The epidemiology of stillbirth

The Epidemiology of Stillbirth Sven Cnattingius and Olof Stephansson

Stillbirths account for an increasing proportion of feto-infant mortality. Yet, causes of stillbirth are rarely reported, and the causes of most stillbirths remain unknown. Few studies focus specifically on the epidemiology of stillbirth. Major risk factors include high maternal age, smoking, and overweight. The prevalence of delayed childbearing and, especially overweight, are increasing in most developed countries. The proportion o f stillbirth attributable to overweight is likely to increase.

Copyright 9 2002 by W.B. Saunders tillbirth currently accounts for m o r e than

S one third of all feto-infant mortality and m o r e than 50% o f all perinatal deaths in develo p e d countries. 1,2 A m o n g n o n m a l f o r m e d fetuses/infants, stillbirth at 28 c o m p l e t e d gestational weeks or later accounts for m o r e than 50% of all feto-infant m o r t a l i t y ) Moreover, the causes of stillbirth differ f r o m those of early neonatal mortality, z,4 Despite the clear importance of stillbirth as a public health problem, few studies have focused specifically on the epidemiotogy and cause of stillbirth.

Causes In contrast to infant mortality, causes of stillbirth are generally not registered i n vital statistics or population-based research registers. T h e r e are also substantial difficulties in d e t e r m i n i n g the cause of stillbirth. First, weight a n d gestational length are, in the case of a stillbirth, estimated at delivery and not at time of death. This leads not only to an overestimation of gestational length, but the fetus may also have lost weight after death. Thus, the i m p o r t a n c e of low birth weight in relation to gestational age may therefore be overestimated in stillbirth. Second, even if diagnostic investigations are p e r f o r m e d , there may be difficulties in achiex4ng valid results. Pathological investigations must consider possible changes occurring between the often u n k n o w n time of death and time of investigation. W h e n looking for an infectious cause, it may be unknown what infections should be considered lethal, and infections may also occur during or after delivery. A n u m b e r of m e t h o d s of g r o u p i n g causes of death in stillbirth a n d neonatal deaths have b e e n used. 5,6 T h e cause of stillbirth differs in m a n y cases f r o m the cause of neonatal deaths,

which necessitates a specific classification system for stillbirth. More importantly, diagnostic routines generally differ substantially between hospitals, and a successful classification of causes of stillbirth is highly d e p e n d e n t on a standardized and systematic clinical procedure. As m o r e than 1 factor may contribute to fetal death, m a n y classifications have recognized the n e e d for a hierarchical classification system, in which potentially lethal anomalies take p r e c e d e n c e over other conditions. 5,6 Two o t h e r i m p o r t a n t causes of stillbirth are prenatal infections, and above all, fetal growth retardation. O t h e r causes include isoimmunization, abruptio placenta, maternal chronic diseases, pregnancy-related disorders (such as preeclampsia and gestational diabetes), and umbilical cord accidents. Yet, despite all these possible causes o f stillbirth, a substantial p r o p o r t i o n of stillbirths r e m a i n unexplained. However, within the g r o u p of "unexplained" stillbirths, there is probably a relatively large g r o u p of fetuses with undiagnosed fetal malnutrition, c h r o m o s o m a l aberrations, or infections.

Stillbirth and G e s t a t i o n a l A g e W h e n stillbirth is defined as a fetal death occurring at 20 weeks or later, 82% of all stillbirths are r e p o r t e d to occur in the p r e t e r m period. 7 Also, when stillbirth is defined as fetal death at 24 weeks or later or even at 28 weeks or later, the From the Department of Medical Epidemiology, Karolinska Instituter, Stockholm. Address ~'eprint requests to Sven Cnattingius, MD, PhD, Department of Medical Epidemiology, Karolinska Instituter, PO Box 281, SE171 77 StockhoZm; e-mail: Sven. [email protected]. Copyright 9 2002 by W.B. Saundev's O146-0005/02/2601-0005535. 00/0 doi:l O.1053/sper.2002.29841

Seminars in Perinatology, Vol 26, No 1 (February), 2002: pp 25-30

25

Cnattingius and Stephansson

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majority of stillbirth occur preterm. 8,9 Since the majority of stillbirths occur preterm, it may seem paradoxical that the risk of stillbirth increases with gestational age. However, as p o i n t e d out by Yudkin et al, 1~ fetuses at risk of stillbirth at a specific gestational age must include all live fetuses at that gestational age. By using this approach, Yudkin et aP ~ showed a consistent increase in risk of stillbirth by gestational age (Fig 1), an observation that has b e e n c o n f i r m e d by o t h e r investigators, n,12 Thus, the risk of stillbirth may be highest in the postterm period, which to a large extent can be explained by increased rates of small-for-gestational-age fetuses b o r n postterm. 1~

