Early Human Development, 23 (1990) 15-26 Elsevier Scientific Publishers Ireland Ltd. EHD QlO68

Prenatal risk factors for cot death in very preterm and small for gestational age infants* Henk Wierengaa, Ronald Brandb, Theo Geudekec, Herman P. van Geijnc, Hans van der Harten’ and S. Pauline Verloove-Vanhorickd *Department of Pediatrics, Wilhebnina Hospital, Europaweg Zuid 1, Postbus 3WI, 9400 RA, Assen V?epartment of Medical Statistics, Leiden University, cDepartments of Pediatrics, Obstetrics and Gynecology, and Pathology, Free University Amsterdam and dDepartment of Neonatology and Paediatrics, University Hospital Leiden (The Netherlands) (Received 3 January 1990; revision received and accepted 4 April 1990)

Summary In a nationwide prospective survey on very preterm and very-low-birthweight infants in The Netherlands, the incidence of cot death in infants discharged alive was 15%0. The postnatal age at death in these infants did not differ significantly from age at death in other cot death infants. Using a case-control design, possible risk factors associated with cot death were identified: lower maternal age at first pregnancy; maternal smoking during pregnancy; hypothermia of the infant immediately after birth; decreased number of white blood cells and thrombocytes in the infant on the first day of life. Intrauterine hypoxia is hypothesized as the entity common to these factors. cot death; risk factors; intrauterine hypothermia; hematological factors.

hypoxia;

smoking

during

pregnancy;

Introduction In infants discharged from a NICU (neonatal intensive care unit), accounts for a substantial part of mortality after discharge. Considerable in the incidence of cot death in these infants has been reported [ 14,19,28,3 study considering only infants less than 1500 g at birth a cot death rate 1000 infants discharged alive was established [ 141.

cot death variation 1,471. In a of 10 per

*Report from the Project On Preterm and Small for Gestational Age Infants in The Netherlands (POPS project). 0378-3782/90/$03.50 0 1990 Elsevier Scientific Publishers Ireland Ltd. Published and Printed in Ireland

16

In the present study a specific subgroup of infants needing neonatal intensive care (viz. infants with a gestational age of less than 32 completed weeks and/or birthweight of less than 1500 g and discharged home) was considered. Apart from bronchopulmonary dysplasia [45] no other risk factors for cot death are known in this specific group of very preterm and very-low-birthweight infants. The aim of the present study was to answer the following questions: -What is the incidence of cot ‘death in very preterm and/or very-low-birthweight infants in The Netherlands?, - Is it possible to identify risk factors for cot death in these infants?

Subjects and Methods Data were collected on all liveborn infants in The Netherlands during 1983 who were born before 32 completed weeks of gestation and/or with a birthweight of less than 1500 g. The total study population consisted of 1338 infants, which is 94% of all live born infants in that year meeting the entry criteria. The POPS survey was conducted throughout the whole country (total population 14.3 million). Data on mortality and morbidity concerning this cohort were published previously [39,41]. During the initial hospital stay 340 infants died. The remaining infants, discharged alive, formed the basis for the present study. For each infant that died between 4 weeks and 2 years of age the letter of discharge was studied and further information obtained. In this way 15 cot death victims could be reliably identified in the data base of the POPS study. The hospitals where these 15 cot death victims and/or their mothers had been cared for were visited by one of the investigators (H.W.). The reports on these 15 infants and their mothers, including laboratory results, were studied. When an autopsy had been performed (ZV= 1l), the reports were collected and the histology was reviewed by a paediatric pathologist (H.H.). Then, the cot death victims were separated into four descriptive categories (Glasgow subgroups) [ 1,2]. Data acquisition was not limited to those factors already recorded within the POPS project, as other relevant factors were also obtained, e.g. factors known from the literature to be associated with cot death but not specific to preterm and/or lowbirthweight infants. For further exploration a case control study model was chosen. For each cot death victim two controls were chosen at random from the same hospital of birth. The POPS data base, from which the cases have also been selected, was used for this purpose. Before visiting each hospital for a second time, a list of all questions and items to be collected on these controls and/or their mothers was compiled (Table I). No information was obtained by the investigators on any item not included in this list. This strategy was used to avoid inflation of the statistical tests to be performed later through spotting “reniarkable differences” between the controls under study and the cases studied during the first visit.

