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The dysmature infant
June 1977 The Journal o f P E D I A T R I C S
943
The dysmature infant Associated factors and outcome at 7 years of age
Dysmaturity, diagnosed according to the Clifford criteria, was studied for the first time in a black population. The infants and matched control subjects were participants in the Collaborative Perinatal Study in Philadelphia from birth to 7years of age. The incidence of dysmaturity was 25/1,000 live births," more boys than girls were born dysmature, reversing the normal male~female ratio found among black infants in the Collaborative Study as a whole. The condition was more common among post-term infants but did occur in earlier gestational weeks. The overall characteristics of the condition among this black population did not differ from those previously reported among white populations of various races. Surviving infants developed mentally and physically as well as control subjects. No prenatal or environmental characteristics were found that distinguished mothers of dysmature infants from those of nondysmature infants.
Rosalind Y. Ting, M.D., M.P.H.,* Monica H. Wang, M.D., and
Thomas F. McNair Scott, M.D., Philadelphia, Pa.
THE TERM " D Y S M A T U R I T Y " used in this paper refers to infants born with absent vernix caseosa, dry desquamating skin, and frequently also with m e c o n i u m staining of the amniotic fluid. This is in contradistinction to "small for gestational age," a term sometimes used for such infants in the literature. The above description was first given to a group of postmature infants by Ballantyne ~ in 1902. Practically no further studies were published until the condition was popularized in G e r m a n y between 1939 and 1943, when a description of the condition appeared in a textbook of obstetrics.-' In the United States it was not generally recognized until Clifford :~ described it in 1945. By 1954 Clifford was able to subdivide such infants into three stages of severity, utilizing clearly recognizable clinical
From The Children's Hospital of Philadelphia and the Department of Pediatrics, School of Medicine of the University of Pennsylvania. Supported by Contract No. Ph43-68-4, National Institutes of Health. *Reprint address: The Children's Hospital of Philadelphia, 34th and Civic Center Blvd. Philadelphia, PA 19104.
criteria,* and suggested the term "placental dysfunction" as the etiologic factor? He suggested that in such infants the normal senile degeneration of the placenta occurred prematurely, thus interfering with fetal nutrition in the last weeks of pregnancy. Although he emphasized that this was mainly a condition encountered in post-term infants, he indicated that it might be observed in infants born within the normal gestational period. In 1957, SjOstedt and colleagues' carried out an extensive study of such infants born at various times of gestation, and introduced the term "dysmaturity" to indicate that the condition was not limited to post-term infants. Engelson and associates" followed this group of infants until age 4 to 5 years. An opportunity to evaluate dysmaturity among a large group of black American infants was provided by a black
*Dysmaturity-three stages of Clifford: I. Cracked, parchment-like peeling skin, thin arms and legs. More awake and alert. May have tendency to respiratory distress or vomiting, bones of skull harder than usual. II. As in I, plus thin trunk, meconium staining of amniotic fluids, green skin, nails, and umbilicus.May vomit meconium-stainedfluid. III. Trunk and limbs extremely thin, dystrophic appearance. Skin peels off in large flakes. Nails and skin yellowish.
Vol. 90, No. 6, pp. 943-948
944
Ting, Wang, and Scott
The Journal qf Pediatrics June 1977
Table I. Maternal age and gravidity versus stages of dysmaturity Maternal age Stages of dysmaturity
Total No. of infants
<_ 19 No.
3 2 1 Total Control
6 23 181 210 210
1 5 52 58 60
I
Gravidit),
20-29
30-45
Total No.
I
%
infants
No.
50.0 13.1 16,0 16.7 17.1
6 22 169 197 196
1 7 51 59 58
%
No.
%
No.
16.7 21.7 28.7 27.6* 28.6*
2 15 100 117 114
33.3 65.2 55.3 55.7 54.3
3 3 29 35 36
1
I
II-IV %
No.
16.7 31.8 30.2 29.9 29.6
2 8 77 87 91
I
>_ V
%
No.
~,
%
33.3 36.4 45.5 44.2 46.4
3 7 41 51 47
50.0 31.8 24.3 25.9 24.0
100.0 100.0 100.0 lO0.O 100.0
*Incidence of teen-age pregnancies for the total Philadelphia Collaborative Study population is 31.0%.
inner-urban population enrolled in the National Collaborative Perinatal Study in Philadelphia. CASES
AND METHODS
OF STUDY
The Collaborative Study established protocols, described elsewhere, ~ for recording details of the mother's health during pregnancy, certain socioeconomic conditions, the course of labor and delivery, the infant's condition at birth, the gross and microscopic state of the placenta, and the pathologic findings on dead infants. Theseprotocols, which mandated a diagnosis of dysmaturity when Clifford's :~ criteria were present, were completed by the staff at the Pennsylvania Hospital. Protocols were also established to follow the physical and mental growth of the children up to the age of 7 years. These protocols were completed by the staff o f the Children',s Hospital of Philadelphia. Both institutions are adjunct hospitals of the School of Medicine of the University of Pennsylvania. The infants diagnosed by dysmature were matched with an equal n u m b e r of nondysmature infants by sex, and by date of birth, within a range of three months. RESULTS O f the 8,476 infants born during the study period, 210 were classified as dysmature, a frequency o f 25/1,000 live births. O f these, 115 were boys and 95 were girls, giving a m a l e / f e m a l e ratio of 120/100 as compared with the m a l e / female ratio of 99/100 for the black study population as a whole. MATERNAL
Table II. Placenta: ratio
FACTORS
Age and gravidity distribution. Table I* displays the distribution of the mothers o f dysmature and nondysma*It will be noted that throughout the tables the total numbers will vary from the basic 210 infants. This is due to the absence of specific information from individual charts, complete data not being recorded on every chart.
