Early Human Development, 28 (1992) 193-200 Elsevier Scientific Publishers Ireland Ltd.

EHD 01232

193

Risk factors associated with antepartum fetal death

Jun Zhang and Wen-wei Cai

Department of Maternal and Child Health, Shanghai Medical University, Shanghai 200032 (P.R. China)

(Received 7 December 1990; revision received 27 April 1991; accepted 5 May 1991)

Summary

This study examined risk factors that contribute to antepartum fetal death. The population-based sample included 416 antepartum fetal deaths and 449 normal births as controls, from 29 hospitals in Shanghai, China. In addition to small-for- gestational-age and severe pregnancy-induced hypertension, exposure to en- vironmental hazards (radiation, chemicals and pesticides) was significantly associated with fetal death. Elevated relative risk of fetal death was also found in pregnant women whose husbands smoked (adjusted odds ratio = 1.4). Clinico- pathologic evidence further confirmed that exposure to hazards, especially in the first trimester, increased the risks of congenital anomalies (odds ratio = 2.7) and antepartum fetal death from congenital malformations (odds ratio = 3.5). This study also showed that threatened abortion was a significant predictor of risk of fetal death. No significant relationships were identified between sex of fetus, mild or moderate pregnancy-induced hypertension, maternal anemia and antepartum fetal death.

Key words: antepartum fetal death; congenital anomaly; exposure to hazards; paternal smoking; risk factor; threatened abortion

Introduction

Although overall perinatal mortality rates have fallen considerably in the past several decades, the fetal component of this statistic has not decreased as rapidly as the neonatal portion [l]. Numerous investigators have reviewed clinical causes of fetal death in various populations [2-41. Some of the deaths were easily attributed to such causes as congenital malformations, birth trauma, umbilical cord anomalies

Correspondence to: Jun Zhang, Department of Epidemiology, CB No. 7400 McGavran-Greenberg Hall, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7400, USA.

0378-3782/92/$05.00 0 1992 Elsevier Scientific Publishers Ireland Ltd. Printed and Published in Ireland

194

and antepartum hemorrhage. Efforts have also been made to identify pathologic and immunologic factors which may contribute to fetal death [5,6]. Chromosomal aber- ration, nonchromosomal malformation and syndromes, chorioamnionitis, large placental infarcts, placental insufficiency and hemorrhagic endovasculitis were found to be associated with late fetal death [5]. Nonetheless, a substantial propor- tion of fetal deaths, ranging from 9.1 to 32%, were still classified as unexplained intrauterine death [ 1,7].

A variety of risk factors have been reported to be related to fetal death [l]. For instance, maternal smoking has been documented to have 1.4 times risk of late fetal death [8] and 3.5 times risk of intrauterine growth retardation [9]. However, epidemiologic studies attempting systematically to evaluate potential risk factors of antepartum fetal death are still limited. Furthermore, in most previous studies on fetal death, the cases included both antepartum and intrapartum fetal deaths [3]. Since intrapartum fetal deaths are often related to obstetric care or some accidental factors, such as prolapse of umbilical cord and birth trauma, exploring the associa- tions between risk factors and fetal death was clouded to some extent.

Our study, conducted in Shanghai, China, aimed to examine systematically a variety of risk factors for late fetal death. To avoid the deficiency mentioned above, the present report only included antepartum fetal deaths. We will also link the significant risk factors with clinical causes and patho]ogic results of the fetal deaths, to confirm the practical significance of these factors.

The population in Shanghai is homogeneous in terms of race and socioeconomic status. There are few teenage pregnancies, virtually no drug abuse and a very low prevalence of smoking and alcohol consumption in pregnant women. Prenatal care is virtually free and during pregnancy almost all pregnant women visit the prenatal health care system regularly and give birth at hospitals [ 10,111. Thus, these data pro- vide an excellent opportunity to study antepartum fetal death arising from biological variation and specific environmental influences.

Methods

A case-control study on perinatal death was conducted in 29 hospitals in Shanghai area, China, from October lst, 1986 to September 30th, 1987. During that period, every perinatal death was registered and matched with a normal live birth without any apparent birth defects (but not necessary full term) occurring just before or after the case in the same delivery room. The perinatal deaths included (1) antepartum fetal deaths (fetal death before onset of delivery); (2) intrapartum fetal deaths (fetal death during delivery); and (3) early neonatal death (neonatal deaths within the first week after birth). Only those whose birthweight was L 1000 g (equivalent to gesta- tional age 128 completed weeks) were recorded. The present analysis was restricted to antepartum fetal death, which consisted of 452 cases and the same number of controls.

