According to genetic studies, human DNA can be clustered into groups that correspond to their ancestral geographic origins.1,2 This genetic variation may contribute to health disparities between populations. For example, the response to antihypertensive treatment varies between black and white patients, such that the recommended treatment differs by racial group.3,4 “Race” in this context identifies those with common geographical ancestry, where natural selection has resulted in the evolution of local traits. It is important to identify conditions with different prevalence between groups and their risk factors, so that the appropriate management can be applied.
In obstetrics, varying rates of meconium-stained amniotic fluid (AF) has been reported between racial groups.5–8 Meconium (fetal colonic contents) is usually passed after birth, and the mechanisms underlying passage before birth are unknown. Meconium-stained AF is uncommon in preterm births (occurring in about 5%) but occurs more frequently with advancing gestational age.9,10 This may be simply an effect of fetal gut maturity, or it may be a reaction to hypoxic stress, which occurs more often as pregnancy advances. Higher rates of stillbirths, low Apgar scores, and hypoxic ischemic encephalopathy has been associated with meconium-stained AF.11–15 However, most newborns with meconium-stained AF have good outcomes, and the umbilical cord blood pH between preterm newborns with and without meconium-stained AF is not significantly different.10,16 The objectives of our study were to estimate the rates of meconium-stained AF and adverse outcome in relation to gestational age and racial group, and to investigate the predictors of meconium-stained AF. We have examined the hypothesis that fetal maturity varies between racial groups, and that this difference influences both meconium-stained AF and adverse perinatal outcomes in relation to gestational age and racial group.
MATERIALS AND METHODS
Routine maternity data were collected prospectively from all pregnancies (585,291) booked at 15 maternity units in North West London, from 1988 to 2000. Data collection on 263 variables (including socioeconomic factors, maternal characteristics, and antenatal, intrapartum, and neonatal outcomes) began from the first antenatal visit up to 28 days postpartum. Computer entry by trained clerks or midwives using online validation, prompting, and standard definitions for clinical measurements, produced high-quality data.17,18 Each year, data from these local units were downloaded into the St. Mary's Maternity Information System and maintained by the Department of Epidemiology and Public Health, Imperial College London. In compliance with Section 60 of the Health and Social Care Act 2001, all direct patient identifiers were removed and analyses were performed on a nonattributable data set. This research was approved by the St. Mary's Local Research Ethics Committee. All analyses were performed using SPSS 16.0 or Microsoft Excel.
The data collected on ethnicity were based on a “self-identification” measure, in line with the UK census. The ethnicity of the neonates was based on maternal ethnicity. Women who self-identified as originating from India, Pakistan, Bangladesh, Sri-Lanka, or other South Asian ethnicity were grouped as South Asian. The black racial group included black British, African, and Caribbean. Women who self-identified as any white ethnicity were grouped as white. All other ethnicities were grouped into “other” as the numbers were too few for a meaningful analysis.
The best estimate of gestational age at delivery was calculated using a combination of fetal biometric ultrasonography and the last menstrual period. Gestational length was estimated from either the first day of the last menstrual period or the first ultrasound fetal biometry performed before 24 weeks of gestation. Last menstrual periods were used provided the women were certain of their menstrual dates and had regular menstrual cycles and there was no significant discrepancy between the estimated dates of delivery (EDDs) by the last menstrual period and ultrasonography. A more detailed description of these methods has been reported previously.19
It is known that the average birth weight varies by ethnic group. Compared with newborns of white race, Pakistani, Indian, and Bangladeshi newborns are 280 g to 350 g lighter, and black Caribbean and black African newborns are 70 g to 150 g lighter.20 Adjusting birth weight by ethnicity results in a better identification of fetal growth restriction than using birth weight alone.21 To avoid inappropriate classification of small for gestational age, we examined the distribution of birth weight for gestational age by developing centile growth curves specific to each racial group, and allocated a centile value to each birth weight.
To explore the distribution of meconium-stained AF by gestational age, we analyzed women who had singleton live births weighing at least 500 g, at 24 or more completed weeks of gestation. We then studied the crude gestation-specific pattern of meconium-stained AF by racial groups and tested whether the meconium-stained AF rates differed significantly between groups.
Secondly, we investigated the variables associated with meconium-stained AF and whether or not racial group is an independent predictor of this condition. Preterm births, before 37 weeks of gestation, were excluded from this part of the analysis owing to the low rate of meconium-stained AF at these gestations. χ2 tests of association were used for qualitative variables and nonparametric Mann Whitney U tests for quantitative variables. Variables significantly associated with meconium-stained AF (P<.05) were selected as predictor variables for the logistic regression analysis (Table 1). A multiple logistic regression model for the outcome variable meconium-stained AF was then created. Interaction terms between gestational age and racial groups improved the model significantly.