Stages of dysmaturity 3 (N = 6) 2 (N = 22) 1 (N = 173) Control (N = 196)
Mean weight and fetal placental
Placental weight (mean +_SD) 540 461 418 433
_+ 87 _+ 92 _+ 98 _+ 98
Fetal/ placental ratio 6.3 7.2 7.4 7.3
+ 1.3 _+ 1.1 _+ 1.2 _+ 1.3
ture infants according to age and pregnancy experience. The overall distribution of the two groups did not differ significantly. However, Stage 3 dysmature infants were born more frequently to older and multiparous women. although such differences were not of statistical significance because of the small numbers involved. Other maternal factors. The distribution of maternal factors, such as height and prepregnant weight, complications of pregnancy, length of prenatal care, duration of labor, type of delivery, and previous reproductive loss, was essentially the same in mothers of dysmature infants as in those of control subjects. PLACENTAL
FACTORS
Gross examination. Size. With all infants, the placenta was measured in three dimensions and was weighed after being stripped of membrane and cord. No significant differences in surface area were found between the dysmature and control groups. But, as shown in Table II, there was a difference in placental weight and fetal/placental ( F / P ) ratio between the two groups. A m o n g the dysmature infants the mean placental weight of Stage 1 infants did not differ from that of the control subjects but as signs of dysmaturity increased the placental weight increased and the F / P ratio decreased. Pathologic findings. Protocol descriptions on 150
Volume90 Number6
Dysmature infants
945
Table III. Mean birth weight and length by gestational age
t.. Group Study Control
Term(37-40wk) N I Weight(+_SD) I N [ Height(+_SD)
N [
96 112
86 51
3,077 _+ 395 3,116 _+ 466
95 110
50.1 _+ 1.9 49.6 _+ 2.2
randomly selected placentas, 72 from dysmature and 78 from control infants were reviewed. The number and size of infarcts and areas of calcification did not differ significantly between the two groups. As expected from the criteria for diagnosis, there was more meconium staining in the dysmature group in a ratio of 2:1. Microscopic examination. Randomly selected placentas from the dysmature (57) and control groups (53) were studied by Dr. L. Froehlich) The most obvious difference was the increased incidence of sickling in the placentas of the dysmature infants as compared with those of the control subjects (10 of 57 = 17.5% versus 4 of 53 -- 7.5%, respectively).* The frequency of fibrinoid change in decidual vessels, commonly found in association with acute toxemia of pregnancy, did not differ in the two groups.t An increased incidence of inflammation of the cord was found among the dysmature infants which appeared to be due to irritation by meconium. The incidence of nonspecific chorioamnionitis was the same in both groups. FETAL AND NEONATAL FACTORS
Gestational age, birth weight, and birth length. By protocol, the gestational age was recorded in relation to the date of the last menstrual period rather than the appearance of the infant. This point is important when considering the appearance of the signs of dysmaturity among infants born at gestational ages less than 37 weeks. According to this criterion, 27/209 (12.9%) of the dysmature infants and 49/210 (23.3%) of the control infants were born before the thirty-seventh week. That these were not all true premature infants is indicated by the heterogeneity of the weights noted in both groups with ranges of 2,350 to 3,860 gm and 1,390 to 4,450 gm in the study and control groups, respectively. The appearance of inappropriately large infants born before the thirty-seventh week as determined by the last menstrual period has been recognized in the Collaborative Study Population as probably due to an error in dating. ~ If _< 2,500 gm is considered a cutoff weight for true prematurity, three *Thisfrequencyamongthe controlsubjects(7.5%)was twiceas great as that foundon routineexaminationof peripheral blood of the 7,780black mothers in our PhiladelphiaProject population(4%). tThe diagnosisof pre-eclampsiain the two groups was essentiallythe same, 27% in dysmatureversus24% in control.
Post-term(> 40 wk) Weight(+_SD) I N [ Height(+_SD) 3,067 ___416 3,360 ___457
83 46
50.4 + 2.3 50.7 ___2.3
such infants were classified as dysmature, giving a frequency of 3/209 or 1.4%. Excluding infants born before the thirty-seventh week by protocol definition, the remainder were born at term, 37 to 40 weeks, or post-term, after 40 weeks. More dysmature than control infants were born after the fortieth week (86/209 = 41.1% versus 51/210 = 24.3%, respectively) (p = < 0.05). The mean gestational age for dysmature infants was 39.9 + 3.5 weeks versus that of the control infants of 38.3 + 3.6 weeks (p = < 0.001). Table III records the weights and lengths of the dysmature and control infants born at term or post-term. The mean lengths of the two groups were essentially the same at term and post-term, but the mean weights of the dysmature infants were less than those of the control subjects, minimally so among the term infants but significantly so among the post-term infants (p = ,~. 0.001). These findings document the clinical impression of dysmature infants being long and thin. Apgar scores. Low scores, < 7 at 1 and 5 minutes, were significantly more frequent among the Stage 2 and 3 dysmature infants than among the control subjects (p = < 0.001). At 1 minute there were 14/25 (56%) dysmature infants versus 31 / 183 (16.9%) control subjects; at 5 minutes there were 8/29 (27.6%) dysmature infants versus 8/198 (4.0%) control subjects. Among the Stage 1 dysmature infants the frequency did not differ significantly from that among the control subjects. At 1 minute there were 32/164 (19.5%) and at 5 minutes there were 8/174 (4.6%). Serum bilirubin. The range of bilirubin levels was the same in each group (1.0 to 20 mg/dl). Hyperbilirubinemia ( > 15 mg/dl) occurred with equal frequency in each group (study 7/200 = 3.5% versus control 6/ 203 = 3.0%). Hematocrit. Although the range was the same for the two groups (30 to 71%), there was a significantly higher incidence of hematocrits ___ 65% among the dysmature infants (15/192 or 7.8% as compared with 6/188 control subjects or 3.2%; p = 0.005). When the infants with high hematocrits in the two groups were compared, a marked difference was found. For the 15 dysmature infants the mean weight, length, and gestational weeks were 3,013 gm, 50 cm, and 40 weeks, respectively; whereas for the six
