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The association of primiparity with intrauterine growth retardation
European Journal and Reproductive
ELSEVIER SCIENCE IRELAND
The association
of primiparity
Ilana Shoham-Vardi*“,
of Obstetrics & Gynecology Biology 53 (1994) 95-101
with intrauterine J.R. Leibermanb,
Gideon
growth retardation Kopernik b
“Epidemiology Unit, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva. Israel ‘Division of Obstetrics and Gynecology, Soroka Medical Center, Beer Sheva. Israel (Accepted
21 October
1993)
Abstract The role of parity in the epidemiology of intrauterine growth retardation (IUGR) is not well understood, as some risk factors for IUGR are associated with young age and primiparity, and some are more frequent among older multiparous women. This paper examines the unique role of primiparity in the etiology of IUGR in a series of 25 614 singleton births in the southern part of Israel. The rates of IUGR were 3.5% among primiparae and 1.7% in multiparae. (Risk ratio = 1.99; 95% confidence interval, 1.69-2.35). Maternal age was associated with IUGR only among primiparae but not in multiparae. Of the obstetric factors examined, the following were found to be significantly associated with IUGR: hypertension, prior infertility, oligohydramnios, gross fetal congenital anomalies, and being a female fetus. After simultaneous adjustment for these risk factors by multiple logistic regression analysis, the odds ratio associated with parity was 1.62 (95% confidence interval, 1.30-2.01), suggesting that primiparity constitutes an independent risk factor for IUGR. Key words: Intrauterine-growth-retardation;
Parity; Maternal
1. Introduction
The role of parity in the epidemiology of intrauterine-growth-retardation (IUGR) is not well understood. Epidemiological studies of IUGR often control for parity as a confounding factor, but do not attempt to assess the effect of parity per se on the incidence of IUGR. Based on an extensive review and meta-analysis of the literature published in the years 1970-1984, Kramer [l] concludes that primiparous women stand a higher risk for IUGR when compared with multiparous women. This conclusion, however, is based on studies which have focused on low birth weight unadjusted for length of gestation, or have restricted their analysis to low birth weight at term (C 2500 g at 40 weeks of gestation). A controlled epidemiological study of risk factors associated with IUGR, conducted in Britain by Ounsted et al. [2], found that primiparity was not a statistically l Corresponding author, Department of Community and Preventive Medicine, University of Rochester Medical Center, 601 Elmwood Ave. Box 644, Rochester NY 14642, USA.
0 1994 Elsevier Science Ireland 002%2243/94/$07.00 SSDI 0028-2243(93)01719-A
age; Obstetric
risk factors
significant predictor of IUGR when other obstetric risk factors were controlled for. Two recently published articles, reporting the results of extensive epidemiological studies in the USA [3,4], suggest that primiparity is associated with higher rates of IUGR. These two studies, however, were conducted in populations characterized by low socioeconomic status, with relatively high rates of IUGR. The two main categories of etiological factors in IUGR are both associated with parity. The lirst category includes factors such as poor maternal nutritional status, infection, poor health status in general, exposure to toxic substances during pregnancy, low pre-pregnancy weight, as well as insufficient weight gain during pregnancy and inadequate prenatal care [3-81. These risk factors seem to cluster among primiparous women where there is a high proportion of unwed, teenage mothers [9]. The other category of risk factors consists of obstetric risk factors complicating pregnancy, mainly hypertension and other vascular disorders [2,4]. While pre-eclampsia is more prevalent in primiparous than in multiparous women, chronic hypertension and other
Ltd. All rights reserved.
96
I. Shohum-Vardi
diseases leading to placental insufficiency are associated with older maternal age and higher parity [7]. The purpose of this paper is to examine the role of parity in the etiology of IUGR in the presence of other obstetric factors, within a large general obstetric population. 2. Material and methods Our data were derived from a computerized record of births (1 January 1986-31 December 1990) in the Soroka Medical Center, which is the only hospital in the Negev area (the southern part of Israel) serving a population of 300 000. Excluded from the present analysis were multiple births and births occurring in the nonJewish (mostly Bedouin) population. The analysis was restricted to Jewish women in an attempt to make the study population as homogenous as possible in terms of information validity. While most pregnant women in the Jewish population enroll in prenatal care in the first trimester of pregnancy [lo], many of the Bedouin women do not register in a prenatal clinic until later in pregnancy. A key variable in our study is gestational age, which can be validly assessed only when based on information obtained early in pregnancy. Since time of prenatal care initiation is not available on our computerized database, it was decided, based on our clinical experience and on personal communication with nurses in the prenatal clinics, to use the ethnicity variable as a proxy for the pattern of prenatal care utilization pattern and to focus in this paper only on the Jewish population. A pre-coded form, containing information about the pregnancy, the birth, and the newborn, is routinely completed by the physician at the time of discharge. Information about obstetric history is obtained by the physician and midwife in the delivery room from the patient, from the prenatal clinic records, and from hospital records of previous pregnancies and births. 2.1. Infertility Infertility was defined as 1 year, at least, of unsuccessful attempts to conceive prior to the current pregnancy. 2.2. Lack of prenatal care Lack of prenatal care was defined as less than three visits at any prenatal care facility. 2.3. Hypertensive disorders Four categories of hypertensive disorders were used in the analysis. 2.3.1. Moderate hypertension: Blood pressure of 140/90 to 159/99 measured for the first time in the second half of pregnancy. 2.3.2. Severe hypertension: Blood pressure of 160/100
PI al. /Eur.