Thirdly, we investigated whether variation in the rate of meconium-stained AF by racial group could be explained by hypoxic stress rather than fetal maturity. We analyzed the rate of poor perinatal outcome (Apgar scores less than 7 at 1 or 5 minutes of life or both, transfer to the neonatal unit, early neonatal death, or a combination) in newborns with no congenital anomaly by racial groups and gestational age. In addition, those significant predictors of meconium-stained AF from 37 completed weeks of gestation onward (Table 1) were analyzed to identify their relationship with poor perinatal outcome. We then excluded cases with factors associated with fetal hypoxia (ie, preterm births, congenital malformations, umbilical cord prolapse, birth weight percentiles less than 10 or more than 90, maternal pyrexia, abnormal cardiotocography with operative delivery, malpresentation, or other predictors of meconium-stained AF that were found to be significantly associated with poor perinatal outcome) or cases with poor perinatal outcome. Exclusion of these cases leaves neonates with or without meconium-stained AF and with no known risk factors of fetal hypoxia, who all had a good perinatal outcome. We then investigated these healthy neonates with respect to whether or not the rate of meconium-stained AF differed by gestational age according to racial groups.
There were a total 585,291 cases. We excluded 16,129 cases with unknown best estimate of gestational age at birth, 54,051 miscarriages before 24 completed weeks of gestation or with birth weights less than 500 g, 13,703 multiple pregnancies, and 2,312 stillbirths or induced abortions. Included in the analysis of meconium-stained AF were the remaining 499,096 singleton live births weighing at least 500 g at 24 or more completed weeks of gestation. Of these, there were 351,701 (70.5%) white, 64,874 (13.0%) South Asian, and 30,463 (6.1%) black newborns. Meconium-stained AF was present in 81,405 cases (16.3%, 95% confidence interval [CI] 16.2–16.4). The crude meconium-stained AF rate differed significantly in neonates born preterm (5.1%, 95% CI 4.9–5.4), at term (16.5%, 95% CI 16.4–16.6), and postterm (27.1%, 95% CI 26.5–27.6), respectively.
Table 2 and Figure 1 demonstrate that although the overall meconium-stained AF rate was lowest among preterm births, before 31 completed weeks of gestation the rate of meconium-stained AF was inversely related to increasing gestational age, with the peak rate at 24 to 25 completed weeks (averaging 10.0%, 95% CI 7.4–12.7) and the lowest rate at 31 completed weeks (3.7%, 95% CI 2.5–4.8). The rate of meconium-stained AF at 24 to 30 completed weeks of gestation (6.47%, 95% CI 5.64–7.30) was statistically significantly higher than the rate of meconium-stained AF at 31 to 36 completed weeks of gestation (4.96%, 95% CI 4.70–5.22). It is a common observation that meconium-stained AF is more likely to occur in fetuses presenting by the breech, and that such malpresentations are more common in preterm births. However, a subgroup analysis of preterm births with cephalic presentation showed that the rate of meconium-stained AF in this group was not significantly different (4.8%, 95% CI 4.6–5.1), and the same pattern of meconium-stained AF with a peak rate at 24 to 25 weeks was observed (9.3%, 95% CI 6.1–12.5). In neonates born at 24 to 30 completed weeks of gestation, the rate of early neonatal death did not differ significantly whether meconium-stained AF was present or absent (odds ratio [OR] 0.98, 95% CI 0.61–1.58).
From 31 completed weeks of gestation, the rate of meconium-stained AF increased with advancing gestational age. From 36 to 42 completed weeks, each weekly increase in the rate of meconium-stained AF was statistically significant. The overall crude rates of meconium-stained AF varied significantly between racial groups as shown in Table 3. The rates of meconium-stained AF were not significantly different before 36 completed weeks of gestation, but from 36 completed weeks onward the rates of meconium-stained AF by racial group differed significantly. In addition, from 38 to 42 weeks, the rates of meconium-stained AF were significantly higher at all gestations in black fetuses in comparison to South Asian fetuses.