946
Ting, Wang, and Scott
The Journal of Pediatrics June 1977
Table IV. Mean weights and heights at various age levels of dysmature and control infants
Group Dysmature Control
Weight (gin) and height (cm) Weight Height Weight Height
Birth (mean • SD) 3,070 50 3,080 50
4 mo
(mean +_ SD)
• 410 (208 6,320 • 860 (176) • 2 (205 63 • 2 (176) • 470 (210 6,190 • 790 (172) • 2 (206) 62 ~ 2 (172)
1 fir (mean • SD) 9,830 74 9,640 73
7yr (mean +__SD)
4yr (mean • SD)
• 1,200 (169) • 3 (169) • 1,280 (165) • 3 (165)
17,140 • 2,200 (117) 25,110 • 3,420 (130) 103 • 4 (117) 125 • 5 (129) 16,780 • 1,870 (114) 24,230 • 3,100 (140) 124 • 5 (140) 103 • 4 (114)
Numbers in parentheses are number in each category,
control subjects the corresponding figures were 3,279 gm, 49 cm, and 38 weeks. Thus, among the dysmature infants, the high hematocrits tended to be associated with longer gestation and longer length but smaller weight than among the control subjects. Mortality. The small numbers available showed no statistical difference in the overall case mortality rate of the dysmature infants (6 of 210) as compared with that of the control subjects (2 of 210), but there was a qualitative difference. The two control infants died of immaturity associated with birth weight of < 1,000 gm* and had no specific disease findings at autopsy. All the dysmature infants who died weighed over 2,500 gm and all had significant pathologic findings.t POSTNATAL
DEVELOPMENT
Weight and height. These were measured at 4 months, 1 year, 4 years, and 7 years (Table IV). The surviving dysmature infants grew as normally as the control subjects. Neurologic examinations. The incidence of neurologically normal children among the survivors was the same in each group at each examination; at 4 months, 158/182 dysmature infants versus 159/176 control subjects; at 1 year, 162/170 versus versus 154/165; at 7 years, 117/130 versus 119/139. Psychological examinations. At 4 years, the StanfordBinet Intelligence Scale F o r m L-M was used. At 7 years, the children were evaluated by the Wechsler Intelligence Scales for children, Bender-Gestalt test for children, educational achievement (WRAT), Goodenough-Harris Draw-a-Person test, abstract language thinking (ITPA), tactile finger recognition test, and a behavioral evaluation. The overall impression then incorporated the results of *This rate, 10/1,000, closely approximates the 12/1,000 death rate of infants below 1,000 gm in the black study population as a whole. tTwo of the six deaths occurred in Stage 3 infants, who represented only 3% of the total dysmature infants. Also five of six infants who died were girls giving a mortality rate of 53/1,000 among dysmature female infants which is significantly greater than that of 18/1,000 among black female infants in the same birth weight range in the study population as a whole (p = < 0,05).
Table V, M e a n IQ scores at 4 and at 7 years 4 yr Stages of dysmaturity 2 and 3
1 Total study Control
Mean IQ + SD 94 94 94 93
_+ 17 __ 13 • 14 + 12
(16) (112) (128) (122)
7 yr
] < 70
Mean [ < 70 IQ +_ SD [ (N)
] (N) 2 9 11 6
88 + 17 (21 90 + 10 (108) 90 • 11 (129) 92 +_ II (132)
2
2 4 1
the above-mentioned subtests. There were no differences between the two groups at either age in terms of the overall impression or the m e a n IQ scores, regardless of stage o f dysmaturity (Table V), or when the mean IQ scores were calculated on the basis o f post-term versus normal gestation at 7 years (post-term dysmature infants [N = 31] = IQ 90, normal gestation dysmature infants [N = 99] = IQ 89; post-term control subjects [N = 14] = IQ 92, normal gestation control subjects (N = l l8) = IQ 92). ENVIRONMENTAL
FACTORS
There were no significant differences between the study and the control groups as related to the marital status and education of the mothers, the source and amount of family income, or the occupation of the head of the family. STAGE
3 DYSMATURITY
Only six such infants were diagnosed in this series. All were born post term; all but one were born to multigravid women; and three were born to w o m e n over 30 years of age. A m o n g these six, as might be expected, the fetal/ placental ratio was lowest; four o f the six were below the average for 40 weeks or over. O f the six neonatal deaths in the study, two occurred in this small group. DISCUSSION This first study o f dysmaturity a m o n g black infants gives an opportunity to compare the characteristics of this condition among the American black population with
Volume 90 Number 6
those reported in several studies among various white races. The overall frequency of 25/1,000 cannot accurately be compared with other studies since even the Swedish study ~ concentrated on post-term infants. However, when comparison is limited to post-term infants, the results found in this black population are very similar to those found among white caucasians. Hinselman ': recorded a study of 5,258 German infants of whom 600 (l 1%) were born after 294 days; 42 of these were dysmature (7%) or 0.8% of the total population. In the present study of 8,470 infants comparable figures are 934 (11%) were born after 286 days; 85 of these were dysmature (8%) or 1% of the total population. The overall figure for post-term dysmaturity of 80/1,000 black infants is intermediate between that given for white Americans 45-50/1,000'" and Swedish 120/1,000? The higher frequency of this condition among black male infants is similar to that reported by Sjbstedt and associates ~ and Selander 11 among Swedish dysmature infants. The mortality rate among our dysmature infants (29/ 1,000), which was triple that among our control subjects (10/1,000), is equivalent to what was calculated by Wagner '3 on statistical and epidemiologic grounds for white dysmature infants. The nonspecific placental lesions reported here are in keeping with Gruenwald's '8 statement that "no given type and extent of pathologic change is uniformally associated with a certain form or degree of effect on the fetus." It is generally agreed that dysmaturity as defined in this paper results from failure of enough nutrients from the maternal circulation to reach the fetus. Several authorsl~. 