17 TABLE I Factors studied in the case-control study. Subdivision

Factor

Maternal data

Maternal age Maternal age at first pregnancy Socio-economic class Ethnic origin Parity Obstetric history Pre-existing maternal disease Pre-existing hypertension Uncertain dates Pregnancy interval Pregnancy control Pregnancy induced hypertension Smoking during pregnancy Medication during pregnancy Hard drugs during pregnancy Alcohol abuse by the mother Multiple pregnancy Abnormal bleeding Hospital admission Electronic fetal heart rate monitoring Premature rupture of membranes Prolonged rupture of membranes Tocolysis > 24 h Administration of glucocorticoids Electronic fetal heart rate monitoring Mode of delivery Sex Gestational age Birth weight Small for gestational age Head circumference Body length Apgar score Hypothermia” Hypoglycemia Hypocalcemia Blood hemoglobin Number of white blood cells Number of thrombocytes Number of erythro-/normoblasts” Capillary pH G 1 h postpartum Idiopatic respiratory distress syndrome Artificial ventilation Continuous positive airway pressure Intracranial hemorrhage Convulsions

Data on pregnancy

Data on delivery

Data at birth and during the first days of hospital stay

Other infant data during initial hospital stay

18 TABLE I (Continued) Subdivision

Infant data after discharge

Factor

Bronchopulmonary dysplasia Apnea 2 15 s and/or bradycardia < lOO/min Age at last apnea and/or bradycardic attack Days of acidemia Days of extra oxygen need Congenital malformations Central nervous system disturbance at discharge Mean duration of initial hospital stay Weight gain during initial hospital stay Weight on discharge Weight gain after discharge Problems with feeding Respiratory problems Psychomotor development Central nervous system disturbance

‘Initially these factors were not thought to be relevant. However, on studying all the reports of the 15 cot death infants these two factors were so striking that they were included (together with other hematologic factors) in the case-control study.

All data obtained on the future cot death victims and their respective controls were kept in a separate data base. Data management, random selection of controls and part of the statistical analysis was carried out with SPSS (Statistical Package for the Social Sciences, version SPSSX-2.1). Differences between cases and controls were analysed by means of (conditional) logistic regression analysis. The analysis was carried out conditionally because the controls were matched to cases individually. Because of the small number of cases in this study compared to the number of factors of interest, each factor was first examined univariately in terms of its risk for cot death using the appropriate conditional logistic regression technique. Factors with P-values < 0.10 were retained for a multivariate analysis. After that a (stepwise, backwards) multivariate analysis was performed on a model containing these factors. The logistic regression was performed by the procedure PROC PHGLM of SAS (Statistical Analysis System). This procedure computes a conditional logistic regression when each stratum contains exactly one case. Age at death in the 15 cot deaths was compared to age at death in all other cot deaths in The Netherlands during 1983 (N = 191) (181, Central Bureau of Statistics, Voorburg, personal communication) by means of a survival analysis (Kaplan-Meier product-limit estimation; Cox Mantel test).

19

TABLE II Descriptive categories of cot death.

A Cause identified B Incidental findings C Negative findings D No cause known, no necropsy

N

%

0 4 I 4

0 27 46 27

Results

The population consisted of 1338 infants of whom 340 died during the initial hospital stay. Of the remaining 998 infants discharged alive, 15 infants (10 boys, 5 girls) died of cot death. Table II shows the descriptive categories of these cot deaths (Glasgow subgroups [ 1,2]). In comparing age at death of these POPS cot deaths to other cot deaths that year,

i ..... ... .._

I

i

i..,“.., J

1

I I i

ii

‘: 8 L i i

\

” I :. . . . . . .

I

“...-“..“l”....-..“..-

. . . .

c

30

60

Qo

120

150

I80

2lo

240

270

300

330

360

NUMBER OF DAYS -

OTH3l

._..”._....wps

P=O.83 (coxMantal) Fig. 1. Comparison of POPS cot death vs. other cot deaths.

20 TABLE III Factors significantly associated at the 10% level with cot death (univariate conditional logistic regression analysis). Item

Maternal age at first pregnancy (per year increase) Smoking during pregnancy (yes/no)d Hypothermia (< 35.5 “C) White blood cells (per 1 x 104/l increaser Thrombocytes (per 100 X l@/lincrease) Duration of hospital stay (per week increase) Weight gain per day in grams (per gram increase)

CLR with MLE of the ORa

Approximate 954roconf. int.

LR test P-valueb

0.79

[0.61, 1.0)

0.03

5.0

[l .o, 251

0.03

10.8 0.81

[1.3,89] [0.65, 1.01

0.004 0.02

0.39

[0.13,1.1]

0.06

1.16

[0.98, 1.41

0.06

0.79

[0.63,0.99]

0.02

‘Conditional logistic regression with maximum likelihood estimation of the odds ratio. bP-value associated with the MLE. ‘As a continuous factor. dMissing in one mother of the case-group: treated as non-smoker.

no significant difference was found in the distribution of postnatal age at death between these two groups (Fig. 1). In the univariate conditional logistic regression analysis 7 significant associations with an increased cot death risk were found (Table III): - lower maternal age at first pregnancy - maternal smoking during pregnancy - hypothermia of the infant immediately after birth TABLE IV Model with remaining associated factors in the multivariate conditional logistic regression analysis. Item

Maternal age at first pregnancy Smoking during pregnancy Hypothermia

Approximate 95% conf. int.

