1 The epidemiology of preterm birth

1 The epidemiology of preterm birth JUDITH

LUMLEY

One of the ways in which epidemiology may contribute to understanding the determinants of a disorder is by comparing the incidence and prevalence of the disorder in different places and in the same place at different times. When the disorder in question is preterm birth there are major problems in making international comparisons or interpreting secular trends. This is in part because of differences in the way that births are registered in different countries, and in part because of changes in definitions within some countries over time (Mugford, 1983; Hoffman et al, 1984). REGISTRATION

The World Health Organization defines preterm birth as birth before 37 completed weeks of gestation or fewer than 259 days since the first day of the last menstrual period. The problematic part of this definition is the stage of pregnancy at which the borderline between spontaneous abortion and birth is set. Stillbirths or late fetal deaths are registered from 16 weeks of gestation in Norway and from 20 weeks of gestation in the USA and Australia; but in England, Sweden and New Zealand (among many other countries) the boundary for registration is 28 weeks. Although relatively few pregnancies end between the 16th and 28th weeks of gestation, the ones that do end at this time contribute a disproportionate number of stillbirths (Table 1). There are no international differences in the definition of a live birth: 'the complete expulsion or extraction from its mother of a product of conception, irrespective of the duration of the pregnancy which after such separation breathes or shows any other evidence of life such as beating of the heart, pulsation of the umbilical cord, or definite movement of the voluntary muscles, whether or not the umbilical cord has been cut or the placenta is attached' (World Health Organization, 1977). These signs of life may be seen transiently in a fetus born early in the second trimester, but at 14 or 15 weeks of gestation it would be most unlikely for that fetus to be registered as a live birth and a neonatal death. Extraneous factors come into play. One set of factors is the local criterion for registration of a stillbirth. If a fetus is born showing signs of life and dies soon after birth it may not be counted as a live birth if it would not have required registration as a stillbirth (Shapiro and Bross, 1980). A careful scrutiny of Baillibre's Clinical Obstetrics and Gynaecology-477 Vol. 7, No. 3, September 1993 Copyright © 1993, by Bailli~re Tindall ISBN 0-7020-1707-8 All rights of reproduction in any form reserved

478

J. LUMLEY Table I. Preterm births and deaths by week of gestation: Victoria, Australia, 1990. Births

Gestation (weeks) 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36

Deaths

Number

%

Cum %

SB + NND

%

Cum %

PMR

39 38 51 47 67 63 72 77 93 96 141 131 248 331 520 770 1709 4493

0.9 0.9 1.1 1.0 1.5 1.4 1.6 1.7 2.1 2.1 3.1 2.9 5.5 7.4 11.6 17.1 38.0 100.0

0,9 1.7 2.8 3.9 5.4 6.8 8.4 10.1 12.2 14.3 17.4 20.4 25.9 33.3 44.8 62.0 100.0 100.0

30 + 9 29 + 9 37+14 26 + 20 34 + 25 20 + 18 17 + 14 17 + 11 19 + 18 12 + 9 13+8 14 + 6 18 + 5 24+6 19 + 16 16 + 9 26 + 12 371 + 209

6.7 6.6 8.8 7.9 10.2 6.6 5.3 4.8 6.4 3.6 3.6 3.4 4.0 5.2 6.0 4.3 6.6 100.0

6.7 13.3 22.1 30.0 40.2 46.7 52.1 56.9 63.3 66.9 70.5 74.0 77.9 83.1 89.1 93.4 100.0 100.0

1000 1000 1000 979 881 603 431 364 399 219 149 153 92.7 90.6 67.3 45.4 22.2 129.1

Cum %, cumulative percentage; NND, Neonatal deaths; PMR, perinatal mortality rate (perinatal deaths per 1000 total births); SB, stillbirths. Source: Perinatal Data Collection Unit, Health Department, Victoria.

h o s p i t a l r e c o r d s in A m s t e r d a m a n d L i v e r p o o l has s h o w n t h a t such u n d e r r e g i s t r a t i o n o f live b i r t h s can b e s u b s t a n t i a l , l e a d i n g to 14% o f p e r i n a t a l d e a t h s g o i n g u n r e c o r d e d ( D o o r n b o s et al, 1987; P o w e l l et al, 1987). I n b o t h cities r e g i s t r a t i o n o f stillbirths d o e s n o t b e g i n until 28 w e e k s o f g e s t a t i o n . A n o t h e r f a c t o r m o d i f y i n g t h e r e g i s t r a t i o n of e x t r e m e l y p r e t e r m (20-27 w e e k s ) l i v e b o r n infants is t h e p e r c e p t i o n o f t h e i r viability. T h e d e v e l o p m e n t o f a local n e o n a t a l i n t e n s i v e c a r e unit can h a v e a d r a m a t i c effect on p e r c e p t i o n s o f v i a b i l i t y , w i t h an a p p a r e n t r e g i o n a l i n c r e a s e in p r e t e r m b i r t h s ( M u t c h et al, 1981). T h e effect m a y e v e n b e n o t i c e a b l e in n a t i o n a l vital statistics. I n c r e a s e s h a v e b e e n r e p o r t e d b o t h f r o m N e w Z e a l a n d a n d S c o t l a n d ( M a c f a r l a n e et al, 1988; M o r e l l , 1990) w h e r e t h e y a r e l i k e l y to reflect b e t t e r a s c e r t a i n m e n t o f e x t r e m e l y p r e t e r m l i v e b o r n infants associa t e d with i m p r o v e d c h a n c e s f o r t h e i r survival. O t h e r social a n d c u l t u r a l factors t h a t influence r e g i s t r a t i o n p r a c t i c e i n c l u d e t h e p r o v i s i o n o f m a t e r n i t y b e n e f i t s , the cost o f f u n e r a l s a n d t h e d i f f e r e n t i a l h o s p i t a l c h a r g e s for a ' m i s c a r r i a g e ' a n d a ' c o n f i n e m e n t ' . T h e listing o f live b i r t h s a n d n e o n a t a l d e a t h s b y i n d i v i d u a l w e e k o f g e s t a t i o n ( T a b l e 1) shows t h e p o t e n t i a l i m p a c t o n b i r t h s a n d d e a t h s o f i n c o m p l e t e r e g i s t r a t i o n b e f o r e t h e 28th w e e k o f g e s t a t i o n . T h u s , i n t e r n a t i o n a l c o m p a r i s o n s t h a t a r e n o t b a s e d on a d e t a i l e d k n o w l e d g e o f t h e f o r m a l a n d i n f o r m a l r e g i s t r a t i o n p r a c t i c e will be s e r i o u s l y m i s l e a d i n g .

