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ORIGINAL RESEARCH |
From the Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Maryland, Baltimore, Maryland; Departments of Obstetrics and Gynecology, Pediatrics and Child Health, and Biochemistry and Medical Genetics, University of Manitoba, Manitoba, Canada.
Address reprint requests to: Ahmet A. Baschat, MD, University of Maryland, Baltimore, Department of Obstetrics, Gynecology, and Reproductive Sciences, 405 West Redwood Street, 4th Floor, Baltimore, MD 21201-1703; E-mail: aabaschat{at}hotmail.com.
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ABSTRACT |
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METHODS: This is a retrospective case-control study in a population managed prospectively by a standardized protocol. Perinatal outcomes were compared between patients with unexplained very low MSAFP (less than or equal to 0.25 multiples of the median) and control pregnancies with normal MSAFP, matched by precise gestational age, parity, maternal age within 1 year, and gender of the newborn.
RESULTS: Of the 84,909 women screened, 464 (0.55%) met the definition of very low MSAFP. On tertiary evaluation, 226 had dates reassigned by ultrasound. After exclusion of overt diabetics, patients who were not pregnant, invalidated MSAFP, and 17 patients lost to follow-up, 178 women (0.21% of the total) had true very low MSAFP. True very low MSAFP was associated with subsequent miscarriage in 67 women and with fetal aneuploidy and/or serious abnormalities in 12 patients, leaving a population of 97 women (1.14 per 1000 women screened) with unexplained very low MSAFP. Without obvious demographic or obstetric factors, these women had heavier babies, more babies above the 90th percentile, more delivery complications caused by large birth weight (41 versus 16, 
2, P < .001) compared with gestational-age matched controls from the same screened population who had normal MSAFP.
CONCLUSION: Very low MSAFP predicts an unusually high rate of large birth weight infants, with increased fetal, intrapartum, and neonatal consequences. Maternal medical conditions or obvious demographic factors do not explain these consequences. These findings suggest a role for close fetal surveillance in the third trimester and extended efforts to assess maternal and neonatal glucose status.
Maternal serum alpha-fetoprotein (MSAFP) is an established prenatal screening tool, traditionally delineated in population-specific multiples of the median (MoM), allowing use of gestational age cutoff values in risk analysis for various perinatal problems. Elevated levels (generally greater than or equal to 2.5 MoM) indicate increased risks for fetal anomalies, such as open neural tube defects, abdominal wall defects, or fetal demise, or may be explained by multiple gestation or wrong dates. Subsequent investigation has clarified that in a significant proportion of women, elevated MSAFP initially "unexplained" is associated with a higher frequency of adverse pregnancy outcomes at later gestations. Such adverse outcomes included hypertensive disorders, intrauterine growth restriction (IUGR), antepartum bleeding, and premature labor and delivery.1–3
Similarly, low MSAFP values are associated with an increased risk for fetal chromosome anomalies including Down syndrome and trisomy 18. After these conditions are ruled out, a significant proportion of women have unexplained values, which are either low (less than or equal to 0.5 MoM) or very low (less than or equal to 0.25 MoM). Data on their evaluation are limited. Some authors have used these categories for comparison with outcomes in groups with normal or elevated MSAFP levels.4–7 Although other studies have addressed the significance of unexplained low levels of MSAFP,8–12 most have focused on findings at the time of initial (prenatal) evaluation. These studies have demonstrated overestimated gestational age at the time the sample was drawn or early pregnancy loss. There is relatively little information available on subsequent outcome in women with continuing pregnancy and unexplained very low MSAFP levels.
The Manitoba MSAFP Program has a very high level of population use. We observed women with large-for-dates babies among the group with very low MSAFP initially evaluated at 15–18 weeks’ gestation. This might be the mirror image of the documented relationship between elevated MSAFP and IUGR.13,14 The aim of this study was to quantify the relationship between very low MSAFP and neonatal size, specifically addressing the possibility of obstetric and perinatal complications associated with "large-for-dates" babies.