LR test P-valueb

0.69

[0.48, 1.OO]

0.01

2.39

[0.73,7.76]

0.12

[0.95,260]

0.02

CLR with MLE of the OR”

16

21

-

decreased number of white blood cells at birth decreased number of thrombocytes at birth longer mean duration of initial hospital stay decreased growth/day during initial hospital stay.

In the multivariate analysis of these factors the univariate association of the latter two disappeared. Table IV shows the odds ratios and their 95% confidence intervals for the remaining factors. Since, in a multivariate analysis, the infant will not enter the computations when at least one of the independent variables has a missing value, the factors white blood cells and thrombocytes were excluded because in five infants at least one of them was absent. However, the coefficients for smoking, hypothermia and maternal age at first pregnancy revealed no relevant changes in their associations with cot death as expressed by the odds ratios when each hematologic factor was added separately to the model. Hence, we may be confident that the hematologic factors were not confounding variables and that estimates of the factors in Table IV are not biased because these two hematologic factors were left out of the model. Although smoking during pregnancy formally does not reach statistical significance it is felt justified in view of high odds ratio in the univariate analysis (5.0, approximate 95% confidence interval 1.0, 25) and numerous data from literature, to consider it as a risk factor of major concern. Almost 80% of the cot death mothers were smokers (40% in the control group). Half of the cot death mothers were heavy smokers (> 10 cigarettes/day) versus 23% in the control group. In one of the case mothers smoking during pregnancy was unknown. She was considered as a non-smoker in the analysis. (If she is treated as a smoker, then the odds ratio for smoking becomes statistically significant at the 5% level.) By comparing the birthweight percentiles according to Kloosterman [16] of future cot death infants and their own controls, no trend towards the lower percentiles was found (Pvalue 0.60; odds ratio 0.99). Discussion Bearing in mind the limitations imposed by the number of infants in the study, it can be concluded that lower maternal age at first pregnancy, maternal smoking during pregnancy, hypothermia on the first day of life and a decreased number of white blood cells and thrombocytes at birth result in increased risk for cot death in very preterm and/or very small for gestational age infants. Bronchopulmonary dysplasia, the only known risk factor in this specific group of very preterm and very-low-birthweight infants, was not found to be associated with cot death in the present study. Well-known risk factors in other infants (e.g. hard drugs during pregnancy, lower socio-economic class, decreased growth after birth) could not be confirmed in this specific group. Bergman and Wiesner were the first to report a relationship between smoking during pregnancy and cot death [6]. Later on this was confirmed in several other studies [13,20,25,34,36]. It has been known for many years that smoking during

22

pregnancy is associated with a lower birthweight [3,10,15,24,32,37,40]. A decreased deposition of subcutaneous fat is frequently supposed to be the main cause for this lower birthweight. Recently, however, a deficit of lean body mass in infants of smoking mothers was demonstrated, suggesting a complex effect of smoking [32]. In addition to nicotine, carbon monoxide, carbon dioxide, cyanide and cadmium, many other compounds of tobacco smoke may have adverse effects [43]. Some authors particularly emphasize the role of nicotine [ 18,2 11, others emphasize the role of carbon monoxide [29]. A combined effect has also been proposed. Nicotine reduces placental blood flow and causes an acute but transient hypoxia in fetal blood. Carbon monoxide is responsible for a morechronic type of fetal hypoxia as it binds to the hemoglobin of the fetus [7]. Carboxyhemoglobin was reported to be combined by an increased oxygen affinity of the remaining fetal hemoglobin (shift of the oxygen dissociation curve to the left) [48]. Little is known from the literature about hypothermia on the first day of life (first recorded body temperature) as a risk factor in future cot death victims. Only more than normal fluctuations around a normal range [25] and episodic hypothermia during the first year of life were reported [ll]. Due to the design of the present study (matching for hospital of birth), the environmental temperature at birth presumably did not differ between cot death infants and their controls. Also future cot death infants appeared not to be more asphyxiated at birth compared to controls, as Apgar scores and capillary blood gases after birth did not differ significantly in both groups. As mean bodyweight and gestational age did not differ significantly, it is difficult to hold that a different fat content in both groups was responsible for the hypothermia, although in fact body composition in both groups is unknown. Given these conclusions, particular attention should be paid to carbohydrate metabolism in searching for an explanation for hypothermia after birth. With respect to hypoglycemia as a possible cause of hypothermia, the findings of Soothill et al. on infants with intrauterine growth retardation should be considered [30]. In umbilical venous blood samples, they found in the majority an oxygen tension below the normal range. Moreover, hypoxia appeared to be correlated with low glucose concentrations. Hypoxia can precede growth retardation. In such cases, hypoxia is probably associated with chronic hypoglycemia and deprivation of other nutrients [27], which may lead to hypothermia. In the present study, intrauterine glucose levels were not available, and almost all infants received intravenous glucose infusion immediately after birth. Thus, intrauterine and/or perinatal hypoglycemia may have been obscured. In the univariate conditional regression analysis, two hematological factors were significantly associated with cot death: fewer white blood cells and fewer thrombocytes at birth. The hemoglobin concentrations tended to be higher in future cot death infants (11.7 + 2.3 vs. 10.8 + 2.0 mmol/l). In mice, intrauterine hypoxia resulted in growth retardation, polycythemia and a transitory postnatal thrombocytopenia [22]. This inverse relationship between hematocrit levels and thrombocyte counts was explained by a competitive mechanism of erythropoiesis and thrombopoiesis on common stem cells. The same phenomenon has been observed in a study on small-for-gestational-age infants [23].

