Prenatal growth and risk of occlusive and haemorrhagic stroke in Swedish men and women born 1915-29: historical cohort study

Evidence for an inverse association of impaired fetal growth with stroke is less securely established than that with coronary heart disease. Even less is known about the association of fetal growth with occlusive stroke and haemorrhagic stroke.

Participants, methods, and results

The cohort comprises all 14 611 births in the Uppsala Academic Hospital between 1915 and 1929.¹ Socioeconomic circumstances and neonatal characteristics, including gestational age (number of completed weeks since last menstrual period), were available for 96% of the subjects from hospital records and follow up is 98% complete. Analyses were restricted to singletons born at 30-45 weeks' gestation for whom information was available in the 1960 and 1970 censuses. Data on occurrence of first stroke were obtained from the Swedish national hospital discharge register² and from the national cause of death register. Two subtypes of stroke were defined—haemorrhagic (ICD-8 (international classification of diseases, 8th revision) 430-431; ICD-9 430-432) and occlusive (ICD-8 432-436; ICD-9 433-436). Each participant was considered at risk from the time of the 1970 census to date of first stroke, emigration, death, or end of follow up (31 December 1996).

The 10 853 men and women had 991 first strokes—156 haemorrhagic, 775 occlusive, and 60 ill defined. Death certificates identified 41 (26%) first haemorrhagic strokes and 17 (2%) occlusive strokes. Of haemorrhagic strokes, 21 (13%) were subarachnoid and 135 (87%) intracerebral or unspecified intracranial haemorrhages.

Cox proportional hazards model showed birth weight inversely associated with risk of haemorrhagic stroke and little evidence of association with occlusive stroke. Hazard ratio per 1 kg increase in birth weight (adjusted for sex and period of birth) was 0.61 (95% confidence interval 0.45 to 0.83) for haemorrhagic stroke and 0.89 (0.77 to 1.03) for occlusive stroke. Adjustment for socioeconomic factors at birth and at the time of the 1960 and 1970 censuses had little effect on estimates (table). When head circumference and birth length were adjusted for separately and in combination, the inverse association between birth weight and haemorrhagic stroke strengthened but there was little effect on the association of birth weight with occlusive stroke. Adjustment for gestational age had no substantive effect on the estimates.

Comment

Impaired fetal growth is strongly associated with haemorrhagic stroke, but not with occlusive stroke. This finding is consistent with results from a smaller cohort of Finnish men.³ The strength of the association between impaired fetal growth and haemorrhagic stroke is appreciably greater than that found with coronary heart disease in the same Swedish cohort.¹ The associations were not accounted for by socioeconomic confounding factors, and they were not affected by adjustment for gestational age.

The inverse association of size at birth with haemorrhagic stroke in the Finnish cohort was apparent only after adjustment for head circumference, and this was interpreted as showing an association between stroke and in utero “head sparing.” We found a pronounced inverse association with birth weight without adjustment for other birth dimensions, and adjustments for both birth length and head circumference strengthened the association with haemorrhagic stroke. These data do not support a special role for birth weight relative to head size, but they suggest that the risk of haemorrhagic stroke is related to impaired growth of soft tissue mass relative to bone growth.⁴

The established aetiology of stroke differs by subtype, although hypertension is an important risk factor for occlusive and haemorrhagic stroke. Raised blood pressure is also associated with impaired fetal growth.⁵ However, whether the difference between stroke subtypes in the strength of the association of stroke with birth weight is mediated by blood pressure has yet to be established.

Table.

Adjusted hazard ratios (95% confidence interval) for haemorrhagic and occlusive stroke according to birth weight in Swedish men and women born between 1915 and 1929^*

	Haemorrhagic stroke						Occlusive stroke
	No	Adjusted for core variables†‡	Adjusted for core variables and head circumference	Adjusted for core variables and birth length	Adjusted for core variables, head circumference, and birth length		No	Adjusted for core variables†	Adjusted for core variables and head circumference	Adjusted for core variables and birth length	Adjusted for core variables, head circumference, and birth length
Birth weight (g):
<2750	17	1	1	1	1		53	1	1	1	1
2750-3249	33	0.49 (0.27 to 0.89)	0.41 (0.22 to 0.77)	0.46 (0.24 to 0.87)	0.39 (0.20 to 0.77)		181	0.90 (0.66 to 1.22)	0.91 (0.67 to 1.25)	0.90 (0.65 to 1.25)	0.92 (0.66 to 1.28)
3250-3749	62	0.54 (0.32 to 0.94)	0.41 (0.22 to 0.78)	0.48 (0.24 to 0.95)	0.38 (0.18 to 0.80)		274	0.80 (0.59 to 1.07)	0.82 (0.59 to 1.14)	0.80 (0.56 to 1.13)	0.82 (0.57 to 1.18)
3750-4249	28	0.46 (0.25 to 0.84)	0.35 (0.17 to 0.73)	0.41 (0.19 to 0.91)	0.33 (0.14 to 0.78)		159	0.87 (0.64 to 1.19)	0.90 (0.63 to 1.29)	0.85 (0.58 to 1.26)	0.88 (0.58 to 1.33)
⩾4250	3	0.17 (0.05 to 0.59)	0.14 (0.04 to 0.52)	0.18 (0.05 to 0.73)	0.15 (0.04 to 0.64)		40	0.79 (0.52 to 1.20)	0.82 (0.52 to 1.31)	0.78 (0.48 to 1.28)	0.81 (0.48 to 1.37)
Hazard ratio per 1 kg increase in birth weight		0.59 (0.43 to 0.83)	0.49 (0.32 to 0.75)	0.53 (0.33 to 0.84)	0.45 (0.27 to 0.76)			0.93 (0.80 to 1.09)	0.96 (0.80 to 1.16)	0.94 (0.76 to 1.15)	0.96 (0.76 to 1.20)
Test for trend		P=0.009	P=0.008	P=0.05	P=0.03			P=0.29	P=0.53	P=0.38	P=0.52

^*Analyses restricted to n=10 009 subjects with information available for all the variables in each stage of modelling. 

^†Core variables=sex, period of birth, and social trajectory. 

^‡Social trajectory consists of parental social characteristics (mother's civil status and social group) and indicators of participant's own social status in adulthood (social group, car ownership from 1960 census, education, income, and car ownership from 1970 census).