Risk F a c t o r s Maternal Age T h e r e is g o o d evidence that it is b e c o m i n g increasingly c o m m o n a m o n g w o m e n to choose to delay childbearing. In the United States, the p r o p o r t i o n of first-time mothers who were age 30 or older increased f r o m 4% in 1969 to 21% in 1994.14 -The t r e n d of delayed childbearing has occurred primarily a m o n g w o m e n with at least high school education and is attributed to w o m e n voluntarily p o s t p o n i n g pregnancies for personal or professional reasons. Several large epidemiological studies have r e p o r t e d that high

2,0 1s 1,e o Q

1,4

1,2

~, 0,8 0,6

Table 1. Odds Ratio (OR) and 95% Confidence Intervals (CI) for Stillbirth by Maternal Age

Age (years)

OR

(95 % CI) (reference group)

<30

1.0

30-34

1.3

(0.9-1.7)

35-39 40+

1.9 2.4

(1.3-2.7) (1.3-4.5)

Data from reference 16.

m a t e r n a l age increases the risk of stillbirth. 15,16 Fretts et aP 6 r e p o r t e d that, c o m p a r e d to w o m e n below 30 years, the risk of fetal d e a t h a m o n g w o m e n aged 35 to 39 years was almost increased 24bld, while c o r r e s p o n d i n g risk for those 40 or older was m o r e than doubled (Table 1). T h e risk of stillbirth is especially p r o n o u n c e d a m o n g delayed childbearers, but probably also increased a m o n g older parous women. Although the risks of pregnancy-related disorders or complications, such as preeclampsia, gestational diabetes, a n d abruptio placenta increase with age, the agerelated increase in stillbirth cannot be explained by these diseases, a2,a6 T h e age-related stillbirth risk increases with advancing gestational age, and older w o m e n have above all an increased risk of u n e x p l a i n e d s t i l l b i r t h / A l t h o u g h the absolute increase in risk for the individual w o m a n may be considered modest, the i m p a c t of delayed childbearing becomes m o r e i m p o r t a n t as the p h e n o m e n o n b e c o m e s m o r e prevalent. T e e n a g e pregnancies are, in contrast to high m a t e r n a l age, m o r e associated with neonatal death than stillbirthJ 7 This is not surprising, since the risk of p r e t e r m birth, and especially very p r e t e r m birth, is increased a m o n g teenage childbearers (and especially very y o u n g teenagers), while the association between restricted fetal growth and teenage childbearing is m o r e controversial.IS

Parity

0,4 0,2 0,0 29

31

33

35

37

39

41

Gestationel age (weeks)

Figure l. Rate of stillbirth by gestational age, per 1,000 live fetuses at that gestational age. (Reprinted with permission. I~)

Studies have r e p o r t e d an increased rate of stillbirth a m o n g nulliparas and g r a n d multiparas. n,m However, in 1 study, the U-shaped pattern between parity and stillbirth risk was, a m o n g older women, evident in the t960s a n d early 1970s, but not in the late 1970s and 1980s/6 T h e authors suggest that the reduction in the parity-related risk of stillbirth over time

Epidemiology of Stillbirth

may be due to i m p r o v e d access to medical care and changes of obstetrical practice.

Smokmg T h e association between smoking and stillbirth risk is well known and there is probably a causal association. First, the risk of stillbirth increases with the a m o u n t smoked. 2,2~ Second, there is a supportive biological hypothesis. Smoking during pregnancy increases fetal carboxihemoglobin concentration and increases the vascular resistance, because of the vasoconstrictive effect of nicotine and the r e d u c e d prostacyclin synthesis. 2~-23These toxic effects of tobacco smoke may partly explain the causal association between smoking and r e d u c e d fetal growthY 4 These effects may also contribute to the placental changes a m o n g smokers, such as decidual necrosis, which in turn may lead to abruptio placenta. 25"26 In a study of Meyer a n d Tonascia, 27 the elevated risk of fetal death in smokers was largely because of higher rates of placental abruption and placenta previa. A n o t h e r study f o u n d a 40% overall increased risk of stillbirth a m o n g smokers, but smokers who did not suffer f r o m placental complications or delivered growth retarded infants had no increased risk of stillbirth, t2 Thus, it appears that the association between smoking and stillbirth is explained by the smoking-related risks of fetal growth retardation and placental complications. Third, the hypothesis of a causal association between smoking during pregnancy and stillbirth is further s t r e n g t h e n e d by a recent Danish study, reporting that smoking cessation in the first trimester reduces the risk of stillbirth c o r r e s p o n d i n g to that of nonsmokers. 23 This result also indicates that smoking exerts its influence on stillbirth after the first trimester. Smoking has b e e n rep o r t e d to primarily influence risk of p r e t e r m stillbirth, ~2 and these results are in turn supp o r t e d by a finding that intrauterine growth retardation is a stronger risk factor for p r e t e r m than for term stillbirth, s Although the prevalence of smoking during p r e g n a n c y has declined in m a n y countries, still between 10% to 30% of the p r e g n a n t population in the western world smoke. 23,29 Thus, smoking continues to be one of the most important preventable risk factors for stillbirth.