E P I D E M I O L O G Y OF PRETERM BIRTH

479

MEASURING GESTATIONAL AGE With rare exceptions, such as births resulting from assisted conception, the time of conception is unknown. As a substitute, gestational age is calculated from the first day of the last menstrual period (LMP), a date about 14 days before conception. The LMP is uncertain or unknown in up to 20% of pregnancies in vital statistics from the USA (National Center for Health Statistics, 1982), slightly more than in Australia where the figure is 13.7% (J. Lumley, unpublished data). There are also cases where the LMP is an unreliable guide to the date of conception, for instance in women with long menstrual cycles or irregular cycles, women ceasing hormonal contraception or women conceiving soon after a spontaneous abortion or while breastfeeding. Dissatisfaction with the LMP approximation has led to the use of alternative estimates which are not, strictly speaking, measures of fetal age but rather of fetal size (ultrasonographic measurements) or fetal maturity (neurobehavioural assessment of the neonate). There is no true 'gold standard' for gestational age. Recent evidence in a large hospital population is that fetal age derived from early ultrasonographic measurements of fetal size gives a better prediction of the date of spontaneous delivery than predictions based on the LMP (Kramer et al, 1988). At the same time, Goldenberg et al (1989) in Alabama demonstrated how the shift from LMP and clinical pregnancy assessment to reliance on ultrasonographic evidence, together with calculation of completed weeks of gestation instead of rounding off the weeks, was associated with an apparent increase in the preterm birth rate from 12% to 17%, despite an unchanged birthweight distribution. This exemplifies the contribution of definitional issues to preterm birth rates. Unfortunately, women with an unknown or uncertain LMP are more likely to be late attenders for antenatal care, in which case their ultrasonographic measurements are a less reliable guide to fetal age (Hall et al, 1985). It is tempting to restrict descriptive and analytic studies to women for whom gestational period at delivery is reasonably certain, but the excluded women have a significantly worse perinatal outcome (Hall and Carr-Hill, 1985). In practice, careful case review by an experienced clinician using all available data may provide a good estimate of gestational age, but this process is not applicable to large routine data systems, which lack sufficient information to do more than give an 'imputed' gestation to those where the month of the LMP is known. Unfortunately, hospital-based studies are rarely large enough to be able to consider births before 28 weeks of gestation or even before 32 weeks as separate categories.

TRENDS IN P R E T E R M BIRTH RATES

In general, preterm birth rates have been relatively stable in developed countries over the past 10-20 years, increasing only in places where the observed effect is likely to be the result of improved ascertainment. In the

480

j. LUMLEY

USA, England and Wales, and Norway, there has been little or no change (Hoffman and Bakketeig, 1984; Kessel and Berendes, 1984; Macfarlane and Mugford, 1984; Paneth, 1986). Over a longer period, there have been some documented reductions, at least at a regional level. The preterm delivery rate in Aberdeen (Scotland) fell from 9.3% of all births in 1951-1955 to 6.8% in 1976-1980 (Hall, 1985). The most striking exception to the widespread stability in preterm birth rates is France, where preterm births declined from 8.2% to 5.6% between 1972 and 1981. There was a reduction of births below 34 weeks of gestation, not just a fall in the mildly preterm group (Papiernik et al, 1985; see also Chapter 2). Attention to the absolute rates shows that the changes in France are equivalent to a move from a level close to that in the USA to a level very similar to that in Australia.

HETEROGENEITY IN PRETERM BIRTHS

Although preterm delivery is often treated as if it were a clear-cut yes/no variable, in reality it is nothing of the kind. At the lower boundary, despite underregistration of infants perceived to be non-viable, the least mature 5 % of infants incur over 40% of preterm deaths (Table 1). Prolongation of pregnancy by 1 week at this stage (20-24 weeks of gestation) would have no effect on the preterm birth rate. Such prolongation might even increase preterm births and preterm deaths if pregnancies ending just before the 20th week were similarly prolonged and some previously excluded fetuses were registered. At the upper boundary more than a third of all preterm infants are born after 36 completed weeks of gestation and more than half after 35 weeks. Even a minor prolongation of pregnancy close to this boundary would make a substantial difference to the rate of preterm birth, yet the probable change in preterm death or other adverse outcomes would be quite small. Thus, one of the ways in which preterm births are heterogeneous is the extent to which gestation is shortened: extremely (20-27 weeks), moderately (28--31 weeks) and mildly (32-36 weeks). About 10% of preterm births are extremely preterm, another 10% are moderately preterm and 80% are mildly preterm. The other major source of heterogeneity is the nature of the preterm delivery--whether the delivery is an elective procedure carried out because of maternal or fetal disorders, whether it results from premature labour complicated by additional adverse factors such as antepartum haemorrhage, or whether it results from preterm labour alone (Rush et al, 1976). In the last 5 years, there has been interest in subdividing preterm labour into spontaneous preterm labour and preterm ruptured membranes, as these appear to have different antecedents (Hadley et al, 1990; Tucker et al, 1991; Savitz et al, 1991; Williams et al, 1992). The relative proportions of the four groups varies in different populations (Rush et al, 1976; Hewitt and Newnham, 1988; Savitz et al, 1991).