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MATERIALS AND METHODS |
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In the Manitoba MSAFP Program, patients are ideally screened between 15–18 weeks’ gestation, although reliable norms have been generated within the program and are applied up to 22 weeks’ gestation for late submissions (up to 24 weeks for the repeat sample). Gestational age of patients is ascertained by last menstrual period or early ultrasound dating when dating is uncertain. The MSAFP levels are reported in MoM by a single central reference laboratory. Correction algorithms are employed for maternal weight and diabetes mellitus. Values from 0.45 to 2.2 MoM were considered normal, and no follow-up was recommended. Values less than or equal to 0.25 MoM were considered unusually low, and centralized tertiary-level fetal ultrasound assessment was offered. All screened women gave informed consent to data acquisition and review as part of their participation in the Manitoba MSAFP program.
Interpretation and management of MSAFP values between 0.25–0.45 MoM varied as the program evolved. From 1985 to 1987, women with a low MSAFP level were followed by a repeat sample drawn at the time of sonographic assessment. All women 35 years or older at estimated time of delivery were offered amniocentesis. Between 1987 and 1991, as the connection between low MSAFP and Down syndrome became clinically established, women between 30–34 years with low AFP values suggesting a Down syndrome risk of 1:200 or greater were also offered amniocentesis. In May 1991, this protocol was adjusted so that all women whose risk for Down syndrome approached 1 in 250 and/or in whom fetal assessment suggested fetal anomaly were offered an amniocentesis. The Manitoba MSAFP screening program switched to triple testing at a later time.
Women with very low MSAFP between 15–24 weeks’ gestation were identified. After exclusion of wrong dates, miscarriage, aneuploidy, and anomalies, patients with true "unexplained" very low MSAFP and ongoing pregnancy were included in the final analysis. These women were matched with consecutively screened women with normal serum MSAFP approximating to 1.0 MoM. Matching criteria were gestational age at the time of MSAFP draw, parity, maternal age within 1 year, and gender of the newborn. Birth weight percentiles were corrected for gestational age, sex, and parity.15
Maternal height, weight, and body mass index (BMI), pregnancy duration, birth weight, and type and frequency of complications were compared between very low MSAFP and normal pregnancies. Birth weight percentiles were correlated with maternal weight, height, and BMI in the very-low MSAFP group. Statistical analysis included the Student t test, paired t test for case-control comparison, 2 analysis, and McNemar test. A P value < .01 was considered statistically significant for paired t tests; P < .05 was considered significant for all other tests.
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RESULTS |
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Of the 67 patients with subsequent miscarriage, 23 (34.3%) were missed abortions and five were incomplete abortions (7.5%). The other 39 (58.2%) miscarried either after ultrasound confirmation of dates or while awaiting results of repeat MSAFP. The average gestational age of discovery of fetal loss was 16.5 ± 1.8 weeks. In addition to a tendency towards lower body weight and shorter stature, patients with subsequent abortions were more likely to be nulliparous and had a lower MSAFP compared with the group of patients with "unexplained" very low MSAFP in continuing pregnancy (Table 1).
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Among the 97 control women matched for parity, age, and fetal gender, the mean MSAFP value was 1.07 ± standard deviation 0.33 MoM. Women with unexplained very low MSAFP were taller than controls by about 2 inches. However, no significant differences were observed for maternal weight or BMI (Table 2). Women with very low MSAFP had significantly heavier babies by an average of 250 g (P < .05). These patients also delivered neonates with a birth weight above the 90th percentile for gestational age more often than their matched controls (25.8% versus 13.4% for controls, P < .05). There were no significant correlations between birth weight and maternal height or weight among patients with very low MSAFP. Patients in the study group did not differ significantly in gestational age at draw date but did deliver significantly later in gestation by an average of 1 week. Among the offspring, in both the study and control groups, the male to female sex ratio was 1:1.1.
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2, P < .001). These complications were directly related to birth weight. Complications were observed in 64.5% of patients greater than the 90th percentile and 29.9% less than the 90th percentile, birth weight corrected for gestational age and gender. Fetal malpresentation was observed more often in patients with very low MSAFP compared with controls (14 versus four, 2, P < .05). Obstetric complications included protracted labor (9.7%), uterine inertia, and postpartum hemorrhage (9.7%). Newborn complications, including meconium aspiration syndrome, transient tachypnea, recurrent apnea, asphyxia, and jaundice were also more often observed in patients with very low MSAFP (13 versus two, 2, P < .05). There were no neonatal deaths in either cases or controls. |
DISCUSSION |
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In the majority of reports to date, the association of very low MSAFP with fetal demise has been confirmed with rates comparable to our results.4,5,8–12 Of note is the relatively high median gestational age of miscarriage in the study population. This indicates that the higher miscarriage risk of patients with very low MSAFP persists even after early pregnancy losses have been included. Interestingly, women with subsequent miscarriage were smaller, lighter, and had significantly lower MSAFP levels compared with the majority of women with very low MSAFP but ongoing pregnancy.