All the mothers of cases and controls identified during that period were interview- ed in the hospitals following delivery (and the stillbirth) by specially trained doctor- or nurse-interviewers. Fetal and maternal information from clinical records was

195

recorded, including gender, birthweight, gestational age (from the last menstrual period), fetal number, parity and maternal age. Based on birthweight and gestational age, infants were classified as small for gestational age (SGA) if their birthweight was below the 10th percentile given their period of gestation [ 121.

In addition to these demographic variables, we investigated maternal exposure to environmental agents which are. known or suspected risk factors for adverse pregnancy outcomes [13,14]. The mothers were asked a series of questions to deter- mine if they were exposed to radiation, chemicals and pesticides during pregnancy, what specific hazard and when they were exposed (first, second or third trimester).

Pregnancy complications were recorded from prenatal health care cards, which are carried by each pregnant woman in Shanghai and filled out by physicians during prenatal visits. The card records all conditions occurring throughout the pregnant period such as blood pressure, uterine height and any specific complications. Pregnancy complications included in the present study were threatened abortion (before 28 completed weeks), maternal anemia and pregnancy-induced hypertension.

Pregnant women were classified as having anemia during pregnancy if their hemoglobin value was I 10 g/d1 during pregnancy. Pregnancy-induced hypertension was classified as mild, moderate and severe. The criteria are described in detail elsewhere [ 151,

Finally, paternal smoking, thought to be a possible risk factor for fetal death [ 161, was identified by asking the mother the number of cigarettes the father smoked per day.

Multiple pregnancies were deleted from both cases and controls (36 cases and 3 controls). Therefore, the final data set included 416 antepartum fetal deaths and 449 normal live births. First, the univariate associations between risk factors and antepartum fetal death were examined and expressed by odds ratios with 95% con- fidence intervals. Next, using logistic regression, fetal sex, parity and maternal age were controlled to examine the adjusted association between potential risk factors and fetal death. The adjusted odds ratios and 95% confidence intervals were calculated from the logistic regression coefficients and standard error [ 171. Then we selected the significant risk factors to explore the relationship between risk factors and clinical causes of fetal death, i.e. to examine whether exposure to some risk fac- tor may increase the risk of fetal death from a specific cause. Finally, we explicitly examined congenital anomalies among the deaths with respect to exposure to hazards. The classification of congenital anomalies was based on the International Classification of Diseases (ICD), 9th revision [18]. The overall autopsy rate was 80%.

Results

Table I presents the univariate and adjusted associations between the potential risk factors and antepartum fetal death. Among univariate associations, SGA fetuses were over five times more likely having died during late pregnancy. Mothers having greater parity experienced elevated risk of fetal death (OR = 1.8, 95% CI 0.9-3.8). Exposure to chemicals during pregnancy and threatened abortion were each

196

TABLE I

Odds ratios of the risk factors to antepartum fetal death

Factors Cases Controls (n = 416) (n = 449)

Univariate OR” (95% CI)

Adjusted OR” (95u/u CI)

Sex Male/Female 2121202 Parity z 1 vs 0 231393 Maternal age

z 35 yearsi< 35 years 1 II405 SGAIAGA b 118/298 Exposure to hazards

Radiation 7 Chemicals 44 Pesticides 7

Maternal anemia 108 Threatened abortion 37 Pregnancy-induced hypertension

No 361 Mild 28

Moderate 10 Severe II

Paternal smoking No 155 Yes 261 l-9 cigarettes/day 96 IO-19 cigarettes/day 84 > 20 cigarettes/day 81

2241225 1.1 (0.8-1.4) 141435 1.8 (0.9-3.8)

II442 1.7 (0.6-4.9) 30/419 5.5 (3.5-8.7)

3 16 0

97 18

408 I.0 25 I .3 (0.7-2.3) 13 0.9 (0.3-2. I) 3 4.1 (1.1-15.6)

203 I.0 246 1.4 (1.04-1.8) 80 I.6 (1.1-2.3) 86 I.3 (0.9-1.9) 80 1.3 (0.9-2.0)

2.5 (0.6-13.9) 3.2 (1.7-6.0)