J. Ohsret. Gynecol. Reprod. Biol. 53 (1994)
95-101
or higher initially detected in the second half of pregnancy. 2.3.3. Chronic hypertension: Blood pressure of 140190 or higher detected during the first half of pregnancy or before. 2.3.4. Superimposed hypertension: Acute hypertension found in the second half of pregnancy in chronically hypertensive patients. 2.4. Diabetes Patients were defined as having diabetes if gestational diabetes (class A) or insulin dependent diabetes (class B-R) as defined by White classification were observed. 2.5. Pre-term contractions Pre-term contractions were defined as regular uterine contractions during pregnancy before 37 completed weeks of gestation not leading to delivery. 2.6. Premature rupture of membranes (PROM) PROM was defined as proven rupture of membranes at least 6 h before labor. 2.7. Pre- term delivery Pre-term delivery was defined as delivery occurring before 37 completed weeks of gestation. 2.8. Polyhydramnios and oligohydramnios Polyhydramnios and oligohydramnios were diagnosed and defined by sonographic criteria. The protocol for prenatal care includes at least one ultrasound examination at week 22. Most women, however, have more than one ultrasound examination during their pregnancy. 2.9. Gestational age The week of pregnancy at birth is determined by at least two of the following criteria: last menstrual period, gynecological examination, pregnancy test, ultrasound, or infertility charts. Only in 3% of the women, was gestational age determined by a single criterion. 2.10. IUGR IUGR was diagnosed by a birth weight lower than the 10th percentile for week of gestation, as reported by Battaglia and Lubchenco [ 111. The diagnosis is confirmed by a neonatal examination. 2.11. Congenital anomalies Congenital anomalies were gross anomalies observed at birth or during the birth hospitalization. 2.12. Statistical analysis Statistical analysis included three components. (a) A univariate comparison of the prevalence of obstetric risk factors in primiparous and multiparous women.
97
1. Shoham-Vardi et al. /Eur. J. Obstei. Gyneeol. Reprod. Biol. 53 (1994) 95-101
its severe manifestations, was more prevalent in primiparous than in multiparous women, while chronic hypertension and diabetes were more prevalent in multiparous women. Polyhydramnios was detected more often in multiparous women, while oligohydramnios was more prevalent in primiparous women. Rates of pre-term contractions, premature rupture of membranes, and premature delivery were significantly higher in primiparous than in multiparous women. The incidence of low birth weight was significantly higher among primiparous women. This reflects not only a higher rate of premature deliveries, but also a significantly higher rate of IUGR. The risk ratio for IUGR associated with primiparity is 1.99 (95% conlidence interval, 1.69-2.35). No differences between primiparous and multiparous women were found with regard to fetal sex distribution, the prevalence of congenital anomalies at birth, and perinatal mortality rates. Fig. 1 presents the rates of IUGR in primiparous and
Statistical significance was determined by the x2 or Fisher’s exact test, as required. (b) Risk factors for IUGR (with 95% confidence intervals) were calculated separately in primiparous and multiparous women and adjusted for the presence of obstetric risk factors one at a time. (c) A multivariate adjustment of risks was performed by logistic regression to assess the unique contribution of each factor to the risk of IUGR [12]. 3. Results In the first stage of the analysis, we compared obstetric and clinical characteristics of primiparous and multiparous women. The findings are presented in Table 1. As can be expected, primiparous women were younger, with fewer abortions in the past, but with a higher rate of history of infertility preceding the current pregnancy. In both primiparous and multiparous women, only a few had not had prenatal care. Hypertension in pregnancy, both in its moderate and
Table 1 Clinical characteristics
of the study population
by parity Primiparae (n = 6866)
P value
Multiparae (n = 18 748)
u/u
”
1%
n
7.3 49.7 32.5 8.1 2.4
0.5 13.2 35.0 36.4 14.9
0.6
498 3416 2232 554 163 3 39
0.5
95 2483 6559 6814 2787 10 85
6.4 2.1
442 142
1.5 5.0
290 944
5.6 1.6 0.5 0.2 6.4 1.0 1.7 4.7 7.4 1.0 1.0
386 109 36 14 439 69 119 322 511 68 69
3.3 0.6 1.3 0.2 9.0 1.5 I.0 2.8 5.3 1.6 0.5
613 119 236 43 1685 285 196 530 999 309 93
3.5 10.0 1.4 1.3 48.5
237 695 98 92 3329
1.7 6.2 1.2 1.2 48.4
325 1201 217 218 9079
<0.001
Age <20 20-24 25-29 30-34 >35 Unknown Lack of prenatal Obstetric history Infertility
care
Abortions Gestational complications Moderate hypertension Severe hypertension Chronic hypertension Superimposed hypertension Diabetes Class A Diabetes Class B-R Pre-term contractions PROM Pre-term delivery Polyhydramnion Oligohydramnion Fetal outcome IUGR Low birth weight (<2.5 kg) Gross Anomalies Perinatal mortality Female fetus PROM,
premature
rupture
of membranes;
IUGR,
intrauterine
growth
retardation.
< 0.001
0.285
I. Shoham-Vardi
98
%IUGR RR~3.03
RRm2.16
30-34
26-29
20-24
Maternal Age BEI Prlmlprrous
17
Multiparous
oonlldenoe
RR: Alek Rsllo (86% lntervell IUGR: lnlrr Uierlne Growth Retrrdallon
Fig. 1. Intrauterine growth retardation (IUGR) in primiparous and multiparous women, by age. RR, risk ratio; numbers in parentheses give the 95% confidence interval.
in multiparous women, by age groups. In all age groups, except for the youngest (i.e. < 20 years), rates of IUGR are significantly higher in primiparous than in multiparous women. Moreover, parity and age seem to
Table 2 Risk ratios for IUGR Risk factor**
in women with selected risk factors,
24
Hypertension Chronic
1
Severe
18
Moderate
18
Oligohydramnios
30
Gross anomalies
10
Age >29
Reprod. Biol. 53 (1994)
95-101
by parity
Risk ratios for IUGR* (95% confidence interval)
n with risk factor and IUGR
Female fetus
J. Obstet. Gynecol.
interact; while in primiparous women, rates of IUGR increase with age, no such trend is observed in the multiparous women. Thus primiparous women, aged 30 or older, are at the highest risk of IUGR. IUGR was more prevalent in preterm births than in full-term births: 7.21% versus 3.1% among primiparous women (P < O.OOl), and 5.31% versus 1.53% among multiparous women (P < 0.001). Of the risk factors examined, oligohydramnios, severe hypertension, congerital anomalies, prior infertility, and the fetus being a female were all significantly associated with an increased risk of IUGR in both primiparous and multiparous women. Moderate and chronic hypertension were found to be significant risk factors for IUGR only in multiparous, but not in primiparous women. Age >29 years was a significant risk factor only in primiparous but not in multiparous women (Table 2). Gestational diabetes (class A) was associated in multiparous women with a reduced risk for IUGR (risk ratio (RR) = 0.59; 95% CI, 0.37-0.95), and with a statistically nonsignificant increased risk in primiparous women (RR = 1.20; 95% CI, 0.75- 1.93). Diabetes class B-R was not associated with IUGR in either of the two groups of women. No differences in rates of IUGR were found between primiparous women and multiparous women with the following risk factors: prior infertility (5.4% vs. 3.4%,
Multiparae
Primiparae
Infertility
et al. /Eur.