Outcomes of patients with very low MSAFP with continuing pregnancy are less clearly defined in the literature. Few studies so far have addressed this issue in detail, and small sample size and a variable definition of very low MSAFP have hampered others. Davenport and Macri followed 180 patients with confirmed MSAFP levels less than or equal to 0.25 MoM and reported a prematurity rate of 4%, a perinatal mortality of 2.2%, and good outcomes in 92 healthy normal babies.10 Burton4 studied 113 patients with unexplained low MSAFP. She noted a perinatal death rate of 0.9% and a 6% frequency of low birth weight less than 2500 g.4 In contrast, we did not observe an increase in low birth weight frequency and/or prematurity rate, thus supporting the results of Milunsky et al.5 There is no specific mention in these studies on high birth weight percentiles or other pregnancy complications.
Although other authors have addressed the question of high birth weight, there are significant methodologic issues. Simpson et al related high birth weight to confirmed (second) MSAFP less than or equal to 0.25 MoM, but only in 37 women.12 Compared with women with normal MSAFP in their population, there was no significant excess of pregnancy-induced hypertension or IUGR, although 13% had gestational diabetes. In our study, the exclusion of diabetics from final analysis and the systematic correction of MSAFP interpretation for diabetes avoid this confounder.
Characteristics of the Manitoba population helped to avoid problems with other studies. In the groundbreaking work of Wald et al, the relationship of high birth weight and low AFP was masked because of inaccurate dating, with overestimation of gestational age leading to early elective delivery.13 Of note, within the subset with MSAFP less than or equal to 0.25 MoM, they found eight heavier infants (mean 3310-g birth weight), none of which were less than 2.5 kg. Our study has the advantages of many more screened patients (nearly 85,000 versus less than 4200 in the 1980 study13) and early ultrasound confirmation of pregnancy dating. With the elimination of babies who were "small" because they were actually premature, the relationship of low MSAFP and high birth weight is clarified.
The relationship between high MSAFP and low birth weight has been quantified by Mariona et al.14 This relationship is emphasized ten-fold when birth weight percentile is evaluated. Our study provides insight at the opposite end of the spectrum: when MSAFP is truly less than or equal to 0.25 MoM, there are almost no growth-restricted babies, and any complications are almost always related to macrosomia.
The relationship is real, with no obvious explanation. Overt diabetics were excluded, and gestational diabetes was equivalent (0.6%) in both cases and controls. Maternal weight and BMI were also equivalent, and weight correction was used in all MSAFP interpretations, so the effect of a 5-cm height difference is likely slight. Further, neither weight nor BMI in mothers with MSAFP levels less than or equal to 0.25 MoM correlated with infant birth weight.
What is the basis for this relationship? Perhaps this group represents a mirror image of the elevated MSAFP-IUGR picture. In that case, fetomaternal hemorrhage is implicated in poor placental function in women with elevated MSAFP,1 a relationship that persists throughout gestation.14,16 In our study, it may be that very low MSAFP is early evidence of optimal placentation and predicts ideal fetal growth, in the absence of fetomaternal bleeding. Further, this ideal placentation may be associated with significant prolongation of the pregnancy; although the 6-day difference is relatively short, it is statistically significant.
Alternate explanations would include a dilutional effect caused by maternal volume expansion, exceeding the correction applied by weight adjustment.17 This may simply be the expression of an optimal pregnancy. Ideal placental function means decreased leakage of AFP into a maternal circulation, which is optimally expanded, nourishing a fetus who is optimally grown for an optimal time. On the other hand, compared with controls, there was an excess of obstetric and neonatal complications, directly related to the increased birth weight of these "optimally grown" fetuses. In this macrosomic group, maternal diabetes could not be demonstrated, but a "prediabetic" effect, with maternal volume expansion and fetal overnutrition, may be operant. Further, prospective evaluation may clarify these issues.