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Maternal Body-mass Index An association between maternal body-mass index (BMI) and stillbirth risk, with the highest risk a m o n g overweight and obese w o m e n was r e p o r t e d in 1993. 2o A Swedish register-based study confirmed this and f o u n d that the association between increasing BMI and stillbirth risk was highest a m o n g nutliparous women. 3~ A recent Swedish study on a n t e p a r t u m stillbirths f o u n d that the association between early pregnancy BMI and stillbirth risk was strongest for term stillbirths, suggesting an increasing effect of a high BMI by gestational length. 31 T h e mechanisms for the BMI-related increases in risk of stillbirth remain a matter of speculation. Overweight and obese w o m e n are m o r e likely to have a low socio-economic status a n d are m o r e often cigarette smokers. Pregnancy complications, such as gestational diabetes, preeclampsia, and eclampsia, are m o r e c o m m o n a m o n g overweight and obese women. After excluding cases and controls with weight-related pregnancy complications, the risk of stillbirth r e m a i n e d increased a m o n g overweight women, but was attenuated a m o n g obese w o m e n (Table 2). 3~ T h e prevalence of overweight and obesity is rising rapidly in developed countries (Fig 2), 32 and in the United States a third of the p r e g n a n t population are overweight (BMI > 25). as If causal, overweight may f r o m a public health perspective be the most i m p o r t a n t risk factor for stillbirth.

Table 2. Odds Ratio (OR) and 95% Confidence Intervals (CI) for Antepartum Stillbirth by Bodymass Index (BMI) Among Nulliparous Women

All Cases and Controls (n = 613/660)* BMI

-<19.9++ 20.0-24.9 25.0-29.9 -->30.0

Excluding Cases and Controls With Gestational Diabetes and Preeclampsia (n = 461/546)*

OR~

(95 % CI)

OR~

(95 % CI)

1.0 1.2 1.9 2.1

(0.8-1.7) (1.2-2.9) (1.2-3.6)

1.0 1.2 2.5 1.5

(0.8-1.8) (1.5-4.0) (0.7-3.0)

* Number of cases/controls. t Adjusted for age, height, occupation, and cigarette smoking. ++Reference group. Data from reference 31.

Cnattingius and Stephansson

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% 20 15

I

D MI 25.0-29,9 [] BMI 30.0-34.9

10

[] BMI 35.0+

5 0 1960-62

1971-74

1976-80

1988-94

Figure 2. Prevalence of overweight and obesity among women aged 20-29 years, United States 19601994. (Data from reference 32.)

Maternal Weight Gain During Pregnancy Few studies have investigated the association between weight gain during pregnancy and stillbirth risk. Weight gain is related to prepregnancy BMI, and w o m e n with a high BMI gain less weight during p r e g n a n c y ? T M Therefore, it is i m p o r t a n t when analyzing the association between weight gain a n d risk of stillbirth to consider p r e p r e g n a n c y BMI as a c o n f o u n d i n g factor. Taffel et a135 showed an association between low m a t e r n a l weight gain and stillbirth risk, whereas-this was not f o u n d by Rydhstr6m et al. ~6 However, n o n e of these studies simultaneously investigated the possible influences by other covariates. A recent Swedish study was able to take such confounders into account and f o u n d no association between pregnancy weight gain a n d a n t e p a r t u m stillbirth risk. 31

Socio-economic Factors Although it is generally known that socio-economic status influences stillbirth risk, 2~ the reasons remain essentially unknown. This is not entirely because most studies have included few covariates, but results f r o m a recent study suggest that the reasons for the association may be h a r d to disentangle. 9 T h e group of w o m e n f r o m low social class was favored by a reduced prevalence of delayed childbearers, but, on the o t h e r hand, they were m o r e often smokers and overweight. Thus, the risks of stillbirth related to low socio-economic status, were after adjustment for maternal age, smoking and body mass index, essentially the same as the crude risks. Moreover, further adjustments for time of admittance to antenatal care, n u m b e r of visits to prenatal care, and a n u m b e r of o t h e r covariates, did not essentially c h a n g e these risks, n o r were the risks e x p l a i n e d by i n c r e a s e d rates o f small-for-

gestational-age pregnancies or pregnancy-related disorders a m o n g w o m e n f r o m low social class9 Residual c o n f o u n d i n g of alcohol a n d illicit drug use is a possible but not p r o b a b l e explanation. Since the risk related to low social class was primarily increased for t e r m stillbirth, one may hypothesize whether these differences are due to subtle differences in care.