158 40
RR
n with risk factor and IUGR
RR
1.64 (1.09-2.47)
10
2.02 (1.09-3.75)
0.82 (0.12-5.71) 5.23 (3.36-8.14) 1.38 (0.86-2.21) 14.28 (10.57-19.28) 3.04 (1.67-5.55) 2.12 (1.63-2.77) 1.75
10
2.52 (1.36-4.66) 12.05 (8.21-17.70) 2.15
(1.26-2.44)
23 22
(1.40-3.29) 31 21 207 163
21.15 (15.53-28.81) 5.90 (3.87-8.99) 1.87 (1.49-2.34) 0.87 (0.70- 1.09)
IUGR, intrauterine growth retardation *Risk ratios comparing women with the risk factors with women without the risk factor, computed separately in primiparae and multiparae. **Included in the table are only factors which were found to be significant risk factors for IUGR in at least one of the two parity groups.
I. Shoham-Vardi et al. /Eur. J. Obstet. Gynecol. Reprod. Biol. 53 (1994) 95-101
P = 0.280), moderate hypertension (4.7% vs. 3.6%, P = 0.399), severe hypertension (16.5% vs. 19.3%, P = 0.704), chronic hypertension (2.8% vs. 4.2%; P = 0.876), oligohydramnios (43.5% vs. 33.3%, P = 0.249), and gross anomalies (10.2% vs. 9.7%, P = 0.953). IUGR was more prevalent in primiparous women with a female fetus than in multiparous women with a female fetus (4.7% vs. 2.3%, P < O.OOl), and in women older than 30 where the rate of IUGR was 5.6% among primiparous women and 1.7% among multiparous women (P < 0.001). To further examine the association of parity and IUGR, a multivariate logistic regression was performed while simultaneously adjusting for all risk factors. Results are presented in Table 3. The model included all risk factors which were significantly associated with Table 3 Results from a multivariate logistic analysis intrauterine growth retardation Risk factor*
Prior infertility 1 yes 0 no Hypertensive disorders Moderate 1 yes 0 normotensive Severe I yes 0 normotensive Chronic 1 yes 0 normotensive Superimposed 1 yes 0 normotensive Gross anomalies 1 yes 0 no Fetal sex I female 0 male Oligohydramnios 1 yes 0 no *The risk category the value of 0.
IUGR in at least one of the two parity groups (prior infertility, hypertension, oligohydramnios, gross anomalies, being a female fetus, age >29 and parity). In addition, an interaction term of age and parity was included to compare the risk of a primiparous woman whose age was over 29 with other women with the same risk profile. The results suggest that the most important predictors of IUGR were oligohydramnios, severe hypertension, and gross anomalies. With these and other risk factors included in the model (moderate and chronic hypertension, prior infertility, the fetus being a female), maternal older age ( > 29 years) does not affect the risk of IUGR, unless it interacts with primiparity (RR = 1.65; 95% CI, 1.06-2.56). Primiparity adjusted for all these variables remains an independent risk factor. 4. Discussion
of risk factors
Multivariate adjusted odds ratio
Parity 1 primipara 0 multipara Maternal age 1 >29 0 129 Parity + Age 1 primiparae >29 0 multiparae and primiparae 5 29
99
for
95% Contidence interval
1.62
1.30-2.01
0.92
0.73-1.15
1.65
1.06-2.56
1.56
1.05-2.30
1.59
1.11-2.30
8.79
6.04-12.79
2.06
0.99-4.29
0.90
0.21-3.74
4.55
3.00-6.88
2.17
1.81-2.61
25.56
17.99-36.3
has the value of 1 and the reference category
I
The role of primiparity in the etiology of IUGR was examined in a large cohort of births representing all births in the Jewish population in a defined geographical area in Israel. Our aim was to study the role of primiparity adjusted for other obstetric risk factors. It was, therefore, essential to have adequate obstetric assessment of the study population. Because most pregnant women in our area are enrolled in prenatal clinics early in pregnancy [lo], identification of problems and complications of pregnancy is rather comprehensive. Gestational age, which is of crucial importance to the study of IUGR [ 131, was determined in most cases early in pregnancy when it can be accurately assessed. Moreover, 97% of the study population had at least two criteria by which gestational age had been determined, allowing for a very specific diagnosis of IUGR. The rate of IUGR in our population is 2.2% (3.5% among primiparous women and 1.7% among multiparous women). These rates are lower than those reported by Wen et al. [3] and by Abrams and Newman [4], but similar to the rate reported by Berkowitz et al. among primiparous women, after adjusting for age [ 141. The strict criteria required for the determination of gestational age in our study may have resulted in high specificity and relatively low sensitivity in the detection of IUGR, leading to an underestimate of IUGR rate in our population. To the extent that such a misclassilication occurred in our study, its effect will be an attenuation of all risk estimates, resulting in a conservative bias [ 121. This and other methodological differences - such as birth weight standards used to determine the cut-off points for IUGR, inclusion or exclusion of congenital anomalies or fetal deaths - partly account for the wide range of reported IUGR rates. We believe, however, that the variance among studies reflects true population differences. In comparison with the populations described by Wen et al. [3] and by Abrams and Newman [4],
100
1. Shoham-Vardi ef al. /Eur. J. Obstet. Gynecol. Reprod. Biol. 53 (1994) 95-101
our population had a markedly lower proportion of unwed teenage mothers, and of women with inadequate prenatal care. Moreover, in our cohort, the proportion of primiparous women was substantially lower (27%, compared with 51% in the study by Wen et al. and 41% in the study by Abrams and Newman). The major risk factors for IUGR identified in our data are consistent with previous reports [l]. Maternal age was found to increase the risk of IUGR only in primiparous women, but not in multiparous women (Fig. 1). Similar findings were reported by others [3,7]. Higher rates of low-birth-weight among older primiparous women, but not of IUGR, were found by Berkowitz et al. [14], whose study is based on a cohort where most of the participants were college graduates. In our population, in contrast, the median years of schooling of women of child bearing age is 11 years [ 151. This difference in study populations may be indicative of different reasons for delaying childbirth, thus making the risk profile of these two groups of older primiparous women not comparable. Of the