EPIDEMIOLOGY OF PRETERM BIRTH

481

EPIDEMIOLOGICAL ASSOCIATIONS The classic epidemiological associations of preterm birth have been identified consistently in Europe and North America over the past 25 years. These associations, which are interrelated, are those of poverty and relative social disadvantage. Preterm birth has almost always been treated as a single category: this means that the findings have been dominated by the high proportion of preterm infants born after 32 weeks of gestation, so that the classic associations are with mildly preterm birth. It cannot be assumed that they will apply equally to the other two categories of preterm birth. Only one recent source has contributed specific information on preterm birth and socioeconomic studies with a sufficiently large data set to examine preterm births within gestation groups. Scottish data from all births in the years 1980-1984 (over 320 000) indicated social class differences of similar magnitude for infants born at 20-27 weeks, 28-31 weeks and 32-36 weeks of gestation. The relative risks for infants born to fathers whose occupation was classed as 'unskilled', compared with those whose occupation was recorded as 'professional', were 1.83 for births at 20-27 weeks, 2.29 for births at 28-31 weeks and 1.71 for preterm births at or after 32 weeks. The relative risks were even greater (2.25, 2.65 and 2.00 respectively) when the father was unemployed or the parents unmarried (Macfarlane et al, 1988). Marital status

The associations of marital status with preterm births are different in different age groups. For women under 25 years old, it seems to be irrelevant whether they are married, living with a partner or single: extremely, moderately and mildly preterm birth rates are not significantly raised in the unmarried groups (Table 2). When the overall association of marital status with preterm birth is calculated taking maternal age into account, the weighted relative risk of birth before 28 weeks is 1.82 for women in de facto relationships and 1.71 for single women. The corresponding weighted relative risks of birth at 28-31 weeks are 1.35 and 1.57, and those for birth at 32-36 weeks are 1.20 and 1.28. Single status was associated with an increased risk of preterm birth in a largely black, indigent population in the USA. The odds ratio adjusted for a wide range of other biological social and behavioural factors was 1.20. (Wen et al, 1990). The inconsistency across age groups of the effects of marital status in Table 2 suggests that marital status may be a poor proxy measure for some more complex social factors such as social support. Maternal age and parity

Table 3 summarizes preterm births, grouped by length of gestation (20-27 weeks, 28-31 weeks and 32-36 weeks), for different combinations of maternal age and parity in the same population as Table 2.

482

J. LUMLEY

Table 2. Preterm birth in singletons, by marital status and maternal age: Victoria, 1986-1990. Gestation (weeks) Age (years)

Marital status

20-27 n/lO00

28-31 n/1000

32-36 n/lO00

All preterm n/1000

<20

Total births n

M DF S

5.5 9.4 7.0

7.5 9.4 8.2

50.1 51.3 52.6

63.1 70.0 67.5

4152 1 599 7718

20-24

M DF S

5.1 5.8 5.8

6.9 7.2 8.9

53.5 52.6 58.1

65.5 65.6 72.8

35 999 4 452 10497

25-29

M DF S

4.0 8.7 10.4

4.7 6.6 10.8

39.2 54.8 64.3

47.9 70.4 85.5

110 557 3926 5085

30-34

M DF S

4.7 11.0 12.5

5.0 9.4 10.1

42.7 59.5 74.6

67.8 79.9 97.2

78 045 2 554 2 078

35-39

M DF S

6.7 13.7 19.3

6.4 10.6 16.3

53.8 67.7 77.3

66.9 92.0 112.9

23917 946 673

40+

M DF S

9.4 26.5 (--)

8.4 (10.6) (9.2)

66.4 100.5 100.9

84.2 137.6 110.1

3 314 189 109

DF, living as married; M, married; S, single, ( ), too few cases. Source: Perinatal Data Collection Unit, Health Department, Victoria.

108

~

.~6t~

.0

E =4¢,j

0

I 0

I 1

I 2

I 3

Parity Figure 1. Preterm delivery rates in siblings of two, three and four pregnancies (broken line, based on cohorts of mothers by sibship size; solid line, based on cross-sectional analysis). From Bakketeig and Hoffman (1981), with permission.

483

EPIDEMIOLOGY OF PRETERM BIRTH

Table 3. Preterm birth in singletons, by parity and maternal age: Victoria, 1986-1990.

Gestation (weeks) Age (years)

20-27 Parity

n/lO00

28-31 n/1000

32-36 n/1000

All preterm n/1000

Total births n

< 20

0 1 2 3

6.8 7.9

7.6 12.5

51.3 55.0 (78.4) (--)

64.9 75.4 78.4 (--)

11551 1765 153 14

20-24

0 1 2 3

4.9 4.6 5.3 8.3

6.7 4.8 6.9 8.3

46.9 42.1 52.4 64.2

57.9 51.4 64.6 80.7

35 778 19065 4923 966

25-29

0 1 2 3

4.6 3.7 4.2 8.4

5.9 4.1 4.2 6.5

49.6 33.8 34.5 44.6

60.0 41.5 42.8 59.5

49301 44604 19 758 5 499

30-34

0 1 2 3

5.3 4.6 3.8 6.0

7.3 4.7 3.9 5.7

60.5 38.6 35.2 40.4

72.9 47.9 42.9 52.1

20 860 30093 22 177 8 036

35-39

0 1 2 3

9.9 7.2 6.0 7.0

11.2 6.4 6.0 6.8

73.8 53.8 49.3 46.6

94.1 67.3 61.3 60.4

4 835 7692 6961 3838

40+

0 1 2 3

15.4 11.0 7.1 8.5

10.8 14.6 10.7 (3.4)

103.2 73.1 55.8 76.4

131.0 98.7 73.5 88.3

649 821 843 589

Parentheses indicate too few cases. Source: Perinatal Data Collection Unit, Health Department, Victoria.