18 have differentiated the pathophysiology of this placental failure from that of intrauterine growth failure as described by Warkany and colleagues, '~ in general suggesting that the latter results from an earlier or more chronic placental dysfunction than in the condition considered here. The findings of a mean placental weight larger than expected for fetal weight and age among the severely dysmature infants in this study would be compatible with a recent change in weight due to edema, cell infiltration, or both associated, by implication, with decreased functions. As this was a study of black infants, the presence of sickle ceils in the placental sections would be expected as the anoxic state of the separated placenta provides an optimal environment for detecting latent sickling. 1'~ The finding of over twice as many placentas with sickling among the dysmature group could be explained on a more prolonged or severe state of anoxia, since Sj~stedt and associates ~ found a lower oxygen saturation in the cord arterial blood of dysmature infants than among their normal control subjects. This condition
Dysmature infants
947
increased with increasing severity of dysmaturity. The greater frequency of high hematocrit readings among dysmature infants in our study might also be suggestive of anoxia. The striking and encouraging point revealed by this study is that the black dysmature infant who survived the neonatal period had an equal chance of growing physically and mentally as normally as the nondysmature control infant. This is in contrast to Engelson and colleagues ~ finding among Swedish infants that the more severe (Stage 2 and 3) infants had a lower weight and lower IQ score at 5 years of age than the nondysmature control infants. However, in another Swedish study, Selander" commented that the postmature children appeared normal on follow-up but did not present data. The tendency for severely dysmature infants to be born to elderly primiparous women, as noted by Clifford, 3 was substantiated in part by both the present and the Swedish series. One half of our small number of Stage 3 infants were born to women 30 years old or above, but most of these were multiparous. Engelson and associates, f~ in a detailed analysis of the Swedish data, found more severely dysmature infants born to women aged 29 years than to those aged 27 years. SUMMARY This prospective study of a black inner city American population revealed the following: 1. The incidence of dysmaturity was 25/1,000, boys being relatively more frequently affected than girls. Dysmature infants were found throughout gestation but were rare before the thirty-seventh and were most common after the fortieth week. The most severely affected infants tended to be born to multiparous women over 30 years of age. 2. Two features distinguished the placentas of the dysmature from the control infants: (a) The placental weight in relation to fetal weight for gestational age tended to be greater among the dysmatures and this tendency increased with increasingly severe dysmaturity. (b) Sickle cells were found twice as frequently in the placentas of the dysmature as in those of the control infants. Otherwise, there were no specific pathologic changes that distinguished the dysmature placentas from those of the control infants. 3. There were more Apgar scores < 7 and more hematocrits _> 65% among the dysmature infants than among the control infants. 4. Outcome: (a) Mortality. Although this was low and the case fatality rate did not differ significantly between the two groups, the only deaths among the control group were immature infants ( < 1,000 gm) without specific
948
Ting, Wang, and Scott
pathologic lesions; the deaths among the dysmature infants occurred in those weighing _> 2,500 gm; all had specific pathologic changes. Of questionable significance, because of the small numbers involved, was the higher case fatality among dysmature female infants (5 of 6). (b) For the surviving infants, no difference was found in frequency of neurologic abnormalities, mean IQ's at 4 and 7 years, and physical growth in height and weight between the two groups. 5. No maternal or socioeconomic characteristics were found to be predictive for the birth of a dysmature infant. We thank Dr. L. Froehlich for the detailed studies of the placentas, and Drs. S. Levene and L. Cuasay for assistance in data collection during the early stages. REFERENCES
1. Ballantyne JW: The problem of the postmature infant, J Obstet Gynecol Br Emp 2:521, 1902. 2. Martius H: Lehrbuch der Obstrik u. Gyn~icologie, Stuttgart, 1943. 3. Clifford SH: Clinical significance of yellow staining of the vernix caseosa, skin, nails and umbilical cord, Am J Dis Child 69:326, 1945. 4. Clifford SH: Postmaturity-with placental dysfunction, J PEDIATR 44:1, 1954. 5. Sj6stedt S, Engelson G, and Rooth G: Dysmaturity, Arch Dis Child 33:123, 1958. 6. Engelson G, Rooth G, and T6rnblom M: A followup study of dysmature infants, Arch Dis Child 38:62, 1963.
The Journal of Pediatrics June 1977
7. Niswander KR, and Gordon M, editors: The women and their pregnancies, Philadelphia, 1972, WB Saunders Company. 8. Froehlich L: Personal communication. 9. Scott TFMcN, and Van Dyck O: Unpublished studies. 10. Kunstadter RH, and Schitz SE: Postmaturity and the placental dysfunction syndrome, JAMA 161:1551, 1956~ 11. Selander P: Postmature infants, Acta Pediatr 43:587, 1954. 12. Hinselman: Zur .Frage der Klinlschen Beurteilung und Behandlung der Ubertragung, Zentralbl Gynaekol 79:597, 1957. 13. Wagner MG: An epidemiologic analysis of dysmaturity, Biol Neonate 6:164, 1964. 14. Gruenwald P: Chronic fetal distress and placental insufficiency, Biol Neonate 5:215, 1963. 15. Warkany J, Monroe BB, and Sutherland BS: Intrauterine growth retardation, Am J Dis Child 102:249, 1961. 16. Wigglesworth JS: Morphological variations in the insufficient placenta, J Obstet Gynaecol Br Commonw 71:871, 1964. 17. Strand A: The function of the placenta and "placenta insufficiency" with special reference to the development of prolonged fetal distress, Acta Obstet Gynecol Scand (Suppl 1) 45:125, 1966. 18. Gruenwald P, editor: The placenta, Baltimore, 1975, University Park Press. 19. Fujikura T, and Froehlich L: Diagnosis of sickling by placental examination, Am J Obstet Gynecol 100:1122, 1968. 20. Wong TC, and Latour IPA: Microscopic measurement of placental components in an attempt to assess the malnourished newborn infant, Am J Obstet Gynecol 94:942, 1966.