obstetric factors examined in our study, oligohydramnios was the strongest predictor of IUGR, but the causal direction of this association is not clear [16]. Of the other risk factors, the following were shown to have an independent contribution to IUGR: severe hypertension, fetal congenital anomalies, fetal female sex, primiparity, moderate hypertension, prior infertility and the interaction between primiparity and age >29 (Table 3). Similarly to other studies [2,4,8,17,18], our data show the important role of pregnancy induced hypertensive disorders, as well as chronic hypertension, in the etiology of IUGR. Many studies of IUGR excluded cases with congenital anomalies. One recent study where these cases were included [2], reports a significantly increased risk of IUGR in fetuses with congenital malformations. This was also demonstrated in our data. Prior infertility has not been extensively studied as a risk factor for IUGR. In his review of the literature, Kramer [1] points out that in order to fully understand the role of prior infertility in the etiology of IUGR, it is necessary to control for several potential confounders, such as prior genital tract infections, uterine malformations, and pre-pregnancy low maternal weight. As we do not have reliable information on these risk factors, it is difficult to interpret the association found between prior infertility and IUGR, mainly among primiparous women. Our findings suggest that primiparous women stand twice the risk of IUGR compared with multiparous women. In a multivariate model, adjusting simultaneously for all risk factors identified in our study, primiparity remains a significant predictor of IUGR. The literature suggests that factors such as toxic expo-
sure, smoking and drug abuse, malnutrition and low pre-gestational maternal weight, and insufficient weight gain increase the risk of IUGR, and that these risk factors are frequently associated with low socioeconomic status and teenage pregnancy [1,3,4,7,8,19]. Lack of information on our computerized data set prevented us from controlling for these variables in the analysis. This, however, should not have affected our main findings. As our population of primiparae contained only few very young mothers, it not likely that risk factors which are usually associated with teenage pregnancies will be more prevalent among the primiparaous women in comparison with the multiparaous women. Morever, other studies have shown that primiparity remains a signilicant risk factor for IUGR, even when such environmental factors were controlled for [3,4]. Based on our findings, and on those of other studies using different methodologies and conducted in populations with different risk profiles, we suggest that primiparity constitutes an independent risk factor for IUGR. This finding is consistent with the hypothesis that among other etiologies, IUGR may be caused by non-symptomatic vascular disorders, compromising uterine blood supply to the feto-placental unit, which, like pre-eclampsia, are more prevalent in first pregnancies [20]. 5. References 1
Kramer MS. Determinants of low birth weight: methodological assessment and meta-analysis. Bull WHO 1987; 65: 663-737.
2
Ounsted M, Moar VA, Scott A. Risk factors associated with small-for-dates and large-for-dates infants. Br J Obstet Gynaecol 1985; 92: 226-232. Wen SW, Goldenberg RL, Cutter GR, Hoffman HJ, Cliver SP. Intrauterine growth retardation and preterm delivery: prenatal risk factors in an indigent population. Am J Obstet Gynecol 1990; 162: 213-218. Abrams B, Newman V. Small-for-gestational-age birth: maternal predictors and comparison with risk factors of spontaneous preterm delivery in the same cohort. Am J Obstet Gynecol 1991; 164: 785-790. Miller HC. Intrauterine growth retardation. Am J Dis Child 1981; 135: 944-948. Ferraz EM, Gray RH, Cunha TM. Determinants of preterm delivery and intrauterine growth retradation in Northeast Brazil. Int J Epidemiol 1990; 19: 101-108. Lee KS, Freguson RM, Corpuz M, Gartner LM. Maternal age and the incidence of low birth weight at term: a population study. Am J Obstet Gynecol 1988; 158: 84-89. Kramer MS, Olivier M, McLean FH, Dougherty GE, Willis DM, Usher RH. Determinant of fetal growth and body proportionality. Pediatrics 1990; 86: 18-26. Gale R, Zengen S, Harlap S, Fischer AF, Steveson DK. Birth out of wedlock and the risk of intrauterine growth retardation. Am J Perinatol 1988; 5: 278-282. lnsler V, Larholt K, Hagay ZJ et al. The impact of prenatal care on the outcome of pregnancy. Eur J Obstet Gynecol Reprod Biol 1986; 23: 211-213. Battaglia FC, Lubchenco LO. A practical classification of newborn infants by weight and gestational age. J Pediatr 1967; 71: 159.
3
4
5 6
I
8
1. Shoham-Vardi et al. /Eur. J. Obstel. Gynecol. Reprod. Biol. 53 (1994) 95-101 12 13
14
15
16
Kelsey JL, Thompson WD, Evans AS. Methods in observational epidemiology. New York: Oxford University Press, 1986. Bergsjo L, Hoffman HS, Davis RO et al. Preliminary results from the Collaborative Alabama and Scandinavian study of sucessive small-for-gestational-age births. Acta Obstet Gynecol Stand 1989; 68: 19-25. Berkowitz GS, Skovron ML, Lapinski RH, Berkowitz RI. Delayed childbearing and the outcome of pregnancy. N Engl J Med 1990; 322: 659-663. State of Israel Central Bureau of Statistics. 1983 census of population and housing publications. No. 5. Jerusalem: State of Israel Central Bureau of Statistics, 1985. Philipson EN, Sokol RJ, Williams T. Oligohydramnios: clinical associations and predictive value for intrauterine growth tion. Am J Obstet Gynecol 1983; 146: 271-278.
retarda-
17
18
19
20
101 Bakketeig Ls, Bjerkedal T, Hoffman HJ. Small for gestational age birth in successive prenancy outcomes: results from a longitudinal study of births in Norway. Early Hum Dev 1986; 14: 187-200. Plovin PF, Breart G, Rabarison Y, Rumeau-Rouquette C, Sureau C, Menard J. Fetal growth retardation in gestational hypertension: relationship with blood pressure, levels and time of onset of hypertension. Eur J Obstet Gynecol Reprod Biol 1983; 16: 253-262. Wen SW, Goldenberg RL, Cutter GR et al. Smoking, maternal age, fetal growth and gestational age at delivery. Am J Obstet Gynecol 1990; 162: 53-58. Leiberman JR. Vascular nature of preeclampsia. Med Hypotheses 1989; 28: 281-283.
