CME/CE

JULY 2008

Maternal Age and Malformations in Singleton Births

Ambica Garg, MBBS, MS; Claire Connolly, BS; Lisa M. Hollier, MD, MPH

The association between maternal age and fetal chromosomal abnormalities is well researched and firmly established. However, it is now emerging that the extremes of maternal age may also be related to nonchromosomal structural anomalies in the fetus.

Continuing Medical Education

GOAL To examine the increased prevalence of nonchromosomal fetal anomalies at the extremes of the childbearing age range in women. OBJECTIVES To discuss the prevalence of specific nonchromosomal, structural fetal anomalies among mothers younger than 20 years and older than 35 years. To consider various forms of bias that may affect research into a relationship between maternal age and nonchromosomal fetal abnormalities. To assess the rationale and cost-effectiveness of screening for nonchromosomal fetal anomalies based on maternal age. ACCREDITATION This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of Albert Einstein College of Medicine and Quadrant HealthCom Inc. Albert Einstein College of Medicine is accredited by the ACCME to provide continuing medical education for health care providers. This activity has been peer reviewed and approved by Brian Cohen, MD, Professor of Clinical ObGyn, Albert Einstein College of Medicine. Review date: June 2008. It is designed for ObGyns, primary care physicians, and nurse practitioners. Albert Einstein College of Medicine designates this educational activity for a maximum of 1 AMA PRA Category 1 Credit™. Health care providers should only claim credit commensurate with the extent of their participation in the activity. Participants who answer 70% or more of the questions correctly will obtain credit. To earn credit, see the instructions on page 43 and mail your answers according to the instructions on page 44. CONFLICT OF INTEREST STATEMENT The “Conflict of Interest Disclosure Policy” of Albert Einstein College of Medicine requires that authors participating in any CME activity disclose to the audience any relationship(s) with a pharmaceutical or equipment company. Any author whose disclosed relationships prove to create a conflict of interest, with regard to their contribution to the activity, will not be permitted to submit. The Albert Einstein College of Medicine also requires that faculty participating in any CME activity disclose to the audience when discussing any unlabeled or investigational use of any commercial product, or device, not yet approved for use in the United States. The authors report no conflicts of interest to this article. The authors report no discussion of off-label use. Dr Cohen reports no conflict of interest. The staff of CCME of Albert Einstein College of Medicine have no conflicts of interest with commercial interest related directly or indirectly to this educational activity.

With an overall prevalence of malformations at birth of approximately 3% to 5%, congenital anomalies are the leading cause of infant death in the United States.1 The most common of such abnormalities include congenital heart defects, cleft lip and palate, Down syndrome, and abdominal wall defects (gastroschisis/omphalocele).1 The association between advancing maternal age and chromosomal abnormalities is well established. A number of large, population-based studies have also evaluated the association between maternal age and structural malformations. Most have concluded that maternal age of more than 35 or 40 years is associated with a small increase in the risk of birth defects. However, mothers of less than 20 years of age have a significantly increased risk of gastroschisis—a finding that is consistent across nearly all studies.

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RESEARCH EFFORTS

As congenital anomalies are the leading cause of infant death, scientific research into the patterns of occurrence of malformations is important to ultimately identify causative or contributory factors. The relationship between maternal age and malformations is of significant interest to clinicians and patients alike. Because birth defects are relatively rare, studies that evaluate their incidence with respect to maternal age often report their findings in terms of an odds ratio (OR) comparing older or younger women with a reference group such as mothers aged 20 to 24 or 25 to 29 years. Studies reporting a statistically significant OR or a relative risk (RR) of 2 or 3 may be reported by the media and the risk sensationalized. More informative to the clinician and patient is an attributable risk or a risk difference that considers the baseline risk and includes the effect of age.

There are several important caveats to interpreting the literature regarding birth defects and maternal age. The studies of birth defects or anomalies are heterogeneous, and many include infants with chromosomal abnormalities. Studies that do not exclude fetuses/infants with abnormal karyotypes do not address the question about the independent association between maternal age and malformations. This also means that the authors report their findings in different ways (births versus live births, for example) and such heterogeneity can make the interpretation of the findings more difficult. In addition, because birth defects are rare, the number of women giving birth at the extremes of age is significantly less than the number of women aged 20 to 35 years giving birth. Thus, rates for individual malformations should be interpreted cautiously, because small changes in the number of infants with birth defects can result in large changes in rates. The data provided in several large studies have been synthesized in this paper to provide rough estimates of attributable risk for use in counseling patients.

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ADVANCED MATERNAL AGE

Childbearing by women in their 30s and 40s continues to increase. The mean age of mothers giving birth in the United States has increased steadily over the last four decades from 24.6 years in 1970 to 27.2 years by 2000.2 In fact, the increase in the mean age at first birth has increased in most developed nations over the last 30 years.3 The birth rate for women aged 30 to 34 years rose to 97.7/1,000 in 2006 (the highest rate since 1964), while the rate for women aged 35 to 39 years rose to 47.3/1,000—the highest rate since 1965.4

The association between advancing maternal age and chromosomal abnormalities is well established, and is not addressed in this paper. By contrast, the role played by maternal age in the frequency of nonchromosomal structural birth defects is less clear. As the proportion of women delaying childbearing increases, the question of such an association is growing in importance.

