19 per cent lighter than those of infants without the pulmonary disorder, owing to a greater number of adrenal cortical cells in the latter infants.44 The smallest glands for body size were found in infants over 35 weeks of gestation who developed the pulmonary disorder (Table 6). It is possible that these underdeveloped adrenals produced inadequate corticosteroids to induce needed surfactant production. Bacterial infections stimulate corticosteroid production and a correlation was found between evidences of antenatal bacterial infection and the absence of hyaline membrane disease. 44 The infected infants also had significantly larger adrenal adult zone cells, cells that produce corticosteroids. 44 Anencephaly is a useful model for study of the possible influence of adrenal function on surfactant production. Fourteen anencephalic neonates, with very subnormal sized adrenal glands had about one half the mass of osmiophilic granules in pulmonary Type II alveolar cells as did same gestational age "normal" control infants.44 The osmiophilic granules are reportedly the anatomic representation of surfactant. 13
Hydramnios and Oligohydramnios36 ,
37. 39, 46
Various reports cite an incidence of hydramnios in pregnancy varying from 0.13 to 3.20 per cent. 25 In almost half of such cases the fetus or newborn infant dies, either as a consequence of early delivery induced by the hydramnios or as the result of congenital malformationsY It has been difficult to devise therapy for hydramnios because the origin of the excess fluid is usually obscure. Current techniques do not permit exact measure-
304
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Table 6. Mean Adrenal Gland Weights in Infants with and without Hyaline Membrane Disease Dying Between 7 and 72 Hours of Age GESTATIONAL
HYALINE MEMBRANE
NO HYALINE
AGE IN WEEKS
DISEASE PRESENT
MEMBRANE DISEASE
20-23 24-27 28-31 32-35 36-39 40 and above
63.6 83.5 93.0 99.9 72.6 63.7
± ± ± ± ± ±
26.7 32.2 32.8 17.6 28.4 32.6
(6) (59) (70) (53) (27) (7)
117.3 104.5 110.3 118.3 104.9 103.5
± ± ± ± ± ±
38.6 34.6 46.4 27.8 46.4 37.5
(11)", (70)" (33)" (7) (17)* (27)'"
Values are in per cent of normal published values. "p value of 0.05 or less in comparison of the two groups. Number of cases are found in parentheses.
ments of the individual contributions of the placenta, fetal membranes, and fetal micturition to the increased amniotic volume. Analysis of the Babies Hospital cases gives evidence that fetal micturition may sometimes be an important contributor to hydramnios.:16 • 37. 39. 46 Autopsy material was examined from 31 anencephalic and 20 control infants from the Babies Hospital series who were stillborn or died in the immediate neonatal period. None had gross renal or gastrointestinal malformations which might explain an amniotic fluid disorder. Eight of the 31 anencephalic gestations were associated with hydramnios. 39 • 46 Also studied was a newborn anencephalic twin with no pituitary who had a completely normal monovular parabiotic partner who survived. Finally, members of 7 twin pairs with the parabiotic transplacental transfusion syndrome were studied.:l2 None of these latter infants was anencephalic. In every instance severe hydramnios was associated with the polycythemic, recipient member of the parabiotic pair while oligohydramnios was reported with the anemic donor memberY2 The anencephalic newborns had very small adrenals, the single ex- . ception being the parabiotic anencephalic twin who had adrenals of near normal size. 46 Glomeruli and renal tubular cells were subnormal in number in most of the anencephalic infants.39. 46 In addition, cytoplasmic mass was subnormal in cells of various parts of the nephron, especially at those sites beyond the proximal convoluted tubule (Table 7). By contrast, such tubular values were normal or near normal in the anencephalic twin who presumably received ACTH from her normal parabiotic partner during fetal life. Whereas renal collecting tubular lumina were almost closed in the anencephalic infants without hydramnios, these lumina were half the normal size in the group with hydramnios (Table 7). Luminal area of these collecting tubules was a mean 138 per cent of control values in recipient twins (hydramnios) and only 8 per cent in donor members (oligohydramnios) of the 7 parabiotic pairs (Figs. 3,4). A pituitary gland was found in all of the anencephalic infants without hydramnios but in only one such infant with hydramnios. 46
305
EPIDEMIOLOGY OF PERINATAL MORTALITY
Table 7. Nephron Measurements in Newborn Infants in Percentages of Control Values Derived from 20 Term and Post-Term Infants ANENCEPHALY
WITHOUT
HYDRAMNIOS
HYDRAMNIOS
(8 Glomeruli Mean diameter Proximal convoluted tubules Diameter of nuclei Cytoplasm per cell Thin segment of Henle's loop Diameter of nuclei Cytoplasm per cell Distal convoluted tubules Diameter of nuclei Cytoplasm per cell Collecting tubules in outer zone of medulla Diameter of nuclei Cytoplasm per cell Collecting tubules in inner zone of medulla Diameter of nuclei Cytoplasm per cell Luminal area of tubules
CASES)
(23
CASES)
96
93
96 74'"
95 76'"
96 55'"
101 59"
92 44*
101 70"
105 53"
98 64*
105 47* 50'"
95 58* 12"
*Indicates a P value of 0.05 or less in comparison with controls.