In pregnancies with very low MSAFP levels, fetal death and overestimated gestational age are leading explanations. Continuing pregnancies with "true" very low MSAFP levels are at risk for fetal macrosomia and the concomitant obstetric and neonatal consequences. These findings suggest a role for close fetal surveillance in the third trimester and extended efforts to assess maternal and neonatal glucose status. On prospective evaluation, very low MSAFP levels may be a key indicator in anticipating and preventing serious consequences in these otherwise normal infants.
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Footnotes |
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Received August 20, 2001. Received in revised form November 29, 2001. Accepted December 11, 2001.
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REFERENCES |
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2. Purdie DW, Young JL, Guthrie KA, Picton CE. Fetal growth achievement and elevated maternal serum alpha-fetoprotein. Br J Obstet Gynaecol 1983;90:433–6.[Medline]
3. Morssink LP, Kornman LH, Beekhuis JR, De Wolf BT, Mantingh A. Abnormal levels of maternal serum human chorionic gonadotropin and alpha-fetoprotein in the second trimester: Relation to fetal weight and preterm delivery. Prenat Diagn 1995;15:1041–6.[Medline]
4. Burton BK. Outcome of pregnancy in patients with unexplained elevated or low levels of maternal serum alpha-fetoprotein. Obstet Gynecol 1988;72:709–13.
5. Milunsky A, Jick SS, Bruell CL, MacLaughlin DS, Tsung YK, Jick H, et al. Predictive values, relative risks, and overall benefits of high and low maternal serum alpha-fetoprotein screening in singleton pregnancies: New epidemiologic data. Am J Obstet Gynecol 1989;161:291–7.[Medline]
6. Simpson JL, Baum LD, Marder R, Elias S, Ober C, Martin AO. Maternal serum alpha-fetoprotein screening: Low and high values for detection of genetic abnormalities. Am J Obstet Gynecol 1986;155:593–7.[Medline]
7. Cho S, Durfee KK, Keel BA, Parks LH. Perinatal outcomes in a prospective matched pair study of pregnancy and unexplained elevated or low AFP screening. J Perinat Med 1997;25:476–83.[Medline]
8. Bennett MJ, Solymar M, Turnbull AC, Cuckle HS, Wald NJ. Pregnancies associated with low maternal serum alpha-fetoprotein concentrations. Am J Obstet Gynecol 1979; 135:545–6.[Medline]
9. Stein SM, Watt MS, Scrimgeour JB. Very low maternal plasma alpha-fetoprotein concentration. An indication for follow-up. Br J Obstet Gynaecol 1981;88:635–9.[Medline]
10. Davenport DM, Macri JN. The clinical significance of low maternal serum alpha-fetoprotein. Am J Obstet Gynecol 1983;146:657–61.[Medline]
11. Haddow JE, Hill LE, Palomaki GE, Knight GJ. Very low versus undetectable maternal serum alpha-fetoprotein values and fetal death. Prenat Diagn 1987;7:401–6.[Medline]
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13. Wald NJ, Cuckle HS, Boreham J, Turnbull AC. Maternal serum alpha-fetoprotein and birth weight. Br J Obstet Gynaecol 1980;87:860–3.[Medline]
14. Mariona FG, Hassan MM, Syner FN, Chik LC, Sokol RJ. Maternal serum alpha-fetoprotein (MSAFP) and fetal growth. J Perinat Med 1984;12:179–83.[Medline]
15. Carr-Hill R, Pritchard C. The development and exploitation of empirical birthweight standards. New York: Stockton Press, 1985.
16. Simpson JL, Palomaki GE, Mercer B, Haddow JE, Andersen R, Sibai B, et al. Associations between adverse perinatal outcome and serially obtained second- and third-trimester maternal serum alpha-fetoprotein measurements. Am J Obstet Gynecol 1995;173:1742–8.[Medline]
17. Haddow JE, Palomaki GE, Knight GJ. Can low birth weight after elevated maternal serum alpha-fetoprotein be explained by maternal weight? Obstet Gynecol 1987;70: 26–8.[Medline]
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  G. J. Mizejewski Physiology of Alpha-Fetoprotein as a Biomarker for Perinatal Distress: Relevance to Adverse Pregnancy Outcome Experimental Biology and Medicine, September 1, 2007; 232(8): 993 - 1004. [Abstract] [Full Text] [PDF]
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