1.3 (0.9-1.8) 2.3 (1.3-4.3)

-

5.5 (3.6-8.4)

2.5 (0.6-9.8) 3.2 (1.8-5.8)

I.3 (0.8-2.1) 2.3 (1.3-4.2)

1.0 1.2 (0.7-2.2) 0.8 (0.4-2.0) 4.2 (1.2-15.2)

I.0 1.4 (1.1-1.8) 1.5 (1.1-2.2) 1.3 (0.9-1.9) 1.3 (0.9-1.9)

OR, odds ratio; Cl, confidence interval. “Logistic regression, adjusted for sex, parity and maternal age. bSGA, small for gestational age; AGA, appropriate for gestational age.

significantly associated with antepartum fetal death. Severe pregnancy-induced hypertension and paternal smoking were also associated with the increased risk of fetal death.

After controlling for sex, parity and maternal age, SGA fetus still had much higher risk of fetal death than AGA fetus. Mothers who were exposed to radiation and chemicals during pregnancy had 2.5 and 3.2 times greater risk of fetal death, respec- tively. Threatened abortion was also significantly associated with antepartum fetal mortality; the adjusted odds ratio was 2.3. Severe pregnancy-induced hypertension significantly increased the risk of the death. Elevated odds ratios were also identified in paternal smoking, although no dose-response was apparent. No significant rela- tionships were found between sex, maternal anemia, mild or moderate pregnancy- induced hypertension and antepartum fetal death.

Associations between risk factors and the major causes of death are presented in Table II. Fetuses whose mother was exposed to hazards were significantly more like- ly to have died of congenital malformations (OR = 3.5, 95% CI 1.6-7.4). Women with threatened abortion had increased risk of fetal deaths from maternal diseases (excluding hypertensive disorder) (OR = 2.9, 95% CI 0.97-8.1). However, since

197

TABLE II

Exposure to risk factors and causes of antepartum fetal death.

Causes of death

Congenital anomalies Cord complications Placental complications Preeclampsia/eclampsia Maternal other diseases Other

Total

Exposure to hazards Threatened abortion

Yes No OR (95%CI)

14 30 3.5 (1.6-7.4) 11 109 0.5 (0.3-1.1) 2 23 0.5 (0.1-2.4) 0 10 - 7 23 2.0 (0.7-5.2)

24 163 0.8 (0.5-1.5)

58 358

Yes No OR (95%CI)

3 41 0.7 (0.0-2.6) 13 107 1.4 (0.6-2.9) 3 22 1.4 (0.0-5.4) 1 9 1.1 (0.6-9.2) 6 24 2.9 (0.97-8.1)

11 176 0.5 (0.2-1.1)

37 379

these estimates were based on a small number of cases, the results should be interpreted with caution.

Table III documents the relationship between exposure to hazards and congenital anomalies. Fetuses with maternal exposure to hazards had more than a twofold relative risk of congenital malformations than those without maternal exposure. Compared with the unexposed group, exposed fetuses had a relatively higher pro- portion of anomalies of central nervous system and facial features. Seventy percent of malformed fetuses exposed to hazards had anomalies of the central nervous system.

TABLE III

Exposure to hazards and congenital anomalies among antepartum fetal deaths.

Congenital anomalies (ICD-9 codes)a Exposed Non-exposed OR (95%CI)

N % N %

No anomaly 38 300 2.7 (1.4-5.2) Having anomaliesb 20 58

Central nervous system (740-742) 70 38 3.8 (1.1-13.2) Eye, ear, face, neck, cleft palate and cleft lip 20 10 2.2 (0.4-10.3)

(743,744,749) Heart & circulatory system (745-747) 20 19 1. I (0.2-4.4) Respiratory system (748) 5 9 0.6 (0.0-5.5) Digestive system (750,751) 10 12 0.8 (0. I-4.9) Urogenital system (752,753) 15 19 0.8 (0.0-3.5) Musculoskeletal 8r limbs (754-756) 15 14 1.1 (0.5-5.4) Integument (757) 0 2 - Other (758,759) 0 9 -

‘ICD, International Classification of Diseases, 9th Revision (Ref. 18). bSome fetuses had multiple malformations in different systems.