W o m e n u n d e r 20 years old h a v e a n i n c r e a s e d rate of p r e t e r m b i r t h with i n c r e a s i n g parity w i t h i n all g e s t a t i o n categories. I n all o t h e r age g r o u p s , p r i m i p a r i t y is associated with a h i g h e r rate of p r e t e r m b i r t h t h a n s e c o n d or third births, with a slightly raised risk of p r e t e r m births for the f o u r t h birth. L o n g i t u d i n a l data f r o m c o n s e c u t i v e births to the s a m e w o m a n give a r a t h e r d i f f e r e n t p i c t u r e ( F i g u r e 1). T a b l e 3 also shows that t h e r e are n o significant differences in p r e t e r m b i r t h across the age g r o u p 20-34 years. Y o u n g e r w o m e n have slightly h i g h e r rates (relative risk stratified for p a r i t y 1.17). W o m e n aged 35-39 years also have a h i g h e r risk of p r e t e r m b i r t h (1.47), a n d w o m e n 40 years old a n d o v e r h a v e a still higher risk (1.95). Ethnicity

D e s p i t e c o n c e p t u a l p r o b l e m s with the n o t i o n s of ' r a c e ' a n d ' e t h n i c i t y ' ( H a h n , 1992), t h e r e is a n extensive use of racial a n d e t h n i c categories in e p i d e m i o l o g i c studies, p r e t e r m b i r t h b e i n g n o e x c e p t i o n . T a b l e 4 uses a n

484

J. L U M L E Y

Table 4. Preterm birth in sifigleton births by mother's country of birth: Victoria, 1986-1990. Gestation (weeks) Mother's country of birth Australia New Zealand UK Germany Greece Italy Malta Poland Yugoslavia India Lebanon Malaysia Philippines Sri Lanka Turkey Vietnam

20-27 n/1000

n/lO00

28-31

4.9 5.3 4.8 7.1 6.7 4.7 4.0 17.1" 5.8 15.0" 4.5 5.5 3.8 2.2 5.9 4.4

5.7 5.9 5.9 4.7 6.3 5.7 3.4 8.1 7.4 6.9 4.2 6.4 7.9 6.6 7.8 5.7

32-36 n/1000 44.0 45.5 43.8 54.2 47.0 43.2 44.3 52.3 51.8 58.3 45.4 48.1 60.9 51.6 52.7 53.3

20-36 n/1000

Total births n

54.7 56.7 53.5 66.0 60.0 53.6 51.7 77.6" 65.0 80.3* 54.0 45.5 72.5 60.5 66.4 63.4

233 432 4 707 17004 1273 2 998 4 232 1 761 1 109 4 617 1 595 3 350 2 017 2 661 1356 2 561 4 745

* Significantly increased when compared with Australian-born women. Source: Perinatal Data Collection Unit, Health Department, Victoria. operational definition of ethnicity--the mother's country of birth. Differe n c e s in p r e t e r m b i r t h c a t e g o r i e s w i t h i n A u s t r a l i a a r e v e r y s m a l l , with t h e e x c e p t i o n o f m o t h e r s b o r n in P o l a n d a n d I n d i a w h o h a v e significantly r a i s e d r a t e s o f e x t r e m e l y p r e t e r m b i r t h (20--27 w e e k s ) , sufficient to give a significantly higher total preterm birth rate. Ethnic differences do not make a m a j o r c o n t r i b u t i o n to p r e t e r m b i r t h in this c o m m u n i t y . O n e o f t h e m o s t s t r i k i n g a s s o c i a t i o n s of p r e t e r m b i r t h is t h e d i f f e r e n c e b e t w e e n b l a c k a n d w h i t e infants in t h e U S A . T a b l e 5 shows t h e r e l a t i v e risk w i t h i n g e s t a t i o n a l g r o u p i n g s for b l a c k infants. T h e r e l a t i v e risk i n c r e a s e s w i t h i n c r e a s i n g s e v e r i t y o f p r e t e r m d e l i v e r y to 3.3 for b i r t h s b e f o r e 28 w e e k s o f g e s t a t i o n . B o t h t h e m a g n i t u d e o f t h e effect a n d its p a t t e r n a r e v e r y d i f f e r e n t f r o m t h a t o f t h e s o c i o d e m o g r a p h i c risk factors ( m a t e r n a l age, m a r i t a l status a n d n u m b e r o f p r e v i o u s c h i l d b i r t h s ) d i s c u s s e d p r e v i o u s l y . Table 5. Birth prevalence of preterm delivery at various gestations by race: USA, 1982. Period of gestation (weeks) <28 28-33 33-36 36-37 All preterm (<37)

Black

White

Relative risk

17.5 23.9 83.1 46.7

5.3 8.6 37.9 27.6

3.3 2.8 2.2 1.7

171.2

79.4

2.2

Adapted from Paneth (1986).

E P I D E M I O L O G Y OF PRETERM BIRTH

485

A recent analysis of infant mortality in the USA in babies whose parents both had a college education found that the same magnitude and pattern of relative risks--greatest in the most preterm category--were present in black subjects even in this highly selected population. Birthweight-specific mortality rates, deaths from congenital malformations and postnatal death rates, including the sudden infant death syndrome, were the same in the two groups (Schoendorf et al, 1992). It is most unlikely that the persisting differences in socioeconomic status which were apparent between black and white families in this study could explain the differences in preterm birth. The hypothesis that black infants have a gestational age distribution with a slightly lower optimal gestation at delivery is also implausible, given their excess of extremely preterm births. In addition, the known inconsistencies in coding of 'race' underestimate, if anything, deaths of black infants (Hahn et al, 1992). Within the state of Victoria (Australia) there is little or no evidence of marked 'racial' differences in preterm birth when the mother's country of birth in Asia is accepted as a proxy for Asian race (Table 4). Maternal size

Findings on maternal height and weight are inconsistent in relation to preterm birth. In the Scottish study there was an increased risk of extremely preterm birth among women below 160cm in height, but there was no adjustment for other factors (Macfarlane et al, 1988). In Alabama, there were no significant associations of maternal height with all preterm birth, but low maternal weight and both low and very high maternal weight gain in pregnancy had significantly increased odds ratios for preterm birth after substantial adjustment for confounders (Wen et al, 1990). Low maternal weight (but not maternal height) was a significant risk factor for preterm birth in southern Brazil (Barros et al, 1992). PRIOR REPRODUCTIVE HISTORY Spontaneous and induced abortion