ELSEVIER SCIENCE IRELAND
The association
of primiparity
Ilana Shoham-Vardi*“,
of Obstetrics & Gynecology Biology 53 (1994) 95-101
with intrauterine J.R. Leibermanb,
Gideon
growth retardation Kopernik b
“Epidemiology Unit, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva. Israel ‘Division of Obstetrics and Gynecology, Soroka Medical Center, Beer Sheva. Israel (Accepted
21 October
1993)
Abstract The role of parity in the epidemiology of intrauterine growth retardation (IUGR) is not well understood, as some risk factors for IUGR are associated with young age and primiparity, and some are more frequent among older multiparous women. This paper examines the unique role of primiparity in the etiology of IUGR in a series of 25 614 singleton births in the southern part of Israel. The rates of IUGR were 3.5% among primiparae and 1.7% in multiparae. (Risk ratio = 1.99; 95% confidence interval, 1.69-2.35). Maternal age was associated with IUGR only among primiparae but not in multiparae. Of the obstetric factors examined, the following were found to be significantly associated with IUGR: hypertension, prior infertility, oligohydramnios, gross fetal congenital anomalies, and being a female fetus. After simultaneous adjustment for these risk factors by multiple logistic regression analysis, the odds ratio associated with parity was 1.62 (95% confidence interval, 1.30-2.01), suggesting that primiparity constitutes an independent risk factor for IUGR. Key words: Intrauterine-growth-retardation;
Parity; Maternal
1. Introduction
The role of parity in the epidemiology of intrauterine-growth-retardation (IUGR) is not well understood. Epidemiological studies of IUGR often control for parity as a confounding factor, but do not attempt to assess the effect of parity per se on the incidence of IUGR. Based on an extensive review and meta-analysis of the literature published in the years 1970-1984, Kramer [l] concludes that primiparous women stand a higher risk for IUGR when compared with multiparous women. This conclusion, however, is based on studies which have focused on low birth weight unadjusted for length of gestation, or have restricted their analysis to low birth weight at term (C 2500 g at 40 weeks of gestation). A controlled epidemiological study of risk factors associated with IUGR, conducted in Britain by Ounsted et al. [2], found that primiparity was not a statistically l Corresponding author, Department of Community and Preventive Medicine, University of Rochester Medical Center, 601 Elmwood Ave. Box 644, Rochester NY 14642, USA.
0 1994 Elsevier Science Ireland 002%2243/94/$07.00 SSDI 0028-2243(93)01719-A
age; Obstetric
risk factors
significant predictor of IUGR when other obstetric risk factors were controlled for. Two recently published articles, reporting the results of extensive epidemiological studies in the USA [3,4], suggest that primiparity is associated with higher rates of IUGR. These two studies, however, were conducted in populations characterized by low socioeconomic status, with relatively high rates of IUGR. The two main categories of etiological factors in IUGR are both associated with parity. The lirst category includes factors such as poor maternal nutritional status, infection, poor health status in general, exposure to toxic substances during pregnancy, low pre-pregnancy weight, as well as insufficient weight gain during pregnancy and inadequate prenatal care [3-81. These risk factors seem to cluster among primiparous women where there is a high proportion of unwed, teenage mothers [9]. The other category of risk factors consists of obstetric risk factors complicating pregnancy, mainly hypertension and other vascular disorders [2,4]. While pre-eclampsia is more prevalent in primiparous than in multiparous women, chronic hypertension and other
Ltd. All rights reserved.
96
I. Shohum-Vardi
diseases leading to placental insufficiency are associated with older maternal age and higher parity [7]. The purpose of this paper is to examine the role of parity in the etiology of IUGR in the presence of other obstetric factors, within a large general obstetric population. 2. Material and methods Our data were derived from a computerized record of births (1 January 1986-31 December 1990) in the Soroka Medical Center, which is the only hospital in the Negev area (the southern part of Israel) serving a population of 300 000. Excluded from the present analysis were multiple births and births occurring in the nonJewish (mostly Bedouin) population. The analysis was restricted to Jewish women in an attempt to make the study population as homogenous as possible in terms of information validity. While most pregnant women in the Jewish population enroll in prenatal care in the first trimester of pregnancy [lo], many of the Bedouin women do not register in a prenatal clinic until later in pregnancy. A key variable in our study is gestational age, which can be validly assessed only when based on information obtained early in pregnancy. Since time of prenatal care initiation is not available on our computerized database, it was decided, based on our clinical experience and on personal communication with nurses in the prenatal clinics, to use the ethnicity variable as a proxy for the pattern of prenatal care utilization pattern and to focus in this paper only on the Jewish population. A pre-coded form, containing information about the pregnancy, the birth, and the newborn, is routinely completed by the physician at the time of discharge. Information about obstetric history is obtained by the physician and midwife in the delivery room from the patient, from the prenatal clinic records, and from hospital records of previous pregnancies and births. 2.1. Infertility Infertility was defined as 1 year, at least, of unsuccessful attempts to conceive prior to the current pregnancy. 2.2. Lack of prenatal care Lack of prenatal care was defined as less than three visits at any prenatal care facility. 2.3. Hypertensive disorders Four categories of hypertensive disorders were used in the analysis. 2.3.1. Moderate hypertension: Blood pressure of 140/90 to 159/99 measured for the first time in the second half of pregnancy. 2.3.2. Severe hypertension: Blood pressure of 160/100
PI al. /Eur.