943
The dysmature infant Associated factors and outcome at 7 years of age
Dysmaturity, diagnosed according to the Clifford criteria, was studied for the first time in a black population. The infants and matched control subjects were participants in the Collaborative Perinatal Study in Philadelphia from birth to 7years of age. The incidence of dysmaturity was 25/1,000 live births," more boys than girls were born dysmature, reversing the normal male~female ratio found among black infants in the Collaborative Study as a whole. The condition was more common among post-term infants but did occur in earlier gestational weeks. The overall characteristics of the condition among this black population did not differ from those previously reported among white populations of various races. Surviving infants developed mentally and physically as well as control subjects. No prenatal or environmental characteristics were found that distinguished mothers of dysmature infants from those of nondysmature infants.
Rosalind Y. Ting, M.D., M.P.H.,* Monica H. Wang, M.D., and
Thomas F. McNair Scott, M.D., Philadelphia, Pa.
THE TERM " D Y S M A T U R I T Y " used in this paper refers to infants born with absent vernix caseosa, dry desquamating skin, and frequently also with m e c o n i u m staining of the amniotic fluid. This is in contradistinction to "small for gestational age," a term sometimes used for such infants in the literature. The above description was first given to a group of postmature infants by Ballantyne ~ in 1902. Practically no further studies were published until the condition was popularized in G e r m a n y between 1939 and 1943, when a description of the condition appeared in a textbook of obstetrics.-' In the United States it was not generally recognized until Clifford :~ described it in 1945. By 1954 Clifford was able to subdivide such infants into three stages of severity, utilizing clearly recognizable clinical
From The Children's Hospital of Philadelphia and the Department of Pediatrics, School of Medicine of the University of Pennsylvania. Supported by Contract No. Ph43-68-4, National Institutes of Health. *Reprint address: The Children's Hospital of Philadelphia, 34th and Civic Center Blvd. Philadelphia, PA 19104.
criteria,* and suggested the term "placental dysfunction" as the etiologic factor? He suggested that in such infants the normal senile degeneration of the placenta occurred prematurely, thus interfering with fetal nutrition in the last weeks of pregnancy. Although he emphasized that this was mainly a condition encountered in post-term infants, he indicated that it might be observed in infants born within the normal gestational period. In 1957, SjOstedt and colleagues' carried out an extensive study of such infants born at various times of gestation, and introduced the term "dysmaturity" to indicate that the condition was not limited to post-term infants. Engelson and associates" followed this group of infants until age 4 to 5 years. An opportunity to evaluate dysmaturity among a large group of black American infants was provided by a black
*Dysmaturity-three stages of Clifford: I. Cracked, parchment-like peeling skin, thin arms and legs. More awake and alert. May have tendency to respiratory distress or vomiting, bones of skull harder than usual. II. As in I, plus thin trunk, meconium staining of amniotic fluids, green skin, nails, and umbilicus.May vomit meconium-stainedfluid. III. Trunk and limbs extremely thin, dystrophic appearance. Skin peels off in large flakes. Nails and skin yellowish.
Vol. 90, No. 6, pp. 943-948
944
Ting, Wang, and Scott
The Journal qf Pediatrics June 1977
Table I. Maternal age and gravidity versus stages of dysmaturity Maternal age Stages of dysmaturity
Total No. of infants
<_ 19 No.
3 2 1 Total Control
6 23 181 210 210
1 5 52 58 60
I
Gravidit),
20-29
30-45
Total No.
I
%
infants
No.
50.0 13.1 16,0 16.7 17.1
6 22 169 197 196
1 7 51 59 58
%
No.
%
No.
16.7 21.7 28.7 27.6* 28.6*
2 15 100 117 114
33.3 65.2 55.3 55.7 54.3
3 3 29 35 36
1
I
II-IV %
No.
16.7 31.8 30.2 29.9 29.6
2 8 77 87 91
I
>_ V
%
No.
~,
%
33.3 36.4 45.5 44.2 46.4
3 7 41 51 47
50.0 31.8 24.3 25.9 24.0
100.0 100.0 100.0 lO0.O 100.0
*Incidence of teen-age pregnancies for the total Philadelphia Collaborative Study population is 31.0%.
inner-urban population enrolled in the National Collaborative Perinatal Study in Philadelphia. CASES
AND METHODS
OF STUDY
The Collaborative Study established protocols, described elsewhere, ~ for recording details of the mother's health during pregnancy, certain socioeconomic conditions, the course of labor and delivery, the infant's condition at birth, the gross and microscopic state of the placenta, and the pathologic findings on dead infants. Theseprotocols, which mandated a diagnosis of dysmaturity when Clifford's :~ criteria were present, were completed by the staff at the Pennsylvania Hospital. Protocols were also established to follow the physical and mental growth of the children up to the age of 7 years. These protocols were completed by the staff o f the Children',s Hospital of Philadelphia. Both institutions are adjunct hospitals of the School of Medicine of the University of Pennsylvania. The infants diagnosed by dysmature were matched with an equal n u m b e r of nondysmature infants by sex, and by date of birth, within a range of three months. RESULTS O f the 8,476 infants born during the study period, 210 were classified as dysmature, a frequency o f 25/1,000 live births. O f these, 115 were boys and 95 were girls, giving a m a l e / f e m a l e ratio of 120/100 as compared with the m a l e / female ratio of 99/100 for the black study population as a whole. MATERNAL
Table II. Placenta: ratio
FACTORS
Age and gravidity distribution. Table I* displays the distribution of the mothers o f dysmature and nondysma*It will be noted that throughout the tables the total numbers will vary from the basic 210 infants. This is due to the absence of specific information from individual charts, complete data not being recorded on every chart.