198

Discussion

The relationship between exposure to hazards and fetal death has been reported [19,20]. This study confirms this relationship and further suggests that congenital anomalies may contribute to this significant association, i.e. exposure to hazards may increase the risk of congenital malformation and, in turn, increase the risk of antepartum fetal death. The relative risks of congenital malformation and death from congenital anomalies were 2.7 (95% CI 1.4-5.2) and 3.5 (95% CI 1.6-7.4), respectively, for the exposed fetus. Furthermore, we found that fetus exposed to hazards had two to four times the risk for anomalies of central nervous system and facial features. Since embryonic central nervous system and facial features are form- ed within the first trimester, these findings suggest that exposure to hazards within the first trimester may be a more important and direct factor attributable to fetal death.

Our analyses also documented a significant relationship between threatened abor- tion and antepartum fetal death. The possible explanation might be that due to maternal, placental or fetal factors, the mothers may be physically no longer compe- tent to bear the fetus and consequently manifest threatened abortion/abortion. Those women therefore experienced higher risk of late fetal death. This hypothesis is in part supported by the association between threatened abortion and elevated risk of fetal death from maternal diseases in our study (but not statistically significant) (Table II). As such, threatened abortion may not be a direct risk factor to fetal death but a significant predictor of risk of the mortality.

The prevalence of maternal smoking was very low in the present study. Paternal smoking, however, was more prevalent and was associated with elevated risk of fetal death. The odds ratios were consistent among different dose groups. Our results are close to those from a recent prospective study in Sweden, in which pregnant women with passive smoking at work had increased risk of intrauterine death compared with pregnancies of unexposed working women (RR = 1.53,95% CI 0.98-2.38) [21]. However, it should be noted that report bias may be possible in our study because the mothers of cases might be inclined to report their husbands being smokers even though the husbands smoked seldom. However, for higher dose groups, increased relative risks were difficult to be explained by report bias. This is because the mothers of cases might exaggerate the number of cigarettes smoked per day a little bit more, but it is unlikely that the reported number of cigarettes were greatly exag- gerated. Since the prevalence of maternal smoking was very low in our population, especially among pregnant women [22], the alternative possible explanation for the relationship between paternal smoking and fetal death might be the sperm-mediated influence of smoking [23] and maternal passive smoking during pregnancy [ 16,24,25]. On the other hand, however, since the dose-response pattern in our study was not apparent, the possibility that this association is due to chance or undetected confounding can not be ruled out. For reasons of public health, this relationship needs further study.

One of the limitations in our study is that due to the one-child-family policy in Shanghai, most pregnant women were primigravidas. Second or third births often occurred following death or abnormality of the former birth. Hence, multiparity in

199

our study implied previous adverse reproductive outcome. As such, this finding may not be applicable to other populations.

SGA was found to be significantly associated with fetal death (OR = 5.5). Although this association has been well established, in terms of the magnitude of the risk, the odds ratio reported here may have been affected by inaccurate gestational age and maceration after death. The recorded gestational age may not be the age when the fetus died and degree of maceration depended on duration between death and stillbirth. Therefore, the relative risk might be slightly exaggerated.

Since our study was a case-control study, recall bias of information on certain rele- vant risk factors such as exposure to hazard during pregnancy may exist. Mothers with fetal loss may have probed their memories more deeply than the control mothers. Therefore, recall bias may have influenced the association between ex- posure to hazard and stillbirth in the current study. However, since most of the other information was cited directly from the clinical record and prenatal care card, recall bias on most of the variables was eliminated. Furthermore the homogeneous nature of the population of Shanghai enables some of the confounding effects, such as race, socioeconomic status, teenage pregnancies and differential access to prenatal care, to be minimized.

In summary, this case-control study examined a variety of risk factors to antepar- turn fetal death. In addition to SGA and severe pregnancy-induced hypertension, ex- posure to hazards during pregnancy was significantly associated with fetal death. Clinico-pathologic evidence further demonstrated that exposure to hazards, especially in the first trimester, increased the risks of congenital anomalies and antepartum fetal death from congenital malformations. Our study also revealed that threatened abortion was a significant predictor of risk of the fetal death. Further- more, father smoking was found to be associated with elevated risk of antepartum fetal death.

Acknowledgement

The authors are grateful to Dr Allen J. Wilcox for his comments on the earlier draft of this paper.