J. Ohsret. Gynecol. Reprod. Biol. 53 (1994)
95-101
or higher initially detected in the second half of pregnancy. 2.3.3. Chronic hypertension: Blood pressure of 140190 or higher detected during the first half of pregnancy or before. 2.3.4. Superimposed hypertension: Acute hypertension found in the second half of pregnancy in chronically hypertensive patients. 2.4. Diabetes Patients were defined as having diabetes if gestational diabetes (class A) or insulin dependent diabetes (class B-R) as defined by White classification were observed. 2.5. Pre-term contractions Pre-term contractions were defined as regular uterine contractions during pregnancy before 37 completed weeks of gestation not leading to delivery. 2.6. Premature rupture of membranes (PROM) PROM was defined as proven rupture of membranes at least 6 h before labor. 2.7. Pre- term delivery Pre-term delivery was defined as delivery occurring before 37 completed weeks of gestation. 2.8. Polyhydramnios and oligohydramnios Polyhydramnios and oligohydramnios were diagnosed and defined by sonographic criteria. The protocol for prenatal care includes at least one ultrasound examination at week 22. Most women, however, have more than one ultrasound examination during their pregnancy. 2.9. Gestational age The week of pregnancy at birth is determined by at least two of the following criteria: last menstrual period, gynecological examination, pregnancy test, ultrasound, or infertility charts. Only in 3% of the women, was gestational age determined by a single criterion. 2.10. IUGR IUGR was diagnosed by a birth weight lower than the 10th percentile for week of gestation, as reported by Battaglia and Lubchenco [ 111. The diagnosis is confirmed by a neonatal examination. 2.11. Congenital anomalies Congenital anomalies were gross anomalies observed at birth or during the birth hospitalization. 2.12. Statistical analysis Statistical analysis included three components. (a) A univariate comparison of the prevalence of obstetric risk factors in primiparous and multiparous women.
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its severe manifestations, was more prevalent in primiparous than in multiparous women, while chronic hypertension and diabetes were more prevalent in multiparous women. Polyhydramnios was detected more often in multiparous women, while oligohydramnios was more prevalent in primiparous women. Rates of pre-term contractions, premature rupture of membranes, and premature delivery were significantly higher in primiparous than in multiparous women. The incidence of low birth weight was significantly higher among primiparous women. This reflects not only a higher rate of premature deliveries, but also a significantly higher rate of IUGR. The risk ratio for IUGR associated with primiparity is 1.99 (95% conlidence interval, 1.69-2.35). No differences between primiparous and multiparous women were found with regard to fetal sex distribution, the prevalence of congenital anomalies at birth, and perinatal mortality rates. Fig. 1 presents the rates of IUGR in primiparous and
Statistical significance was determined by the x2 or Fisher’s exact test, as required. (b) Risk factors for IUGR (with 95% confidence intervals) were calculated separately in primiparous and multiparous women and adjusted for the presence of obstetric risk factors one at a time. (c) A multivariate adjustment of risks was performed by logistic regression to assess the unique contribution of each factor to the risk of IUGR [12]. 3. Results In the first stage of the analysis, we compared obstetric and clinical characteristics of primiparous and multiparous women. The findings are presented in Table 1. As can be expected, primiparous women were younger, with fewer abortions in the past, but with a higher rate of history of infertility preceding the current pregnancy. In both primiparous and multiparous women, only a few had not had prenatal care. Hypertension in pregnancy, both in its moderate and
Table 1 Clinical characteristics
of the study population
by parity Primiparae (n = 6866)
P value
Multiparae (n = 18 748)
u/u
”
1%
n
7.3 49.7 32.5 8.1 2.4
0.5 13.2 35.0 36.4 14.9
0.6
498 3416 2232 554 163 3 39
0.5
95 2483 6559 6814 2787 10 85
6.4 2.1
442 142
1.5 5.0
290 944
5.6 1.6 0.5 0.2 6.4 1.0 1.7 4.7 7.4 1.0 1.0
386 109 36 14 439 69 119 322 511 68 69
3.3 0.6 1.3 0.2 9.0 1.5 I.0 2.8 5.3 1.6 0.5
613 119 236 43 1685 285 196 530 999 309 93
3.5 10.0 1.4 1.3 48.5
237 695 98 92 3329
1.7 6.2 1.2 1.2 48.4
325 1201 217 218 9079
<0.001
Age <20 20-24 25-29 30-34 >35 Unknown Lack of prenatal Obstetric history Infertility
care
Abortions Gestational complications Moderate hypertension Severe hypertension Chronic hypertension Superimposed hypertension Diabetes Class A Diabetes Class B-R Pre-term contractions PROM Pre-term delivery Polyhydramnion Oligohydramnion Fetal outcome IUGR Low birth weight (<2.5 kg) Gross Anomalies Perinatal mortality Female fetus PROM,
premature
rupture
of membranes;
IUGR,
intrauterine
growth
retardation.
< 0.001
0.285
I. Shoham-Vardi
98
%IUGR RR~3.03
RRm2.16
30-34
26-29
20-24
Maternal Age BEI Prlmlprrous
17
Multiparous
oonlldenoe
RR: Alek Rsllo (86% lntervell IUGR: lnlrr Uierlne Growth Retrrdallon
Fig. 1. Intrauterine growth retardation (IUGR) in primiparous and multiparous women, by age. RR, risk ratio; numbers in parentheses give the 95% confidence interval.
in multiparous women, by age groups. In all age groups, except for the youngest (i.e. < 20 years), rates of IUGR are significantly higher in primiparous than in multiparous women. Moreover, parity and age seem to
Table 2 Risk ratios for IUGR Risk factor**
in women with selected risk factors,
24
Hypertension Chronic
1
Severe
18
Moderate
18
Oligohydramnios
30
Gross anomalies
10
Age >29
Reprod. Biol. 53 (1994)
95-101
by parity
Risk ratios for IUGR* (95% confidence interval)
n with risk factor and IUGR
Female fetus
J. Obstet. Gynecol.
interact; while in primiparous women, rates of IUGR increase with age, no such trend is observed in the multiparous women. Thus primiparous women, aged 30 or older, are at the highest risk of IUGR. IUGR was more prevalent in preterm births than in full-term births: 7.21% versus 3.1% among primiparous women (P < O.OOl), and 5.31% versus 1.53% among multiparous women (P < 0.001). Of the risk factors examined, oligohydramnios, severe hypertension, congerital anomalies, prior infertility, and the fetus being a female were all significantly associated with an increased risk of IUGR in both primiparous and multiparous women. Moderate and chronic hypertension were found to be significant risk factors for IUGR only in multiparous, but not in primiparous women. Age >29 years was a significant risk factor only in primiparous but not in multiparous women (Table 2). Gestational diabetes (class A) was associated in multiparous women with a reduced risk for IUGR (risk ratio (RR) = 0.59; 95% CI, 0.37-0.95), and with a statistically nonsignificant increased risk in primiparous women (RR = 1.20; 95% CI, 0.75- 1.93). Diabetes class B-R was not associated with IUGR in either of the two groups of women. No differences in rates of IUGR were found between primiparous women and multiparous women with the following risk factors: prior infertility (5.4% vs. 3.4%,
Multiparae
Primiparae
Infertility
et al. /Eur.