Stages of dysmaturity 3 (N = 6) 2 (N = 22) 1 (N = 173) Control (N = 196)
Mean weight and fetal placental
Placental weight (mean +_SD) 540 461 418 433
_+ 87 _+ 92 _+ 98 _+ 98
Fetal/ placental ratio 6.3 7.2 7.4 7.3
+ 1.3 _+ 1.1 _+ 1.2 _+ 1.3
ture infants according to age and pregnancy experience. The overall distribution of the two groups did not differ significantly. However, Stage 3 dysmature infants were born more frequently to older and multiparous women. although such differences were not of statistical significance because of the small numbers involved. Other maternal factors. The distribution of maternal factors, such as height and prepregnant weight, complications of pregnancy, length of prenatal care, duration of labor, type of delivery, and previous reproductive loss, was essentially the same in mothers of dysmature infants as in those of control subjects. PLACENTAL
FACTORS
Gross examination. Size. With all infants, the placenta was measured in three dimensions and was weighed after being stripped of membrane and cord. No significant differences in surface area were found between the dysmature and control groups. But, as shown in Table II, there was a difference in placental weight and fetal/placental ( F / P ) ratio between the two groups. A m o n g the dysmature infants the mean placental weight of Stage 1 infants did not differ from that of the control subjects but as signs of dysmaturity increased the placental weight increased and the F / P ratio decreased. Pathologic findings. Protocol descriptions on 150
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Dysmature infants
945
Table III. Mean birth weight and length by gestational age
t.. Group Study Control
Term(37-40wk) N I Weight(+_SD) I N [ Height(+_SD)
N [
96 112
86 51
3,077 _+ 395 3,116 _+ 466
95 110
50.1 _+ 1.9 49.6 _+ 2.2
randomly selected placentas, 72 from dysmature and 78 from control infants were reviewed. The number and size of infarcts and areas of calcification did not differ significantly between the two groups. As expected from the criteria for diagnosis, there was more meconium staining in the dysmature group in a ratio of 2:1. Microscopic examination. Randomly selected placentas from the dysmature (57) and control groups (53) were studied by Dr. L. Froehlich) The most obvious difference was the increased incidence of sickling in the placentas of the dysmature infants as compared with those of the control subjects (10 of 57 = 17.5% versus 4 of 53 -- 7.5%, respectively).* The frequency of fibrinoid change in decidual vessels, commonly found in association with acute toxemia of pregnancy, did not differ in the two groups.t An increased incidence of inflammation of the cord was found among the dysmature infants which appeared to be due to irritation by meconium. The incidence of nonspecific chorioamnionitis was the same in both groups. FETAL AND NEONATAL FACTORS
Gestational age, birth weight, and birth length. By protocol, the gestational age was recorded in relation to the date of the last menstrual period rather than the appearance of the infant. This point is important when considering the appearance of the signs of dysmaturity among infants born at gestational ages less than 37 weeks. According to this criterion, 27/209 (12.9%) of the dysmature infants and 49/210 (23.3%) of the control infants were born before the thirty-seventh week. That these were not all true premature infants is indicated by the heterogeneity of the weights noted in both groups with ranges of 2,350 to 3,860 gm and 1,390 to 4,450 gm in the study and control groups, respectively. The appearance of inappropriately large infants born before the thirty-seventh week as determined by the last menstrual period has been recognized in the Collaborative Study Population as probably due to an error in dating. ~ If _< 2,500 gm is considered a cutoff weight for true prematurity, three *Thisfrequencyamongthe controlsubjects(7.5%)was twiceas great as that foundon routineexaminationof peripheral blood of the 7,780black mothers in our PhiladelphiaProject population(4%). tThe diagnosisof pre-eclampsiain the two groups was essentiallythe same, 27% in dysmatureversus24% in control.
Post-term(> 40 wk) Weight(+_SD) I N [ Height(+_SD) 3,067 ___416 3,360 ___457
83 46
50.4 + 2.3 50.7 ___2.3
such infants were classified as dysmature, giving a frequency of 3/209 or 1.4%. Excluding infants born before the thirty-seventh week by protocol definition, the remainder were born at term, 37 to 40 weeks, or post-term, after 40 weeks. More dysmature than control infants were born after the fortieth week (86/209 = 41.1% versus 51/210 = 24.3%, respectively) (p = < 0.05). The mean gestational age for dysmature infants was 39.9 + 3.5 weeks versus that of the control infants of 38.3 + 3.6 weeks (p = < 0.001). Table III records the weights and lengths of the dysmature and control infants born at term or post-term. The mean lengths of the two groups were essentially the same at term and post-term, but the mean weights of the dysmature infants were less than those of the control subjects, minimally so among the term infants but significantly so among the post-term infants (p = ,~. 0.001). These findings document the clinical impression of dysmature infants being long and thin. Apgar scores. Low scores, < 7 at 1 and 5 minutes, were significantly more frequent among the Stage 2 and 3 dysmature infants than among the control subjects (p = < 0.001). At 1 minute there were 14/25 (56%) dysmature infants versus 31 / 183 (16.9%) control subjects; at 5 minutes there were 8/29 (27.6%) dysmature infants versus 8/198 (4.0%) control subjects. Among the Stage 1 dysmature infants the frequency did not differ significantly from that among the control subjects. At 1 minute there were 32/164 (19.5%) and at 5 minutes there were 8/174 (4.6%). Serum bilirubin. The range of bilirubin levels was the same in each group (1.0 to 20 mg/dl). Hyperbilirubinemia ( > 15 mg/dl) occurred with equal frequency in each group (study 7/200 = 3.5% versus control 6/ 203 = 3.0%). Hematocrit. Although the range was the same for the two groups (30 to 71%), there was a significantly higher incidence of hematocrits ___ 65% among the dysmature infants (15/192 or 7.8% as compared with 6/188 control subjects or 3.2%; p = 0.005). When the infants with high hematocrits in the two groups were compared, a marked difference was found. For the 15 dysmature infants the mean weight, length, and gestational weeks were 3,013 gm, 50 cm, and 40 weeks, respectively; whereas for the six