Recurrent Stillbirth T h e tendency to repeat pregnancy o u t c o m e s in successive births is well known and also includes risk of stillbirth. W o m e n with a previous stillbirth may, c o m p a r e d to w o m e n with no previous stillbirth, have a 6 to 10-fold increased risk of stillbirth in next pregnancy. 37,3s Although recurrence of stillbirth is m o r e c o m m o n a m o n g w o m e n with diabetes or pregnancy-induced hypertensive diseases, and may also be associated with recurrence of fetal growth retardation, such factors probably only partly explain the risk of repeating stillbirth, s7-~9

Maternal Hemoglobin Concentration During normal pregnancy, the h e m o g l o b i n concentration falls until the 20th week of gestation, remains fairly constant up to 30 weeks and thereafter rises slightly. These changes in h e m o g l o b i n concentration are mainly due to an increased plasma volume. In developed countries, b o t h high a n d low h e m o g l o b i n concentration during p r e g n a n c y have b e e n associated with small-forgestational-age and p r e t e r m births. Two studies have r e p o r t e d increased rates of perinatal death with b o t h low and high h e m o g l o b i n concentration during pregnancy, 4~ and 1 study f o u n d a similar u-shaped association for stillbirth rates. 42 In a recently published study the risk of stillbirth was increased for b o t h low (--<115 g / L ) and high (>--146 g / L ) early pregnancy h e m o g l o b i n concentration, 43 and a relatively large decrease in h e m o g l o b i n concentration during p r e g n a n c y t e n d e d to be protective. T h e risk related to high h e m o g l o b i n values was confined to a n t e p a r t u m stillbirths without malformations, and especially p r o n o u n c e d if the fetus also was growth-retarded (Table 3). T h e biological m e c h a n i s m for the increased risk of stillbirth for high h e m o g l o bin concentration may be that plasma expansion enhances fetal growth. T h e r e d u c e d b l o o d viscosity may favor b l o o d flow in the m a t e r n a l in-

Epidemiology of Stillbirth

T a b l e 3. O d d s Ratio (OR) a n d 95% C o n f i d e n c e Intervals (CI) for Stillbirth by H e m o g l o b i n C o n c e n t r a t i o n in First T r i m e s t e r

Antepmr Stillbirth Without Malformations All (n = 519/610)*

SGA-stillbirths (n = 137/390)*

First Hb g/L

ORt

(95% CI)

OR?

(95% CI)

--<115 116-125 126-135 (ref.) 136-145 -->146

1.7 0.9 1.0 1.0 2.0

(1.0-2.8) (0.6-1.2)

1.5 0.4 1.0 1.1 4.2

(0.6-3.9) (0.2-0.8)

(0.7-1.4) (1.1-3.8)

(0.6-2.1) (1.3-13.9)

* Number of cases and controls. t Adjusted for age, height, BMI, occupation, smoking, early pregnancy weekly change in Hb, and week of first Hb measurement. Source: Stephanssou et al. JAMA 2000;284:2611-7.

tervillous space and prevent thrombosis in the uteroplacental circulation.

Multiple Birth Since twins are m o r e likely to be growth-retarded and to be delivered preterm, they have an increased risk of stillbirth and (above all) neonatal death. A particular concern is monozygotic twins, who have p o o r e r survival than dizygotic twins. 44,45 If 1 twin dies in utero, the cotwin is n o t only at increased risk of fetal death, but also runs an increased risk of cerebral palsy and o t h e r cerebral impairments. 44 The relative i m p o r t a n c e of twin pregnancy as a risk factor for stillbirth is likely to increase, as the rate of twin pregnancies are increasing. 46

Conclusions In contrast to infant mortality, the decline in stillbirth rates have, in most countries, b e e n less obvious. The majority of stillbirths dies unexpectedly preterm, when possibilities to detect warning signs, such as fetal growth restriction, are limited. Major maternal risk factors include m a t e r n a l smoking, high maternal age, and overweight, but why high maternal a g e and overweight influence stillbirth risk remains to be determined. In contrast to smoking, the prevalence of delayed childbearing and overweight are increasing in most developed countries.

29

Thus, the relative i m p o r t a n c e of these factors is likely to increase.

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