Figure 3. The luminal areas of renal collecting and other tubules are normal or increased in size in recipient members of the parabiotic, transplacental, twin transfusion syndrome. (Verhoeff and van Gieson stains, X 780.)
ANENCEPHALY
WITH
306
RICHARD
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Figure 4. The lumina of renal tubules are almost closed in this donor partner of a parabiotic, twin transfusion pair. Tubules of the recipient partner are seen in Figure 3. (Verhoeff and van Gieson stains, x 780).
The aforementioned renal abnormalities offer clues to the origin of hydramnios and oligohydramnios. Pituitary posterior lobe function in the fetus appears to influence development of the more distal portions of the renal tubule. 3g • 46 Parabiotic recipient twins with hydramnios have enlarged renal tubular lumina, while donor twins with oligohydramnios have almost closed tubular lumina. These latter donor members of transplacental transfusion pairs have small bladders at birth, with scanty urine, while their polycythemic recipient partners have enlarged full bladders and increased urinary output during the early postnatal period. These findings strongly suggest that increased fetal urinary output contributes to hydramnios in recipient twins and that a reduced renal output is at least partially responsible for oligohydramnios in the donor members. A similar relationship between renal tubular luminal size and fetal urine flow is likely for the anencephalic infants since collecting tubules in those with hydramnios have much larger lumina than do collecting tubules in the infants with a normal or reduced amniotic volume. After a relationship between renal tubular structure and amniotic fluid volume in parabiotic twins and in anencephaly was found, other examples of unexplained hydramnios and oligohydramnios were sought among the cases from Babies Hospital. After exclusion of infants with gross renal or gastrointestinal malformations, there remained 21 cases of hydramnios and 8 of oligohydramnios. The infants with hydramnios were heterogenous in their clinical background and neonatal findings; 4 had congenital heart disease, 4 hydrops, 7 malformations which might have interfered with fetal swallowing, 2 diabetic mothers, and 4 other conditions. as All 8 cases of olighohydramnios had a chronic leak of amniotic
M 'd ....
I:) l>j
is:
:5t-<
o
Table 8.
Nephron Measurements in Newborn Infants Whose Gestations Were Associated with Hydramnios
Glomeruli Mean diameter
CONGENITAL
IDIOPATHIC
RH
SWALLOWING
DIABETIC
PLACENTAL
HEARTt
HYDROPS
HYDROPS
DEFECTS
MOTHERS
ANGIOMATOSIS
HEPATITIS
l>j
OTHER
82 ±21
101
126 ± 10'
104
94
91
95
100 ±9 78 ±31
100± 13 87 ±32
104 90
101 ±9 90 ± 16
107 109
99 97
98 87
92 91
89 ± 17 127 ±45
99 92
100 ±9 115 ±43
99 101
106 100
99 94
101 108
Collecting tubules, outer zone of medulla Diameter nuclei 99 ± 12 Cytoplasm/cell 72 ±30 Luminal area 323 ± 138"
110 ± 12 109 ± 29 228 ±69*
98 68 103
100 ± 12 133 ± 57 145 ± 49*
102 83 156
92 123 68
99 55 163
103 141 79
Thin segment of Henle's loop Luminal area
268 ± 124*
104
222 ± 101'"
117
64
205
69
Distal convoluted tubules Diameter nuclei Cytoplasm! cell
~ 2!
:» >-l :» 82 ± 16
Proximal convoluted tubules Diameter nuclei Cytoplasm/cell
><
'"0"
&
CIRRHOSIS
C1
o
96 ± 16 61 ± 22"
195 ± 58*
t-<
~ o
":» >-l
t-<
::; ><
*P value of 0.05 or less in comparison with controls. t All figures are in per cent of control values as defined in the text.
1.>:1 Q
'-l
308
RICHARD
L. N AEYE
fluid for 3 or more weeks prior to delivery as a basis for their reducE;ld amniotic volume. Renal tubular lumina were abnormally enlarged in all but two of the subgroups with hydramnios (Table 8). Most other nephron measurements were normal or near normal (Table 8). If dilated renal tubules reflect increased micturition as a contributor to hydramnios it is likely that a substantial fetal urine flow contributed to the hydramnios in many of these cases. Nephron measurements, including tubular luminal areas, were normal in the infants with chronic amniotic fluid leak. 36 SUMMARY A recent study has shown that epidemiologic studies of perinatal mortality based on death certificates are unreliable. Use of the autopsy instead of the death certificate for epidemiologic investigations offers the possibility of new and useful data about common perinatal disorders. The current study illustrates the value of conducting careful autopsies on every infant dying just before or after birth. ACKNOWLEDGMENT
We are greatly indebted to Dr. William Blanc, Babies Hospital, New York City, who directly aided the projects. Dr. Douglas Shanklin, The Chicago Lying-in Hospital, and Dr. Dorothy Tatter, The Los Angeles County Hospital, provided valuable autopsy material.
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