946
Ting, Wang, and Scott
The Journal of Pediatrics June 1977
Table IV. Mean weights and heights at various age levels of dysmature and control infants
Group Dysmature Control
Weight (gin) and height (cm) Weight Height Weight Height
Birth (mean • SD) 3,070 50 3,080 50
4 mo
(mean +_ SD)
• 410 (208 6,320 • 860 (176) • 2 (205 63 • 2 (176) • 470 (210 6,190 • 790 (172) • 2 (206) 62 ~ 2 (172)
1 fir (mean • SD) 9,830 74 9,640 73
7yr (mean +__SD)
4yr (mean • SD)
• 1,200 (169) • 3 (169) • 1,280 (165) • 3 (165)
17,140 • 2,200 (117) 25,110 • 3,420 (130) 103 • 4 (117) 125 • 5 (129) 16,780 • 1,870 (114) 24,230 • 3,100 (140) 124 • 5 (140) 103 • 4 (114)
Numbers in parentheses are number in each category,
control subjects the corresponding figures were 3,279 gm, 49 cm, and 38 weeks. Thus, among the dysmature infants, the high hematocrits tended to be associated with longer gestation and longer length but smaller weight than among the control subjects. Mortality. The small numbers available showed no statistical difference in the overall case mortality rate of the dysmature infants (6 of 210) as compared with that of the control subjects (2 of 210), but there was a qualitative difference. The two control infants died of immaturity associated with birth weight of < 1,000 gm* and had no specific disease findings at autopsy. All the dysmature infants who died weighed over 2,500 gm and all had significant pathologic findings.t POSTNATAL
DEVELOPMENT
Weight and height. These were measured at 4 months, 1 year, 4 years, and 7 years (Table IV). The surviving dysmature infants grew as normally as the control subjects. Neurologic examinations. The incidence of neurologically normal children among the survivors was the same in each group at each examination; at 4 months, 158/182 dysmature infants versus 159/176 control subjects; at 1 year, 162/170 versus versus 154/165; at 7 years, 117/130 versus 119/139. Psychological examinations. At 4 years, the StanfordBinet Intelligence Scale F o r m L-M was used. At 7 years, the children were evaluated by the Wechsler Intelligence Scales for children, Bender-Gestalt test for children, educational achievement (WRAT), Goodenough-Harris Draw-a-Person test, abstract language thinking (ITPA), tactile finger recognition test, and a behavioral evaluation. The overall impression then incorporated the results of *This rate, 10/1,000, closely approximates the 12/1,000 death rate of infants below 1,000 gm in the black study population as a whole. tTwo of the six deaths occurred in Stage 3 infants, who represented only 3% of the total dysmature infants. Also five of six infants who died were girls giving a mortality rate of 53/1,000 among dysmature female infants which is significantly greater than that of 18/1,000 among black female infants in the same birth weight range in the study population as a whole (p = < 0,05).
Table V, M e a n IQ scores at 4 and at 7 years 4 yr Stages of dysmaturity 2 and 3
1 Total study Control
Mean IQ + SD 94 94 94 93
_+ 17 __ 13 • 14 + 12
(16) (112) (128) (122)
7 yr
] < 70
Mean [ < 70 IQ +_ SD [ (N)
] (N) 2 9 11 6
88 + 17 (21 90 + 10 (108) 90 • 11 (129) 92 +_ II (132)
2
2 4 1
the above-mentioned subtests. There were no differences between the two groups at either age in terms of the overall impression or the m e a n IQ scores, regardless of stage o f dysmaturity (Table V), or when the mean IQ scores were calculated on the basis o f post-term versus normal gestation at 7 years (post-term dysmature infants [N = 31] = IQ 90, normal gestation dysmature infants [N = 99] = IQ 89; post-term control subjects [N = 14] = IQ 92, normal gestation control subjects (N = l l8) = IQ 92). ENVIRONMENTAL
FACTORS
There were no significant differences between the study and the control groups as related to the marital status and education of the mothers, the source and amount of family income, or the occupation of the head of the family. STAGE
3 DYSMATURITY
Only six such infants were diagnosed in this series. All were born post term; all but one were born to multigravid women; and three were born to w o m e n over 30 years of age. A m o n g these six, as might be expected, the fetal/ placental ratio was lowest; four o f the six were below the average for 40 weeks or over. O f the six neonatal deaths in the study, two occurred in this small group. DISCUSSION This first study o f dysmaturity a m o n g black infants gives an opportunity to compare the characteristics of this condition among the American black population with
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those reported in several studies among various white races. The overall frequency of 25/1,000 cannot accurately be compared with other studies since even the Swedish study ~ concentrated on post-term infants. However, when comparison is limited to post-term infants, the results found in this black population are very similar to those found among white caucasians. Hinselman ': recorded a study of 5,258 German infants of whom 600 (l 1%) were born after 294 days; 42 of these were dysmature (7%) or 0.8% of the total population. In the present study of 8,470 infants comparable figures are 934 (11%) were born after 286 days; 85 of these were dysmature (8%) or 1% of the total population. The overall figure for post-term dysmaturity of 80/1,000 black infants is intermediate between that given for white Americans 45-50/1,000'" and Swedish 120/1,000? The higher frequency of this condition among black male infants is similar to that reported by Sjbstedt and associates ~ and Selander 11 among Swedish dysmature infants. The mortality rate among our dysmature infants (29/ 1,000), which was triple that among our control subjects (10/1,000), is equivalent to what was calculated by Wagner '3 on statistical and epidemiologic grounds for white dysmature infants. The nonspecific placental lesions reported here are in keeping with Gruenwald's '8 statement that "no given type and extent of pathologic change is uniformally associated with a certain form or degree of effect on the fetus." It is generally agreed that dysmaturity as defined in this paper results from failure of enough nutrients from the maternal circulation to reach the fetus. Several authorsl~. 