After exclusion of preterm births, 468,042 cases remained. Table 1 showed the results of the logistic regression model for meconium-stained AF and its independent predictors, or associations, from 37 completed weeks of gestation onward (P<.001). Accounting for confounders, advancing gestational age was an independent predictor of meconium-stained AF (OR 1.39, 95% CI 1.38–1.40). In addition, being black (OR 8.4, 95% CI 2.4–28.8) or South Asian (OR 3.3, 95% CI 1.3–8.3) was an independent predictor of meconium-stained SAF compared with being white. There were significant interactions between both racial groups and gestational age. Although the incidence of meconium-stained AF increased with advancing gestational age, this occurred more rapidly for black and South Asian than for white fetuses.
The rate of meconium-stained AF increased significantly with increasing maternal body mass index (BMI, calculated as weight (kg)/[height (m)]2). The meconium-stained AF rates were 14.2% (95% CI 13.9–4.5), 16.3% (95% CI 16.2–16.5), 18.6% (95% CI 18.4–18.9), and 20.4% (95% CI 19.9–20.8) in women with BMI of less than 20, 20 to 24, 25 to 29 and 30 or more, respectively. The same relationship was observed between maternal BMI and the rate of poor perinatal outcome. The rates of poor perinatal outcome were 11.5% (95% CI 11.2–11.8), 12.2% (95% CI 12.1–12.3), 14.0% (95% CI 13.8–14.2), and 16.8% (95% CI 16.4–17.1), respectively. After exclusion of cases with maternal diabetes, maternal obesity (BMI of 30 or more) was associated with an increased risk of poor perinatal outcome when compared with a normal BMI of 20 to 24 (OR 1.37, 95% CI 1.33–1.42). However, maternal age of 40 or older did not increase the risk of poor perinatal outcome when compared with maternal age of 20 to 29 years (OR 1.06, 95% CI 0.99–1.13). The risk of poor perinatal outcome was slightly increased with maternal smoking when compared with nonsmokers (OR 1.08, 95% CI 1.06–1.10). Fetal female sex was a significant predictor of meconium-stained AF compared with male, but male newborns had a higher rate of poor perinatal outcome when compared with female (OR 1.26, 95% CI 1.24–1.28).
After accounting for birth-weight percentiles, we found that maternal medical complications such as diabetes and hypertensive disorders were not associated with an increased risk of meconium-stained AF. These women were more likely to experience induction of labor and deliver at an earlier gestation when compared with women with no medical problems. For example, the median gestational length in women with preexisting diabetes was 38 completed weeks, whereas in women with no diabetes the median gestational length was 40 completed weeks (P<.001). However, maternal anemia was an independent predictor of meconium-stained AF. The odds of meconium-stained AF occurring was highest with maternal hemoglobin levels below 9 g/dL.
After exclusion of preterm births, individuals with risk factors of fetal hypoxia, or both, or individuals with a poor perinatal outcome, or any combination of the three,321,654 cases remained. The rates of meconium-stained AF in these fetuses still increased with advancing gestational age (Fig. 2). In addition, the rate of meconium-stained AF was still highest in black (17.87%, 95% CI 17.30–18.44), followed by South Asian (11.78%, 95% CI 11.47–12.09), and lowest in white fetuses (11.24%, 95% CI 11.11–11.37). At every gestation, the meconium-stained AF rates in black fetuses were still significantly higher than in white fetuses.
Of all pregnancies with meconium-stained AF from 37 completed weeks of gestation onward, 22.5% had a poor perinatal outcome compared with 10.9% with no meconium-stained AF (OR 2.39, 95% CI 2.34–2.43; absolute risk 12 per 100). On the other hand, the rate of poor perinatal outcome in newborns with or without meconium-stained AF was almost 100% at the threshold of viability, decreased with advancing gestational age at birth, and reached a nadir of 11.0% at 39 completed weeks of gestation (Fig. 1). For all births from 37 completed weeks of gestation onward, the rate of poor perinatal outcome was 12.9%. Beyond 39 completed weeks of gestation, the rate of poor perinatal outcome began to increase with advancing gestational age (Fig. 3). Using white neonates who delivered at 40 weeks as reference, the excess poor perinatal outcome (absolute risk) at 41 and 42 completed weeks of gestation for white neonates were 2 per 100 and 5 per 100, respectively. The absolute risks were higher in South Asian (3 and 7 per 100, respectively) and highest in black neonates (7 and 11 per 100, respectively). Figure 3 demonstrates that beyond 39 completed weeks of gestation, the rate of poor perinatal outcome began to increase in parallel with the rise in meconium-stained AF rates.