A relationship between prior termination of pregnancy and preterm birth has been proposed on many occasions, though analyses that have taken into account confounding social, demographic and behavioural factors have failed to detect a significant association, or have found it only in situations where it could have been explained by illegal or traumatic abortion (Hogue et al, 1982). The problem with both individual studies and reviews is that they have not been large enough to look at the three categories of preterm birth separately. Table 6 is derived from data on first births in Victoria (Australia). The total number of births in the 5-year period exceeded 300 000. Preterm birth rates are calculated within the three gestational categories, according to whether this first birth was the woman's first pregnancy or had been

486

J. LUMLEY

Table 6, Preterm birth in first births (singletons) according to prior obstetric history: Victoria, 1986-1990. Gestation (weeks) Prior pregnancies 0 1 SA 2 SA 3 +SA 1 IA 2 IA 3 +IA

20-27 n/1000

28-31 n/1000

32-36 n/1000

Total preterm n/1000

Total births n

4.2 7.0 12.3 24.3 6.5 10.3 23.1

6.1 7.6 11.1 9.4 9.4 6.5 16.2

48.9 53.6 57.4 99.3 54.1 78.7 120.1

59.3 68.2 80.8 133.0 70.1 95.5 159.4

97116 10600 1707 534 9 365 1550 433

IA, induced abortions; SA, spontaneous abortions. Source: Perinatal Data Collection Unit, Health Department, Victoria.

preceded by one or m o r e spontaneous or induced abortions. For the purposes of this analysis w o m e n who had experienced both spontaneous and induced abortions were excluded. The associations are different in the three gestation categories, being particularly striking for births before 28 weeks. In this category, there is also evidence for a dose-response relationship between the n u m b e r of prior lost pregnancies and the prevalence of p r e t e r m birth: relative risks of 1.66 and 1.55 for one spontaneous or induced abortion, of 2.94 and 2.46 for two, and of 5.89 and 5.58 for three or more. These last four relative risks are substantially greater than any of those associated with maternal age, marital status, parity or socioeconomic status: that is, the association is most unlikely to be explained by confounding factors of a sociodemographic kind. As far as spontaneous abortion is concerned, the association of multiple spontaneous abortions with extremely p r e t e r m birth might be a reflection of some c o m m o n factor, either genetic or to do with implantation, causing both outcomes. This hypothesis does not readily explain the association with induced abortion which requires further analysis in case-control studies.

Prior preterm delivery Cross-sectional population studies show that p r e t e r m delivery rates are increased in w o m e n with a previous shortened pregnancy. Longitudinal studies of consecutive pregnancies to the same w o m a n have confirmed this finding and d e m o n s t r a t e d that the relative risk of p r e t e r m birth increases with the n u m b e r or previous p r e t e r m births: 2.2 for one, 3.7 for two and 4.9 for three or more. For each birth which is not p r e t e r m the risk of a subsequent p r e t e r m birth decreases (Bakketeig and H o f f m a n , 1981). A study of the first two singleton births in Norway (1967-1976) demonstrated further that the extent to which the birth was p r e t e r m predicted the gestation at delivery of the subsequent infant (Table 7). The association is particularly striking for births before 28 weeks of gestation.

487

EPIDEMIOLOGY OF PRETERM BIRTH Table 7. Gestation at delivery in first two singleton births: Norway, 196%1976.

First pregnancy Gestation at delivery (weeks)

16-27 28-35 36-38 39-41 >41

Second pregnancy Gestation at delivery (weeks) 16-27 (%) RR

28-35 (%) RR

36-38 (%) RR

39-41 (%) RR

> 41 (%) RR

8.2 (20.5) 1.5 (3.8) 0.8 (2.0) 0.4 (1.0) 0.3 (0.8)

11.6 (5.5) 10.6 (5.0) 4.5 (2.1) 2.1 (1.0) 1.5 (0.7)

20.4 (1.8) 26.4 (2.4) 24.0 (2.1) 11.2 (1.0) 6.5 (0.6)

50.6 (0.7) 55.3 (0.7) 62.2 (0.8) 73.3 (1.0) 64.1 (0.9)

9.3 (0.7) 8.2 (0.6) 8.5 (0.7) 13.0 (1.0) 27.6 (2.1)

RR, relative risk. The highest relative risks in each column are in bold type.

From Hoffman and Bakketeig (1984). CURRENT PREGNANCY COMPLICATIONS

Multiple gestation Confinements resulting in multiple births comprise just over 1% of all confinements and contribute 2.6% of all births. Just under half of all multiple births (44.2%) are delivered preterm. Thus, these pregnancies make up a substantial proportion of all preterm births: 16.6% of births at 20-27 weeks, 21.0% of births at 28-31 weeks, and 16.8% of births at 32-36 weeks (Perinatal Data Collection Unit, unpublished data).

Elective and complicated preterm birth Maternal, fetal and iatrogenic contributions to elective preterm birth and to spontaneous preterm birth complicated by additional risk factors are summarized in Table 8. Many of these conditions confer substantially higher relative risks of preterm birth than the classic social risk factors described earlier. Distinguishing between complications and idiopathic causes depends to some extent on how intensively the woman has been investigated: uterine anomalies may require hysterography between pregnancies for their diagnosis; antepartum placental abruption may go unrecognized if the placenta is not examined carefully. A recent review by Savitz et al (1991) found that elective preterm birth, medically indicated, comprised 18.7% to 28.8% of cases in 16 different studies, mainly hospital series. Antepartum haemorrhage is the major factor in spontaneous, complicated preterm birth, associated with up to 20% of cases (Hewitt and Newnham, 1988). It is also a complication that tends to recur in subsequent pregnancies and thus contributes to recurrent preterm birth (Bakketeig and Hoffman, 1981).

Spontaneous preterm birth Increasing attention has been given to differentiating between spontaneous

488

J. LUMLEY Table 8. Maternal, placental, fetal and iatrogenic factors in preterm delivery. Maternal factors

Relative risk

General

Diabetes mellitus Liver disease Nephritis Absent kidney Chronic hypertension Cardiac/cardiovascular disease

5.5 4.1 4.8 2.1 1.9 1.8

In current pregnancy

Viral pneumonia Pyelonephritis Other febrile states Urinary tract infection Appendicitis Low systolic/diastolic blood pressure Hyperemesis Isoimmunization Anaemia (Hb <70g/l) Pre-eclampsia Eclampsia

2.0 ? ? ? 2.8 2.5/3.1 4.1 4.3 4.2 6.4 5.8

Uterine attomalies

Congenital malformations Uterine myomas Retained intrauterine device Diethylstilboestrol exposure Cervical trauma

3.1 1.9 ? ? ?