References

Petitti, D.B. (1987): The epidemiology of fetal death. Clin. Obstet. Gynecol., 30, 253-258. Naeye, R.L. (1977): Causes of perinatal mortality in the US Collaborative Perinatal Project. J.Am. Med. Assoc., 238, 228-229. Morrison, I. and Olsen J. (1985): Weight-specific stillbirths and associated causes of death: an analysis of 765 stillbirths. Am. J. Obstet. Gynecol., 152, 975-980. Whitlield, C.R., Smith, N.C., Cockburn, F. and Gibson A.A.M. (1986): Perinatally related wastage-a proposed classification of primary obstetric factors. Br. J. Obstet. Gynaecol., 93, 694-703. Carey, J.C. (1987): Diagnostic evaluation of the stillborn infant. Clin. Obstet. Gynecol., 30, 342-351. Branch, D.W. (1987): Immunologic disease and fetal death. Clin. Obstet. Gynecol., 30, 295-311. Kochenour, N.K. (1987): Other causes of fetal death. Clin. Obstet. Gynecol., 30, 312-321. Cnattingius, S., Haglund, B. and Meirik, 0. (1988): Cigarette smoking as risk factor for late fetal and early neonatal death. Br. Med. J., 297, 258-261.

200

9

IO

11

12

13

14

15

16

17

18

19

20

21

22

23 24

25

Ounsted, M. (1985): Risk factors associated with small-for-dates and large-for-dates infants. Br. J. Obstet. Gynaecol., 92, 226-232. Hu, X.J. and Zhang, B.J. (1982): Women’s health care. In: Health Services in Shanghai County. Am. J. Publ. Health 72 (Suppl.), 33-35. Parker, R.L. and Hinman, A.R. (1982): Use of health services. In: Health Services in Shanghai County. Am. J. Publ. Health 72 (Suppl.), 71-77. FIGCI Committee on Perinatal Epidemiology and Health Statistics. Report on Methodology of Measurement and Recording of Infant Growth in the Perinatal Period, September 1985. Fanaroff, A.A. and Martin, R.J. (1987): Neonatal-perinatal medicine: diseases of the fetus and in- fant. C.V. Mosby, St. Louis, MO. Meyer, R.E., Aldrich, T.E. and Easterly, C.E. (1989): Effects of noise and electromagnetic fields on reproductive outcomes. Environ. Health Perspect., 81, 193-200. Haesslein, H.C. (1987): Hypertensive Disease. In: Manual of Obstetrics, p. 238. Editor: K.R. Niswander, Little, Brown and Company, Boston. Rubin, D.H., Krasilnikoff, P.A., Leventhal, J.M., Weile, B. and Berget, A. (1986): Effect of passive smoking on birthweight. Lancet, ii, 415-417. Hosmer, D.W. and Lemeshow, S. (1989) Applied Logistic Regression. John Wiley & Sons, New York. World Health Organization (1977): International Classification of Diseases, 9th revision, 1975. Vol. I., WHO, Geneva. Savitz, D.A., Whelan, E.A. and Kleckner, R.C. (1989): Effect of parents’ occupational exposures on risk of still birth, preterm delivery and small-for gestational-age infants. Am. J. Epidemiol., 129, 1201-1218. Arulkumaran, S. (1989): Antenatal monitoring of the high risk fetus. Singapore Med. J., 30, 202-204. Ahlborg, G. and Bodin, L. (1991): Tobacco smoke exposure and pregnancy outcome among work- ing women: a prospective study at prenatal care centers in Orebro County, Sweden. Am. J. Epidemiol., 133, 338-347. Deng, J. and Gao, Y.T. (1985): The prevalence of cigarette smoking habit among 110000 adult residents in Shanghai urban area. Chin. J. Prev. Med., 19, 271-274. Weisberg, E. (1985): Smoking and reproductive health. Clin. Reprod. Fertil., 3, 175-186. Ueda, Y., Morikawa, H. and Funakoshi, T., et al. (1989): Estimation of passive smoking during pregnancy by cotinine measurement and its effect on fetal growth. Nippon Sanka Fujinka Gakkai Zasshi, 41, 454-460. Martin, T.R. and Bracken, M.B. (1986): Association of low birth weight with passive smoke ex- posure in pregnancy. Am. J. Epidemiol., 124, 633-642.