There was a “J-shaped” relationship between meconium-stained AF and advancing gestational age, with a nadir at 31 weeks of gestation. Beyond 36 weeks, each advancing week increased the adjusted meconium-stained AF rates significantly, by about 39%. There were 2.4 times more adverse outcomes with meconium-stained AF than without; but the absolute risk was 12 per 100 births. Thus, meconium-stained was mainly associated with fetal maturity rather than hypoxia. Belonging to either black or South Asian racial group independently predicts meconium-stained AF, even after accounting for gestational age, factors associated with fetal hypoxia, adverse perinatal outcome, and socioeconomic factors. The most economical and effective method of categorizing pregnant women is to rely on self-identified ancestry, rather than genetic cluster analysis. In this study, the self-identified groups are clearly different, and this difference suggests earlier fetal maturity rather than a higher incidence of hypoxia in blacks and South Asians compared with whites. Consequently, the adverse effect associated with prolonged pregnancy was observed relatively earlier, and at a steeper rate, in blacks and South Asians than in white neonates. We did not account for racial admixture, but the only effect this will have is to reduce the differences that actually exist to those we have observed. Thus, the true racial differences will be even greater.
The strength of this study is the large sample size and high statistical power. The extensive data collection allowed the identification of pregnancies with adverse outcomes and investigation of risk factors of meconium-stained AF. The calculation of EDDs was robust, based on a combination of last menstrual period and ultrasonography. We accounted for material deprivation using the Carstairs index, which explains many variations in health status.22,23 Meconium was not classified as “thick” or “thin” because this is subjective and can result in observation bias. Although thin meconium-stained AF is generally considered less harmful than freshly passed, thick meconium, fetal urinary lactate levels suggest that fetuses with thin meconium-stained AF have been subjected to hypoxic stress for a longer period of time than those with thick AF.24
A previous study also has reported a higher meconium-stained AF rate at 28 weeks (7.4%) than at 32 weeks of gestation (3.3%), but, owing to the small sample size, this difference was not significant.10 In support of the maturity hypothesis, there is no difference in acid-base status at birth (allowing for gestational age) in pregnancies with or without meconium-stained AF beyond 31 weeks of gestation.25 Conversely, pregnancies with meconium-stained AF before 32 weeks of gestation have an increased incidence of intra-amniotic infection.26 In support of variation in the rate of fetal maturity, it is known that black and South Asian neonates born preterm suffer less respiratory distress syndrome compared with white neonates of the same gestational age, with similar observations in female compared with male neonates.5,27–29 Furthermore, there are several reports of a shorter gestational length in blacks and South Asians compared with white pregnancies.6,30,31 This suggests early maturation of the fetoplacental unit.
We have shown in a previous study that being South Asian independently predicts stillbirth after 36 weeks, and that the late gestation rise in stillbirth rates begins earlier, and at a steeper rate, compared with white neonates.15 A similar pattern also was observed in black neonates; however; owing to the smaller sample of black pregnancies and the lower incidence of stillbirths (when compared with perinatal morbidity), this difference was not significant. One explanation for the higher rate of perinatal morbidity at late-term gestation is “relative placental insufficiency,” where the placenta can no longer keep up with the demands of the fetus.32 Additionally, when meconium-stained AF is superimposed on fetal acidemia, there is an increased risk of meconium aspiration syndrome, early-onset respiratory distress in a neonate born through meconium.33 Furthermore, the presence of meconium-stained AF alone independently increases the risk of neonatal respiratory morbidity.5
Other significant predictors of meconium-stained AF include malpresentation or vaginal breech delivery. Because perinatal mortality rate is known to be higher in this group, fetal hypoxia is the likely explanation for the increased rate of meconium-stained AF.34 Another explanation is that the fetal abdomen is squeezed to a greater extent as it passes through the birth canal than occurs in neonates born with cephalic presentation. Fetal hypoxia (associated with abnormal cardiotocography, operative delivery, extreme birth-weight percentile, maternal pyrexia, smoking, and obesity) is probably also an explanation for some cases of meconium-stained AF. We have also reported previously that maternal obesity is an independent predictor antepartum stillbirth.15
A Cochrane systematic review of 19 trials, most of which took place in developed countries, has reported that a policy of routine induction of labor at 41 weeks of gestation reduced the risk of perinatal mortality (relative risk [RR] 0.30, 95% CI 0.09–0.99) without increasing the risk of operative delivery.35 Four trials involving 1,325 women showed that the same policy reduced the risk of meconium aspiration syndrome (RR 0.29, 95% CI 0.12–0.68). Consideration should be given to increased monitoring, or labor induction, earlier than 41 weeks of gestation in South Asian and black women.
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© 2011 by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.
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