Disorders of the placenta and membranes

Polyhydramnios/oligohydramnios Chorioamnionitis First or second trimester bleeding Abruptio placentae Placenta praevia

2.6 ? 2.1 8.0 6.0

Fetal factors

Fetal anomaly

2.0-2.4*

latrogenic

Elective induction of labour Repeat elective caesarean delivery

? ?

?-Relative risk uncertain from studies cited; *= Range calculated from different studies. From Bakketeig and Hoffman (1981); Committee to Study the Prevention of Low Birth Weight (1985).

p r e t e r m l a b o u r s that b e g i n with u t e r i n e c o n t r a c t i o n s a n d those b e g i n n i n g with p r e m a t u r e r u p t u r e of the m e m b r a n e s ( P R O M ) . T h e p r e s u m p t i o n is that t h e r e m a y be exposures r e l a t e d specifically to o n e or the o t h e r process a n d that c o m b i n i n g p r e t e r m l a b o u r a n d P R O M will a t t e n u a t e a n y true association with a specific e x p o s u r e (de H a a s et al, 1991). T h e m a i n finding u s i n g this a p p r o a c h so far has b e e n the c o n f i r m a t i o n that P R O M is m o r e c o m m o n in g r o u p s with a high rate of p r e t e r m delivery (e.g. blacks in the

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489

USA), and idiopathic preterm labour is predominant in lower-risk white populations (Savitz et al, 1991). Aetiologic heterogeneity may explain the disappointing results of some preterm birth prevention programmes in the USA whose focus has been early detection and aggressive treatment of increased uterine activity (Main et al, 1985; Tucker et al, 1991).

N E W E R IDEAS AND M E C H A N I S M S

The social differences associated with preterm birth are not explanations, but pointers towards the need for a more detailed look at aspects of the woman's whole environment. These differences reflect control over personal, family and social resources as well as social mores. Aspects of all these components are under investigation as mediators or pathways in preterm delivery. Lack of antenatal care

There is a consistent association between preterm delivery and nonattendance or late attendance at antenatal care, so much so that USA policy recommendations for reducing the incidence of low birthweight including preterm birth have made prenatal care a priority (Committee to Study the Prevention of Low Birth Weight, 1985; Public Health Service, 1989). In contrast, confidential enquiries into perinatal deaths in Victoria (Australia) identified lack of antenatal care as a possibly avoidable factor in only 0.3% of the 3457 perinatal deaths reviewed from 1985 to 1989 (Consultative Council on Obstetric and Paediatric Mortality and Morbidity, 1986-1989). One methodological issue is that women who deliver early have had less opportunity to attend for antenatal care, and some early studies failed to take this into account. In subsequent work taking a life-table approach and adjusting for confounders, the association between inadequate prenatal care and preterm birth is attenuated. Showstack et al (1984) and Tyson et al (1990), taking this approach, were unable to detect a beneficial effect of prenatal care on births before 30 weeks of gestation. They also drew attention to the limitations of non-experimental methods in terms of drawing conclusions about the effectiveness of care. Persisting differences between black and white women in the USA in the utilization of antenatal care, even among women with a college education (Schoendorf et al, 1992), together with strong circumstantial evidence that early antenatal care is associated with greater apparent benefits to perinatal outcome in blacks than whites (Murray and Bernfield, 1988) leave the role of this possible risk factor unresolved. The residual problem, virtually impossible to disentangle by statistical manipulation, is that non-use of antenatal care may be merely a marker for true (but unknown) causal factors. Examination of the usual content of prenatal care, especially before 28 weeks' gestation, leaves one puzzled as to what components of care might be effective in preventing preterm birth, especially since the multicomponent prevention of preterm birth programmes, all of which include enhanced

490

J. LUMLEY

frequency and continuity of antenatal care, have not been found to be effective (Lumley, 1991).

Cigarette smoking The effect of cigarette smoking on the m e a n gestational period at delivery is very small, a m a t t e r of a few days only; however, there is an excess of p r e t e r m births between 24 weeks and 34 weeks of gestation in smokers, greatest in those who s m o k e m o r e than 20 cigarettes a day (Meyer, 1977). These w o m e n are m o r e p r o n e to three pregnancy complications: placenta praevia, abruptio placentae and p r e m a t u r e rupture of the m e m b r a n e s , all precursors of spontaneous and elective p r e t e r m delivery. Table 9 summarizes the

Table 9. Preterm birth and smoking: relative and attributable risks. Study Cardiff England and Wales Montreal Ontario California: White Black Tasmania: 22-31 weeks 22-31 weeks 32-37 weeks 32-37 weeks

Proportion of smokers

Relative risk

Attributable risk (%)

0.465 0.274 0.432 0.435

1.36 1.47 1.38 1.36

14 11 14 14

0.402 0.338

1.10 1.25

4 8

0.156" 0.049t 0.156" 0.049t

1.65~ 2.30J 1.44~ 1.55J

15 9

* 20-30 cigarettes a day. t 30+ cigarettes a day. Preterm delivery was defined as < 38 weeks for Cardiff and Ontario; < 37 weeks for England and Wales, Montreal and California. Sources: Department of Obstetrics and Gynaecology, University of Tasmania and Royal Australian College of Obstetricians and Gynaecologists(1985) and unpublished tables; Meyer (1977). Reproduced from Lumley (1987), with permission.

relative risks of p r e t e r m birth in smokers from six population studies. The proportion of all p r e t e r m births attributable to this particular risk factor ranges f r o m 4% of all p r e t e r m births in California (USA) to 15% of births prior to 32 weeks of gestation in Tasmania (Australia). Meta-analysis of trials to reduce smoking in pregnancy confirms that p r e t e r m birth is less c o m m o n in the experimental groups (J. Lumley, unpublished data). The effect of stressful life events or p o o r psychosocial profile on pregnancy outcome is partly mediated through smoking (Newton and H u n t , 1984; Z u c k e r m a n et al, 1989; McCormick et al, 1990; Cliver et al, 1992), and smoking rates are increased by u n e m p l o y m e n t of the subject or partner (Morrison et al, 1989). One possible mechanism for its association with p r e t e r m birth is via the specific pregnancy complications listed above.

