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Is Small for Gestational Age a Marker of Future Fetal Survival In Utero?

From the ¹Department of Obstetrics, Gynecology, and Reproductive Sciences, UMDNJ-Robert Wood Johnson Medical School, New Brunswick, New Jersey; ²Department of Epidemiology, UMDNJ-School of Public Health, New Brunswick, New Jersey; and ³School of Medicine and ⁴School of Public Health, University of Alabama at Birmingham, Birmingham, Alabama.

	ABSTRACT

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OBJECTIVE: We sought to assess whether small for gestational age is a risk factor for stillbirth of a subsequent sibling.

METHODS: The Missouri maternally linked cohort data set, containing data on births from 1978 through 1997, was used. We identified the study group (women who delivered a SGA infant in the first pregnancy) and a comparison group (women who delivered a non-SGA infant in their first pregnancy) and compared the outcome (stillbirth) in the second pregnancy between both groups.

RESULTS: We analyzed information on the first and second pregnancies of 402,015 women (43,549 [10.8%] in the study arm and 358,466 [89.2%] in the comparison arm). Of the 1,883 cases of stillbirth in the second pregnancy, 314 cases occurred in mothers with a history of SGA (stillbirth rate 7.2/1,000) and 1,569 in the comparison group (stillbirth rate 4.4/1,000), P < .001. The adjusted risk of stillbirth was 60% higher in women with a prior SGA (odds ratio [OR] 1.6, 95% confidence interval [CI] 1.4–1.8). The risk for stillbirth in the second pregnancy increased with decreasing gestational age at birth of the SGA infant in the first pregnancy (term: OR 1.4, 95% CI 1.2–1.6; preterm: OR 2.8, 95% CI 2.0–3.8; and very preterm: OR 4.2, 95% CI 2.4–7.3), P for trend < .001.

CONCLUSION: Small for gestational age is a marker for subsequent stillbirth, and the risk rises with decreasing gestational age of the SGA birth. This information is potentially useful for counseling parents of SGA infants.

LEVEL OF EVIDENCE: II-2

A recent well-conducted epidemiologic study from Sweden⁴ found an increased risk of subsequent stillbirth in women with a history of small for gestational age (SGA) delivery. However, the study was conducted in a highly homogeneous setting and comprised only white women, and to our knowledge there are no data linking SGA to subsequent stillbirth in a "complex" or "heterogeneous" population, such as that in the United States. This is important because the ability to show this association, even in a setting with a widely diverse population, is strong evidence of the existence of the linkage. Accordingly, we conducted this study with the main objective of determining whether SGA is a marker for stillbirth in a subsequent gestation using a population setting that is reasonably diverse.

	MATERIALS AND METHODS

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We used the Missouri maternally linked cohort data files from 1978 through 1997, inclusive. In this data set, siblings are linked to their biologic mothers with unique identifiers. The methods and algorithm used in linking birth certificate data into sibships and the process of validation have been described in detail previously.⁵ The Missouri vital record system is a very reliable one that has been adopted as "gold standard" to validate U.S. national data sets that involve matching and linking procedures.⁶

The Missouri maternally linked cohort data contains information on both live birth and fetal death for each sibling and provides a platform for a longitudinal study of birth outcomes for each pregnancy. Of the 1,577,082 births in Missouri during the period 1978 through 1997, we selected pregnancies that satisfied the following inclusion criteria:

1. Singleton live births
   
2. Gestational age range of 20–44 weeks, inclusive
   
3. Women who delivered both first and second consecutive singleton infants.
   

We then categorized the study population as the exposed group consisting of those women who experienced an SGA live birth in the first pregnancy and a comparison group (those that had a non-SGA live birth in the first pregnancy). Small for gestational age was defined as less than the 10th percentile of birth weight for gestational age using population-based national reference curves for singletons.⁷ In a subanalysis, we classified SGA into 3 subtypes based on gestational age at delivery: term ( 37 weeks), preterm (< 37 weeks), and very preterm (< 33 weeks).

These women were then followed during their second pregnancies to evaluate pregnancy outcome. The main end point of interest was occurrence of stillbirth in the subsequent pregnancy, which we defined as intrauterine fetal death at 20 weeks of gestation or later.

Information on maternal characteristics for each woman in the second pregnancy was considered to evaluate any differences in sociodemographic features (maternal age, marital status, educational status, cigarette smoking during pregnancy, body mass index [BMI], interpregnancy interval, and adequacy of prenatal care) between the 2 study arms. We categorized BMI into 4 groups: underweight (< 19.8 kg/m²), normal (19.8–26.0), overweight (26.1–29.0), and obese (> 29.0) based on previous publication.⁸ Adequacy of prenatal care was assessed with the revised graduated index algorithm, which has been found to be more accurate than several others, especially in describing the level of prenatal care use among groups that are high risk.^9,10 This index assesses the adequacy of care based on the trimester in which prenatal care began, number of visits, and the gestational age of the infant at birth. The interval between the first day of the last menstrual period of the second pregnancy and the date of birth of the child in the first pregnancy was used to compute interpregnancy interval in days.