158 40
RR
n with risk factor and IUGR
RR
1.64 (1.09-2.47)
10
2.02 (1.09-3.75)
0.82 (0.12-5.71) 5.23 (3.36-8.14) 1.38 (0.86-2.21) 14.28 (10.57-19.28) 3.04 (1.67-5.55) 2.12 (1.63-2.77) 1.75
10
2.52 (1.36-4.66) 12.05 (8.21-17.70) 2.15
(1.26-2.44)
23 22
(1.40-3.29) 31 21 207 163
21.15 (15.53-28.81) 5.90 (3.87-8.99) 1.87 (1.49-2.34) 0.87 (0.70- 1.09)
IUGR, intrauterine growth retardation *Risk ratios comparing women with the risk factors with women without the risk factor, computed separately in primiparae and multiparae. **Included in the table are only factors which were found to be significant risk factors for IUGR in at least one of the two parity groups.
I. Shoham-Vardi et al. /Eur. J. Obstet. Gynecol. Reprod. Biol. 53 (1994) 95-101
P = 0.280), moderate hypertension (4.7% vs. 3.6%, P = 0.399), severe hypertension (16.5% vs. 19.3%, P = 0.704), chronic hypertension (2.8% vs. 4.2%; P = 0.876), oligohydramnios (43.5% vs. 33.3%, P = 0.249), and gross anomalies (10.2% vs. 9.7%, P = 0.953). IUGR was more prevalent in primiparous women with a female fetus than in multiparous women with a female fetus (4.7% vs. 2.3%, P < O.OOl), and in women older than 30 where the rate of IUGR was 5.6% among primiparous women and 1.7% among multiparous women (P < 0.001). To further examine the association of parity and IUGR, a multivariate logistic regression was performed while simultaneously adjusting for all risk factors. Results are presented in Table 3. The model included all risk factors which were significantly associated with Table 3 Results from a multivariate logistic analysis intrauterine growth retardation Risk factor*
Prior infertility 1 yes 0 no Hypertensive disorders Moderate 1 yes 0 normotensive Severe I yes 0 normotensive Chronic 1 yes 0 normotensive Superimposed 1 yes 0 normotensive Gross anomalies 1 yes 0 no Fetal sex I female 0 male Oligohydramnios 1 yes 0 no *The risk category the value of 0.
IUGR in at least one of the two parity groups (prior infertility, hypertension, oligohydramnios, gross anomalies, being a female fetus, age >29 and parity). In addition, an interaction term of age and parity was included to compare the risk of a primiparous woman whose age was over 29 with other women with the same risk profile. The results suggest that the most important predictors of IUGR were oligohydramnios, severe hypertension, and gross anomalies. With these and other risk factors included in the model (moderate and chronic hypertension, prior infertility, the fetus being a female), maternal older age ( > 29 years) does not affect the risk of IUGR, unless it interacts with primiparity (RR = 1.65; 95% CI, 1.06-2.56). Primiparity adjusted for all these variables remains an independent risk factor. 4. Discussion
of risk factors
Multivariate adjusted odds ratio
Parity 1 primipara 0 multipara Maternal age 1 >29 0 129 Parity + Age 1 primiparae >29 0 multiparae and primiparae 5 29
99
for
95% Contidence interval
1.62
1.30-2.01
0.92
0.73-1.15
1.65
1.06-2.56
1.56
1.05-2.30
1.59
1.11-2.30
8.79
6.04-12.79
2.06
0.99-4.29
0.90
0.21-3.74
4.55
3.00-6.88
2.17
1.81-2.61
25.56
17.99-36.3
has the value of 1 and the reference category
I
The role of primiparity in the etiology of IUGR was examined in a large cohort of births representing all births in the Jewish population in a defined geographical area in Israel. Our aim was to study the role of primiparity adjusted for other obstetric risk factors. It was, therefore, essential to have adequate obstetric assessment of the study population. Because most pregnant women in our area are enrolled in prenatal clinics early in pregnancy [lo], identification of problems and complications of pregnancy is rather comprehensive. Gestational age, which is of crucial importance to the study of IUGR [ 131, was determined in most cases early in pregnancy when it can be accurately assessed. Moreover, 97% of the study population had at least two criteria by which gestational age had been determined, allowing for a very specific diagnosis of IUGR. The rate of IUGR in our population is 2.2% (3.5% among primiparous women and 1.7% among multiparous women). These rates are lower than those reported by Wen et al. [3] and by Abrams and Newman [4], but similar to the rate reported by Berkowitz et al. among primiparous women, after adjusting for age [ 141. The strict criteria required for the determination of gestational age in our study may have resulted in high specificity and relatively low sensitivity in the detection of IUGR, leading to an underestimate of IUGR rate in our population. To the extent that such a misclassilication occurred in our study, its effect will be an attenuation of all risk estimates, resulting in a conservative bias [ 121. This and other methodological differences - such as birth weight standards used to determine the cut-off points for IUGR, inclusion or exclusion of congenital anomalies or fetal deaths - partly account for the wide range of reported IUGR rates. We believe, however, that the variance among studies reflects true population differences. In comparison with the populations described by Wen et al. [3] and by Abrams and Newman [4],
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our population had a markedly lower proportion of unwed teenage mothers, and of women with inadequate prenatal care. Moreover, in our cohort, the proportion of primiparous women was substantially lower (27%, compared with 51% in the study by Wen et al. and 41% in the study by Abrams and Newman). The major risk factors for IUGR identified in our data are consistent with previous reports [l]. Maternal age was found to increase the risk of IUGR only in primiparous women, but not in multiparous women (Fig. 1). Similar findings were reported by others [3,7]. Higher rates of low-birth-weight among older primiparous women, but not of IUGR, were found by Berkowitz et al. [14], whose study is based on a cohort where most of the participants were college graduates. In our population, in contrast, the median years of schooling of women of child bearing age is 11 years [ 151. This difference in study populations may be indicative of different reasons for delaying childbirth, thus making the risk profile of these two groups of older primiparous women not comparable. Of the obstetric