E P I D E M I O L O G Y OF PRETERM BIRTH

491

Alcohol, coffee and substance abuse There is a substantial disagreement about the effects of alcohol on preterm birth. One case-control study found a three-fold increase in preterm birth among women drinking two or more standard drinks a day (Berkowitz et al, 1982), but three large cohort studies, in the USA and Australia, could find no effect (Lumley et al, 1985; Bell and Lumley, 1989; Wen et al, 1990). A hospital-based survey in the USA detected an association of shortened gestation with alcohol consumption before but not during pregnancy (Hingson et al, 1982). The question remains unresolved. Coffee consumption of three or more cups a day in the first trimester was associated with a more than doubled rate of PROM, with some evidence of a dosage effect, persisting after adjustment for multiple confounders (Williams et al, 1992). Cocaine use in pregnancy is associated with a substantially increased risk of preterm birth (2.4), mediated at least in part by increased uterine contractility caused by increased catecholamines and in part also by a four-fold to five-fold increase in abruptio placentae (Volpe, 1992). Dependency on narcotics or other drugs is a risk factor for preterm birth (Committee to Study the Prevention of Low Birth Weight, 1985). Pharmacological effects of illegal drugs are particularly difficult to disentangle from other deleterious factors associated with their use, such as lack of antenatal care, use of other agents, poor nutrition, maternal depression, a stressful and disrupted social environment and, in some places, serious infections (Zuckerman et al, 1989).

Nutrition Although nutritional factors might be a component of the causal path from social disadvantage to preterm birth, neither descriptive studies of nutritional intake nor experimental nutrition intervention studies have been able to show a reduction in preterm delivery with improved nutrition. High-density protein supplements are consistently associated with a decrease rather than an increase in mean birthweight, owing to an increased chance of very preterm delivery (reviewed by Rush, 1989).

Work and physical activity Regular, moderate physical activity (golf, swimming, walking, cycling) was associated with a three-fold reduction in preterm birth rates in the only case-control study to have investigated this factor (Berkowitz et al, 1983). It is possible, even likely, that the apparent protective effect of moderate exercise merely reflects sdf-selection of a very healthy subgroup of women, although the effect persisted after taking into account a wide range of confounders. Strenuous exercise (jogging, track running and gymnastics) was unusual in cases and controls, but slightly more common in the former. Two subsequent small cohort studies have identified an increase in preterm birth among women exercising vigorously into the third trimester, with evidence of a dose-response effect (Clapp and Dickstein, 1984; Kulpa

492

J. LUMLEY

et al, 1987). Exercise before pregnancy or restricted to the first 20 weeks had no such effect. Attention to the extent, timing, duration and type of exercise is essential in future studies, as there is evidence, in at least some countries, of women's increasing participation in regular strenuous exercise. Inconsistent findings on the relationship of maternal work and pregnancy outcome is in part explicable by changing patterns of employment and social class, in part by difficulty in defining the relevant aspects of domestic and paid employment, and in part by simple comparisons that take no account of the methodological pitfalls. The work of Mamelle et al (1984), which identified sources of occupational fatigue with a high explanatory power for preterm birth, has been confirmed by similar results from surveys in Canada and the USA (McDonald et al, 1988; Teitelman et al, 1990); however, a small population-based, prospective study in London could detect no association of workload with shortened gestation (Rabkin et al, 1990). A large prospective study in Guatemala found associations of manual work with the birth of infants who were both preterm and growth-retarded, and some evidence of a doserelated effect as well (Launer et al, 1990). The best attempt so far to separate the effects of physically demanding work from the adverse social circumstances that often accompany it was a large survey of female resident physicians in the USA; this survey compared such residents with the spouses of their male counterparts (Klebanoff et al, 1990). No significant effect of workload on preterm birth was detected, except a marked increase where the mother worked more than 100 hours a week. This latter finding is in agreement with the French and Canadian work discussed above. The interaction between domestic workload and paid workload has not received serious examination. Thus, the evidence at present is inconclusive though sufficient to justify continuing research on all forms of physical activity. Stress and social support

Maternal emotions and stressful life events were once believed to be potent sources of harm to the fetus but the pendulum of professional opinion swung away from this view in the late nineteenth century. Interest in the possible role of stress has been revived since neuroendocrine and other mechanisms have been described by which changes in the mother may alter the fetal environment. It has been argued that difficult life circumstances and lack of social support might be the key factors underlying the association between social disadvantage and preterm birth (Oakley et al, 1982). The hypothesis has been taken further by three recent descriptive studies of public patients in the USA, which demonstrated the links between stressful life events, lack of social support, anxiety, depression, use of cigarettes, alcohol and other substances, and low birthweight, although none of them dealt specifically with preterm birth (Zuckerman et al, 1989; McCormick et al, 1990; Cliver et al, 1992). The most recent of the three demonstrated a protective effect of a greater pre-pregnancy weight for height against these adverse psychosocial factors.

E P I D E M I O L O G Y OF PRETERM BIRTH

493

On the other hand, interventions designed to give additional support have not been effective. Eight randomized trials of enhanced social support in pregnancy, provided in diverse ways, did not reduce preterm birth (odds ratio 0.99), extremely preterm birth (OR 0.94) or perinatal death (OR 1.19) (Elbourne, 1991).