We performed crude frequency comparisons for the presence of common obstetric complications, namely, anemia, cardiac disease, type 1 diabetes, other types of diabetes mellitus, chronic hypertension, preeclampsia, eclampsia, abruptio placenta, and placenta previa for the years during which these were reported. We also constructed a composite variable indicating the presence of at least one of these conditions.

Stillbirth rates were computed by dividing the number of stillbirths by the sum of live births and stillbirths and multiplying by 1,000. Chi-square test was used to determine differences in sociodemographic characteristics and maternal pregnancy complications between the 2 groups. We assessed dose-response using the ² test for linear trend.¹¹ Student t test was used when the outcome was continuous (eg, interpregnancy intervals). We used unconditional logistic regression analysis to model history of SGA as a determinant of subsequent stillbirth. Odds ratios were calculated before and after adjustment for maternal sociodemographic characteristics. All tests of hypothesis were 2-tailed, with a type 1 error rate fixed at 5%. All analyses were performed with SAS 9.1 (SAS Institute, Cary, NC). This study was approved by the Office of the Institutional Review Board at the University of Medicine & Dentistry of New Jersey (reference number: 5547).

	RESULTS

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The final total number of individuals for the analysis was 402,015 mothers. This total comprised 358,466 (89.2 %) women who had a non-SGA birth in the first pregnancy and 43,549 (10.8%) women who delivered SGA infants in the first pregnancy. We present selected maternal sociodemographic characteristics as documented in the second pregnancy in Table 1. The 2 maternal cohorts differed in all characteristics considered in the analysis. Mothers who had SGA neonates in the first pregnancy were more likely to be younger, less educated, and unmarried. They were also more likely to be smokers, of black race, and have a lower body mass index and lower level of adequate prenatal care received in the second pregnancy than their counterparts who had a non-SGA birth in the first pregnancy. The mean interpregnancy interval was 972.8 days (standard deviation [SD] ± 835). Women with a history of SGA in the first pregnancy had a longer interpregnancy interval (Mean ± SD 990.5 ± 889 versus 970.8 ± 828 days), P < .001.

Comparison of the frequency of maternal complications in both study groups in the second pregnancy is given in Table 2. Women with a history of SGA in the first pregnancy had a 42% higher likelihood of having at least one complication during the second pregnancy compared with the control group. When examined individually, complications such as anemia, type 2 diabetes, chronic hypertension, preeclampsia, and abruption placenta were more prevalent in the second pregnancy in those with a prior SGA birth in the first pregnancy. On the other hand, the occurrence of type 1 diabetes, eclampsia, and placenta previa was similar in both groups.

In total, there were 1,883 cases of stillbirth in the second pregnancy; 314 (16.7% of all cases) occurred in mothers with a history of SGA and 1,569 (83.3% of all cases) among those without such history. The rate (per thousand) of stillbirth in the second pregnancy in women whose first delivery resulted in an SGA neonate was 7.2/1,000 compared with 4.4/1,000 for those who had a non-SGA birth in their first delivery, P < .001. When this analysis was repeated within each of the 2 main racial groups in the state, a more pronounced absolute risk difference was noted between whites (6.8/1,000 in those with a history of SGA versus 3.9/1,000 in those with no prior history of SGA; P < .001) than between blacks (8.7 /1,000 versus 7.4/1,000; P = .1). Nevertheless, the level of absolute risk for subsequent stillbirth was greater in blacks, regardless of the risk status. In fact, the absolute risk of stillbirth in the second pregnancy was greater in blacks with a non-SGA infant in the first pregnancy than in whites who had an SGA birth in the first pregnancy (Fig. 1).

View larger version (16K): [in this window] [in a new window]   Fig. 1. Comparison of stillbirth rates by maternal race among mothers who had small for gestational age (SGA) infants in the first pregnancy versus those who had non-SGA infants. AGA, appropriate for gestational age. Salihu. SGA as a Marker of Subsequent Stillbirth. Obstet Gynecol 2006.

Table 3 summarizes the relationship between SGA in the first pregnancy and the likelihood of stillbirth in the second pregnancy after adjustment for confounders. Overall, women who experienced SGA in the first pregnancy had a 60% greater risk for stillbirth in the second pregnancy. However, there was a lack of homogeneity in the adjusted risk estimates; while white women showed the same level of risk elevation as noted for the general population, the relative risk for subsequent stillbirth was considerably attenuated and did not reach statistical level of significance in blacks.

Results of subanalysis to assess the influence of time of delivery of SGA in the first pregnancy and the risk of subsequent stillbirth are displayed in Table 4. The risk for stillbirth in the second pregnancy rose progressively as gestational age of occurrence of SGA in the first pregnancy declined (P for trend < .001). These findings were observed for both the absolute and adjusted risks. Reanalyzing the data by adjusting for the presence or absence of pregnancy complications within the period of study for which these complications were reported did not change the results.