23

The higher hemoglobin concentration combined with a lower platelet count and fewer white blood cells, as found in the present study, may be explained again by competition on a common stem cell owing to hypoxia. It is difficult to distinguish between the effects of hypoxia and growth retardation as they are interrelated. In the present study, growth retardation in future cot death infants was absent, but this may be because the study was confined to very preterm infants (mean gestational age at birth 30.3 weeks in both groups). Growth retardation in this early stage of the third trimester was possibly not severe enough to be manifest. Data from the literature are in agreement with a growth retardation-cot death relationship [13,33,44]. A higher cot death incidence in twins seems generally restricted to lower birthweight [4,17], and particularly the lighter twin appears to be at increased risk [4,13]. This may be another argument for a hypoxic component. Studies which do not account for both gestational age and birthweight are of limited importance as growth retardation is ignored. Presence of intrauterine hypoxia, however, could not be demonstrated in the present study. How can this lack of evidence be explained? In many infants electronic monitoring of fetal heart rate was not performed. Moreover, variability in the interpretations of fetal heart rate patterns, even by experts, is striking and worrisome [38]. It may be questioned if present assessment of fetal condition is sensitive enough to detect correctly the presence of hypoxia [42]. Acidemia may be absent at birth in spite of intrauterine hypoxia [5]. In the present study future cot death infants had normal Apgar scores but their value in assessing the infant’s condition (e.g. perinatal hypoxia) has been questioned [9,35]. Assuming intrauterine hypoxia, why were we unable to demonstrate abnormal psychomotor development or central nervous system disturbance in the cot death group? Caution is needed in interpreting these results as four infants died soon after discharge without any check-up and another five infants died before the corrected age of 3 months and had not received standardized assessments. A striking fact is the lack of evidence of a difference in postnatal age at death in this specific group. With regard to birthweight, Goldberg et al. [12] also demonstrated that even in very low birthweight groups the age at death did not differ from that of infants with normal weight at birth. Likewise, Wagner et al. [44] and Norvenius 1261were unable to show a different age at death in their studies. This fact seems very important for our thinking about cot death as (partly) a developmental phenomenon resulting in high vulnerability at a specific age. In conclusion, intrauterine hypoxia emerged as an entity common to many of these factors. This might result in subtle damage of the brain stem, thereby leading to abnormal sleeping patterns and abnormal arousal responses to hypoxia and/or hypercapnia after birth. This, together with another striking finding, namely equal chronological age at death (notwithstanding the very preterm birth) has led us to propose the following framework for further research on contemplation about cot death: - Future cot death infants experience intrauterine discrete tissue damage.

insults (hypoxia) resulting in

24

After birth, these infants are vulnerable for cot death due to these intrauterine insults. - In postnatal life a normally innocent factor may trigger the final pathway to death during sleep. - The vulnerability is related to a specific postnatal age distribution. -

Not all cot death infants can be included in such a model (e.g. those arising from some inborn errors of metabolism) but it should serve to provoke further research on the network of causes involved in cot death [46]. Acknowledgements This study was financially supported by the Praeventiefonds, The Hague (grant 28-1429). We thank the paediatricians and the obstetricians of the hospitals involved in this study. Also, we are grateful to Professor Brian Hopkins for his helpful comments and Mrs Gellie Wierenga for typing the manuscript. References 1 2

3 4

5

6 7

8 9 10 11 12 13 14

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