Uncertain gestation period In a regional study in Scotland over a third of spontaneous preterm births occurred in pregnancies where the length of gestation was uncertain or only known approximately (Hall and Carr-Hill, 1985; Hall et al, 1985). The association of preterm birth with uncertainty was not attributable to less favourable sociodemographic factors and it had greater explanatory power than the social differences. Hall and Carr-Hill commented that 'uncertainty of gestation may be identifying some behavioural or physical trait not identified by the factors usually considered', and drew attention to the possibly analogous trait of non-compliance, associated in some drug trials with a worse outcome regardless of whether it is the placebo or the active agent that is not being taken. A physical trait linking uncertain gestation period with preterm birth could be an abnormality of the menstrual cycle at the time of ovulation or implantation, a factor that would shift the emphasis from events in mid-pregnancy that precipitate preterm birth, to events set in train at the beginning of pregnancy. These possible physical or behavioural factors lend themselves to investigation in case-control studies of preterm birth.

Infection From an epidemiological point of view, one of the main issues in the debate about the role of infection in preterm birth has been disentangling the temporal sequence: does infection precede or succeed preterm labour and PROM? The other issues have been the low statistical power of some of the descriptive microbiological studies, and the earlier emphasis on a single specific cause. One large prospective (cohort) study has confirmed significantly increased odds of spontaneous preterm birth in women with vaginal carriage of Gardnerella vaginalis and Ureaplasma urealyticum between 22 weeks and 28 weeks of gestation (McDonald et al, 1992). This study was not large enough to distinguish between P R O M and spontaneous preterm labour, nor to separate out the extremely preterm and moderately preterm groups. Earlier publications with more inconsistent findings (summarized by McGregor, 1988) have drawn attention to the links between the sociodemographic risk factors and the probability of carriage of relevant organisms, so that there is a need to investigate further both host resistance factors (micronutrients, smoking) and other behavioural characteristics which might interact with the microbiological factors (McGregor, 1988). Sexual activity has often been proposed as an intermediary factor in this context (Naeye and Ross, 1982; McDonald et al, 1992), but reviews of the

494

J. LUMLEY

evidence available at present do not confirm a significant association between sexual activity and p r e t e r m birth (Lumley and Astbury, 1989). The other epidemiological contribution has been meta-analysis. This has d e m o n s t r a t e d a relationship between asymptomatic bacteriuria and p r e t e r m birth ( R o m e r o et al, 1991), and also shown, in meta-analysis of randomized trials, that antibiotic treatment of asymptomatic bacteriuria reduces pret e r m birth (Smaill, 1992). Assisted conception

Table 10 summarizes p r e t e r m birth rates in the three categories 20-27 weeks, 28-31 weeks and 32-36 weeks of gestation for pregnancies following assisted conception by in vitro fertilization (IVF) and gamete intrafallopian transfer ( G I F T ) . W h e n these rates are c o m p a r e d with those in Tables 2, 3 and 4 from similar populations, it is apparent that there is a substantially raised relative risk of p r e t e r m birth in all three categories even a m o n g singleton I V F and G I F T pregnancies. Because of the high proportion of multiple births a m o n g assisted conceptions, the overall rate of p r e t e r m birth is over 3 % before 28 weeks, a further 4% between 28 weeks and 31 weeks, and another 20% before 37 weeks ( A I H National Perinatal Statistics Unit and Fertility Society of Australia, 1991). Possible explanations for these findings include stress, infection (as a cause both of infertility and p r e t e r m birth), cervical t r a u m a as a result of investigative procedures for infertility, disturbed implantation and a hitherto unrecognized side-effect of clomiphene exposure. The association is not due Table 10. Preterm birth in pregnancies following assisted conception: Australia and New

Zealand 1979-1989. Gestation (weeks) 20-27 Singleton IVF GIFT Twin IVF GIFT Triplet IVF GIFT Total IVF GIFT

n/lO00

28-31 n/1000

32-36 n/1000

20-36 n/1000

Total births n

27.1 18.1

19.6 31.3

131.3 97.1

178.0 146.5

2803 1215

48.6 76.9

75.7 65.1

427.1 440.8

551.4 582.8

700 338

146.6 104.5

189.7 194.0

637.9 656.7

974.1 955.2

116 67

35.3 34.4

36.9 47.9

205.3 192.8

277.6 275.0

3628" 1629t

* Eight quadruplet and one quintuplet pregnancies included. t Nine quadruplet pregnancies included. Thirty-four IVF and nine GIFT infants have been excluded from the table as their gestational ages were not reported. Source: AIH National Perinatal Statistics Unit (1991).

EPIDEMIOLOGY OF PRETERMBIRTH

495

to iatrogenic elective delivery and is still present after standardization for age and parity (A. Venn and J. Lumley, unpublished analysis). Pregnancies following assisted conception offer an unrivalled--and so far untapped----opportunity of studying the aetiology of preterm birth, in singleton and multiple gestations. Their high prevalence of preterm birth and the fact that these women are in medical care before conception suggest that this setting is an ideal one for randomized trials of preterm birth prevention strategies.

SUMMARY Secular trends in the prevalence of preterm birth and international comparisons of the rates of preterm birth are difficult to interpret because of differences, both formal and informal, in the registration of extremely preterm births. Accurate estimation of gestational age is another problem in the measurement of preterm birth. Preterm birth is heterogeneous in several ways. It is heterogeneous in terms of the extent to which the birth is preterm (20-27 weeks, 28-31 weeks or 32-36 weeks of gestation); in whether the birth was elective or spontaneous; and among spontaneous idiopathic preterm births, in whether there was preterm labour or premature rupture of the membranes. Casecontrol study designs taking account of these subgroups have been a recent feature of epidemiologic approaches. The classic social associations of preterm birth--low socioeconomic status, extremes of maternal age, primiparity, being u n m a r r i e d - - a p p l y to extremely preterm and moderately preterm births as well as to the mildly preterm group. The strength of these associations is small compared with factors in the prior reproductive history and with medical and obstetric complications of the current pregnancy. Recent epidemiological research activities have focused on the ways in which risk factors such as physical workload, drugs and alcohol, lack of social support and infection might be mediating factors between sociodemographic status and preterm birth. As Eastman (1947) pointed out almost 50 years ago, 'only when the factors causing prematurity are clearly understood can any intelligent attempt at prevention be made'.

Acknowledgements The Centre for the Study of Mothers' and Children's Health is supported by a programme grant from the Victorian Health Promotion Foundation.

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