	DISCUSSION

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Overall this study shows that both the absolute and the relative risks for stillbirth were elevated in the second pregnancy when the first pregnancy was complicated by smallness for gestational age. The association between SGA and subsequent stillbirth was considerably influenced by the gestational age at delivery of the SGA infant. When classified as term, preterm, and very preterm SGA, there was a significant linear monotonic increase in the risk of stillbirth in the pregnancy that followed. These findings are in agreement with those of the literature,⁴ and the risk elevation for subsequent stillbirth in a woman with a prior SGA may imply that SGA is a marker for future stillbirth and that affected women need to be counseled accordingly. Interestingly, the results in this study also reveal that SGA should be considered a heterogeneous disease in terms of risk amplitude for subsequent stillbirth. A woman with a term SGA in an index pregnancy is at a lower risk level than her counterpart who experiences a preterm SGA, and the greatest risk for a subsequent stillbirth occurs in women with very preterm SGA.

It remains poorly understood why the occurrence of SGA in a previous pregnancy influences intrauterine survival subsequently. One reasonable explanation is that similar factors may impact both SGA and stillbirth, as evidenced by the fact that many stillbirth infants are simultaneously found to be small for gestational age.^12,13 The persistence of maternal complications (eg, chronic hypertension, diabetes mellitus, heritable disorders) from one pregnancy into the next may also explain the linkage between SGA in the first pregnancy and risk elevation in the second pregnancy. As reasonable as this explanation seems, it may not adequately explain all cases of stillbirth recurrence. Unfortunately, research on SGA and stillbirth linkages is scarce, which further compounds our ability to offer evidence-based alternative explanations. We are also limited in our analysis in offering sufficient biologic explanation for our findings because the data source does not contain details on causes of stillbirth or SGA.

Subanalysis within the 2 main racial groups in the state of Missouri revealed an important difference between blacks and whites. Whereas the risk of a stillbirth in a subsequent pregnancy for a white woman with a history of SGA in the first pregnancy was 60% greater than her counterpart with a non-SGA infant in the first pregnancy, the difference in risk among blacks was only 20% and was statistically not significant. In other words, history of SGA did not express itself as a strong marker for subsequent stillbirth in blacks as it did in whites. One possible explanation for this finding is that prior SGA expresses itself as a better marker for subsequent stillbirth in low-risk rather than in high-risk individuals. This is analogous to previous studies that have detected wider differences in adverse birth outcomes among whites of different social strata than among blacks.^14,15

An important limitation of the data to bear in mind in making interpretation is the long period of follow-up of these women, which spanned over 20 years. Different infant cohorts were aggregated and analyzed together. Because these infants were exposed to varying obstetric practices across the period of study, the results we have presented might have been biased by this cohort effect. However, by controlling for year of birth in computing adjusted relative risk estimates, the impact of this potential source of bias on our results must have been minimized considerably. Additionally, the analyses in this study are based on raw data derived from birth certificates, and the interpretation of our results should be within the limits of the accuracy of this data source. Another limitation of the data to bear in mind is the likelihood that early first-trimester pregnancy losses might not have been reported in many instances. To minimize biases due to underreporting, we excluded à priori women with pregnancies delivered before 20 weeks of gestation.

A strength of this study is that it is population-wide, and the results are therefore minimally affected by selection biases (eg, referrals), a source of concern in data derived from individual health facilities. The advantage is that the findings are reasonably generalizable. Another merit of this work is that it adds new data to a domain that is still poorly understood and underresearched (to date, very little is known about the impact of fetal growth perturbation on the fate of a subsequent gestation). Nevertheless, our findings should not be construed as definite, but rather as an impetus for more refined studies that will potentially offer answers to many questions emanating from this study.

In summary, we found a positive correlation between SGA in the first pregnancy and stillbirth in the subsequent (second) pregnancy. The timing of SGA during pregnancy strongly determines the occurrence of stillbirth in a subsequent pregnancy, a finding that defines SGA as a heterogeneous marker of subsequent birth outcomes. The results of this study are also potentially useful for the counseling of mothers with SGA infants regarding subsequent conception.

	Footnotes

 
This work was supported through a Young Clinical Scientist Award to Dr. Hamisu Salihu by the Flight Attendant Medical Research Institute (FAMRI). The funding agency did not play any role in any aspect of the study. The authors thank the Missouri Department of Health and Senior Services for providing the data files used in this study.

Corresponding author: Hamisu Salihu, MD, PhD, Department of Obstetrics, Gynecology, and Reproductive Sciences, UMDNJ-Robert Wood Johnson Medical School, New Brunswick, NJ 08901-1977; e-mail: hamisu.salihu{at}gmail.com.

doi:10.1097/01.AOG.0000206185.55324.5b

	REFERENCES

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5. Herman AA, McCarthy BJ, Bakewell JM, Ward RH, Mueller BA, Maconochie NE, et al. Data linkage methods used in maternally-linked birth and infant death surveillance data sets from the United States (Georgia, Missouri, Utah and Washington State), Israel, Norway, Scotland and Western Australia. Paediatr Perinat Epidemiol 1997;11 suppl:5–22.

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