18 have differentiated the pathophysiology of this placental failure from that of intrauterine growth failure as described by Warkany and colleagues, '~ in general suggesting that the latter results from an earlier or more chronic placental dysfunction than in the condition considered here. The findings of a mean placental weight larger than expected for fetal weight and age among the severely dysmature infants in this study would be compatible with a recent change in weight due to edema, cell infiltration, or both associated, by implication, with decreased functions. As this was a study of black infants, the presence of sickle ceils in the placental sections would be expected as the anoxic state of the separated placenta provides an optimal environment for detecting latent sickling. 1'~ The finding of over twice as many placentas with sickling among the dysmature group could be explained on a more prolonged or severe state of anoxia, since Sj~stedt and associates ~ found a lower oxygen saturation in the cord arterial blood of dysmature infants than among their normal control subjects. This condition
Dysmature infants
947
increased with increasing severity of dysmaturity. The greater frequency of high hematocrit readings among dysmature infants in our study might also be suggestive of anoxia. The striking and encouraging point revealed by this study is that the black dysmature infant who survived the neonatal period had an equal chance of growing physically and mentally as normally as the nondysmature control infant. This is in contrast to Engelson and colleagues ~ finding among Swedish infants that the more severe (Stage 2 and 3) infants had a lower weight and lower IQ score at 5 years of age than the nondysmature control infants. However, in another Swedish study, Selander" commented that the postmature children appeared normal on follow-up but did not present data. The tendency for severely dysmature infants to be born to elderly primiparous women, as noted by Clifford, 3 was substantiated in part by both the present and the Swedish series. One half of our small number of Stage 3 infants were born to women 30 years old or above, but most of these were multiparous. Engelson and associates, f~ in a detailed analysis of the Swedish data, found more severely dysmature infants born to women aged 29 years than to those aged 27 years. SUMMARY This prospective study of a black inner city American population revealed the following: 1. The incidence of dysmaturity was 25/1,000, boys being relatively more frequently affected than girls. Dysmature infants were found throughout gestation but were rare before the thirty-seventh and were most common after the fortieth week. The most severely affected infants tended to be born to multiparous women over 30 years of age. 2. Two features distinguished the placentas of the dysmature from the control infants: (a) The placental weight in relation to fetal weight for gestational age tended to be greater among the dysmatures and this tendency increased with increasingly severe dysmaturity. (b) Sickle cells were found twice as frequently in the placentas of the dysmature as in those of the control infants. Otherwise, there were no specific pathologic changes that distinguished the dysmature placentas from those of the control infants. 3. There were more Apgar scores < 7 and more hematocrits _> 65% among the dysmature infants than among the control infants. 4. Outcome: (a) Mortality. Although this was low and the case fatality rate did not differ significantly between the two groups, the only deaths among the control group were immature infants ( < 1,000 gm) without specific
948
Ting, Wang, and Scott
pathologic lesions; the deaths among the dysmature infants occurred in those weighing _> 2,500 gm; all had specific pathologic changes. Of questionable significance, because of the small numbers involved, was the higher case fatality among dysmature female infants (5 of 6). (b) For the surviving infants, no difference was found in frequency of neurologic abnormalities, mean IQ's at 4 and 7 years, and physical growth in height and weight between the two groups. 5. No maternal or socioeconomic characteristics were found to be predictive for the birth of a dysmature infant. We thank Dr. L. Froehlich for the detailed studies of the placentas, and Drs. S. Levene and L. Cuasay for assistance in data collection during the early stages. REFERENCES
1. Ballantyne JW: The problem of the postmature infant, J Obstet Gynecol Br Emp 2:521, 1902. 2. Martius H: Lehrbuch der Obstrik u. Gyn~icologie, Stuttgart, 1943. 3. Clifford SH: Clinical significance of yellow staining of the vernix caseosa, skin, nails and umbilical cord, Am J Dis Child 69:326, 1945. 4. Clifford SH: Postmaturity-with placental dysfunction, J PEDIATR 44:1, 1954. 5. Sj6stedt S, Engelson G, and Rooth G: Dysmaturity, Arch Dis Child 33:123, 1958. 6. Engelson G, Rooth G, and T6rnblom M: A followup study of dysmature infants, Arch Dis Child 38:62, 1963.
The Journal of Pediatrics June 1977
7. Niswander KR, and Gordon M, editors: The women and their pregnancies, Philadelphia, 1972, WB Saunders Company. 8. Froehlich L: Personal communication. 9. Scott TFMcN, and Van Dyck O: Unpublished studies. 10. Kunstadter RH, and Schitz SE: Postmaturity and the placental dysfunction syndrome, JAMA 161:1551, 1956~ 11. Selander P: Postmature infants, Acta Pediatr 43:587, 1954. 12. Hinselman: Zur .Frage der Klinlschen Beurteilung und Behandlung der Ubertragung, Zentralbl Gynaekol 79:597, 1957. 13. Wagner MG: An epidemiologic analysis of dysmaturity, Biol Neonate 6:164, 1964. 14. Gruenwald P: Chronic fetal distress and placental insufficiency, Biol Neonate 5:215, 1963. 15. Warkany J, Monroe BB, and Sutherland BS: Intrauterine growth retardation, Am J Dis Child 102:249, 1961. 16. Wigglesworth JS: Morphological variations in the insufficient placenta, J Obstet Gynaecol Br Commonw 71:871, 1964. 17. Strand A: The function of the placenta and "placenta insufficiency" with special reference to the development of prolonged fetal distress, Acta Obstet Gynecol Scand (Suppl 1) 45:125, 1966. 18. Gruenwald P, editor: The placenta, Baltimore, 1975, University Park Press. 19. Fujikura T, and Froehlich L: Diagnosis of sickling by placental examination, Am J Obstet Gynecol 100:1122, 1968. 20. Wong TC, and Latour IPA: Microscopic measurement of placental components in an attempt to assess the malnourished newborn infant, Am J Obstet Gynecol 94:942, 1966.