factors examined in our study, oligohydramnios was the strongest predictor of IUGR, but the causal direction of this association is not clear [16]. Of the other risk factors, the following were shown to have an independent contribution to IUGR: severe hypertension, fetal congenital anomalies, fetal female sex, primiparity, moderate hypertension, prior infertility and the interaction between primiparity and age >29 (Table 3). Similarly to other studies [2,4,8,17,18], our data show the important role of pregnancy induced hypertensive disorders, as well as chronic hypertension, in the etiology of IUGR. Many studies of IUGR excluded cases with congenital anomalies. One recent study where these cases were included [2], reports a significantly increased risk of IUGR in fetuses with congenital malformations. This was also demonstrated in our data. Prior infertility has not been extensively studied as a risk factor for IUGR. In his review of the literature, Kramer [1] points out that in order to fully understand the role of prior infertility in the etiology of IUGR, it is necessary to control for several potential confounders, such as prior genital tract infections, uterine malformations, and pre-pregnancy low maternal weight. As we do not have reliable information on these risk factors, it is difficult to interpret the association found between prior infertility and IUGR, mainly among primiparous women. Our findings suggest that primiparous women stand twice the risk of IUGR compared with multiparous women. In a multivariate model, adjusting simultaneously for all risk factors identified in our study, primiparity remains a significant predictor of IUGR. The literature suggests that factors such as toxic expo-
sure, smoking and drug abuse, malnutrition and low pre-gestational maternal weight, and insufficient weight gain increase the risk of IUGR, and that these risk factors are frequently associated with low socioeconomic status and teenage pregnancy [1,3,4,7,8,19]. Lack of information on our computerized data set prevented us from controlling for these variables in the analysis. This, however, should not have affected our main findings. As our population of primiparae contained only few very young mothers, it not likely that risk factors which are usually associated with teenage pregnancies will be more prevalent among the primiparaous women in comparison with the multiparaous women. Morever, other studies have shown that primiparity remains a signilicant risk factor for IUGR, even when such environmental factors were controlled for [3,4]. Based on our findings, and on those of other studies using different methodologies and conducted in populations with different risk profiles, we suggest that primiparity constitutes an independent risk factor for IUGR. This finding is consistent with the hypothesis that among other etiologies, IUGR may be caused by non-symptomatic vascular disorders, compromising uterine blood supply to the feto-placental unit, which, like pre-eclampsia, are more prevalent in first pregnancies [20]. 5. References 1
Kramer MS. Determinants of low birth weight: methodological assessment and meta-analysis. Bull WHO 1987; 65: 663-737.
2
Ounsted M, Moar VA, Scott A. Risk factors associated with small-for-dates and large-for-dates infants. Br J Obstet Gynaecol 1985; 92: 226-232. Wen SW, Goldenberg RL, Cutter GR, Hoffman HJ, Cliver SP. Intrauterine growth retardation and preterm delivery: prenatal risk factors in an indigent population. Am J Obstet Gynecol 1990; 162: 213-218. Abrams B, Newman V. Small-for-gestational-age birth: maternal predictors and comparison with risk factors of spontaneous preterm delivery in the same cohort. Am J Obstet Gynecol 1991; 164: 785-790. Miller HC. Intrauterine growth retardation. Am J Dis Child 1981; 135: 944-948. Ferraz EM, Gray RH, Cunha TM. Determinants of preterm delivery and intrauterine growth retradation in Northeast Brazil. Int J Epidemiol 1990; 19: 101-108. Lee KS, Freguson RM, Corpuz M, Gartner LM. Maternal age and the incidence of low birth weight at term: a population study. Am J Obstet Gynecol 1988; 158: 84-89. Kramer MS, Olivier M, McLean FH, Dougherty GE, Willis DM, Usher RH. Determinant of fetal growth and body proportionality. Pediatrics 1990; 86: 18-26. Gale R, Zengen S, Harlap S, Fischer AF, Steveson DK. Birth out of wedlock and the risk of intrauterine growth retardation. Am J Perinatol 1988; 5: 278-282. lnsler V, Larholt K, Hagay ZJ et al. The impact of prenatal care on the outcome of pregnancy. Eur J Obstet Gynecol Reprod Biol 1986; 23: 211-213. Battaglia FC, Lubchenco LO. A practical classification of newborn infants by weight and gestational age. J Pediatr 1967; 71: 159.
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Kelsey JL, Thompson WD, Evans AS. Methods in observational epidemiology. New York: Oxford University Press, 1986. Bergsjo L, Hoffman HS, Davis RO et al. Preliminary results from the Collaborative Alabama and Scandinavian study of sucessive small-for-gestational-age births. Acta Obstet Gynecol Stand 1989; 68: 19-25. Berkowitz GS, Skovron ML, Lapinski RH, Berkowitz RI. Delayed childbearing and the outcome of pregnancy. N Engl J Med 1990; 322: 659-663. State of Israel Central Bureau of Statistics. 1983 census of population and housing publications. No. 5. Jerusalem: State of Israel Central Bureau of Statistics, 1985. Philipson EN, Sokol RJ, Williams T. Oligohydramnios: clinical associations and predictive value for intrauterine growth tion. Am J Obstet Gynecol 1983; 146: 271-278.
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101 Bakketeig Ls, Bjerkedal T, Hoffman HJ. Small for gestational age birth in successive prenancy outcomes: results from a longitudinal study of births in Norway. Early Hum Dev 1986; 14: 187-200. Plovin PF, Breart G, Rabarison Y, Rumeau-Rouquette C, Sureau C, Menard J. Fetal growth retardation in gestational hypertension: relationship with blood pressure, levels and time of onset of hypertension. Eur J Obstet Gynecol Reprod Biol 1983; 16: 253-262. Wen SW, Goldenberg RL, Cutter GR et al. Smoking, maternal age, fetal growth and gestational age at delivery. Am J Obstet Gynecol 1990; 162: 53-58. Leiberman JR. Vascular nature of preeclampsia. Med Hypotheses 1989; 28: 281-283.