When considering the overall risk of structural birth defects, there is a significant association between increased odds of birth defects and both maternal age less than 20 years and maternal age of 35 to 39 years and 40 years or more (Figure).5 This U-shaped curve is consistent across a number of studies and across various populations.5-8 One population-based study of live births limited to British Columbia, Canada, found no association between the incidence of birth defects and advancing maternal age9; this study did not include abnormalities from stillbirths or abortions, in contrast to other studies.5,8 The work by Reefhuis and Honein included defects in both live births and in stillborns older than 20 weeks’ gestation.7

Click to enlarge

Figure. Prevalance of nonchromosomal abnormalities by maternal age group.2

Using data from several studies, the prevalence of birth defects ranges from 32 to 44/1,000 births for mothers aged 35 to 39 years.5,8 Compared with mothers aged 25 to 29 years, the increase in nonchromosomal structural abnormalities is about 5 to 12/1,000 births.5,8 For mothers aged 40 years and older, the prevalence of nonchromosomal structural abnormalities is about 24 to 50/1,000 births. The increase in nonchromosomal structural abnormalities is about 6 to 11/1,000 births compared with mothers aged 25 to 29 years.5,8

Specific abnormalities that have been found to be associated with advancing maternal age include: heart defects,5,7,10 hypospadias,7 other male genital defects,7 craniosynostosis,7 club foot,5 and diaphragmatic hernia.5 Estimates for the increase in the odds of congenital heart defects range from ORs of 1.12 to 1.43 for women aged 35 to 39 years and 3.95 for women aged 40 years and older.5,7 Using a prevalence of about 1% for all types of congenital heart disease (CHD), women who are aged 35 to 39 years could have an additional 1 to 4/1,000 cases of CHD (11 to 14/1,000 versus 10/1,000 births). For women aged 40 years and older, an OR of 3.95 could mean approximately 30/1,000 additional cases of CHD. The increase in the odds of hypospadias was 1.85 for women age 35 to 39 years.7 Using an estimated prevalence of 5/1,000 births for hypospadias, women aged 35 to 39 years could have an additional 4/1,000 cases of hypospadias (9/1,000 versus 5/1,000 births). Thus, while the ORs are statistically significantly increased compared with younger women, the absolute increase in the number of fetuses/newborns with malformations is small.

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YOUNG MATERNAL AGE

Concomitant with the rise in births to older women, there were significant declines in births among teenagers until 2006. The birth rate for teenagers declined by 2% in 2005, falling to 40.4/1,000 births among women aged 15 to 19 years—a 35% drop compared with the most recent peak in 1991 (61.8 births), and the lowest ever recorded in the 65 years for which a consistent series of rates is available.4 This decline was not sustained in 2006, though, when the birth rate for teenagers rose by 3% to 41.9 births/1,000 women age 15 to 19 years.4

As with older mothers, when considering the overall risk of structural birth defects, there is a significant association with increased odds of birth defects and maternal age less than 20 years (Figure). The finding of an increase in birth defects among young mothers is consistent across multiple studies in multiple populations.5-8 Unlike older mothers, however, the defects in this young population are usually seen in chromosomally normal fetuses. Estimates of the prevalence of nonchromosomal structural abnormalities among mothers aged less than 15 years ranges from 37 to 46.9/1,000 births.5,8 Based on these data and compared with mothers aged 25 to 29 years, the increase in abnormalities is as much as 28/1,000 births.

The specific abnormalities that have been found to be associated with young maternal age include: anencephaly,6,7 hydrocephaly without neural tube defect (NTD),7 all ear defects,7 cleft lip,7 female genital defects,7 polydactyly,7 omphalocele,6,7 and gastroschisis.6,7 Estimates of the increase in the odds of anencephaly for younger mothers range from 1.81 to 3.6,7 In the United States, the average prevalence of anencephaly is now approximately 1.1/10,000 live births.11 Using this estimate, women who are aged less than 20 years could have an additional 1 to 2/10,000 cases of anencephaly (2 to 3.3/10,000 versus 1/10,000 births).

The increase in the prevalence of gastroschisis among young mothers is by far the largest risk increase for any of the abnormalities that have been studied. The estimates for the increase in odds of gastroschisis for mothers aged less than 20 years range from 2.8 to 7.8.6,7,12 In the United States, the average prevalence of gastroschisis is approximately 3.8/10,000 live births.1 Using this figure, women who are younger than 20 years of age could have an additional 7 to 26/10,000 cases of gastroschisis (11 to 30/10,000 versus 3.8/10,000 births). Thus, although the RR is very high, gastroschisis is relatively rare—so the absolute number of affected infants is small.

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BIASES AND MECHANISMS

The biologic mechanisms that explain the increase in the risk of nonchromosomal abnormalities at the extremes of maternal age are unclear. Certain biases may be present as well. The use of prenatal testing is higher among older mothers compared with their younger counterparts. This could lead to more frequent diagnoses of abnormalities such as anencephaly and gastroschisis, and hence to more terminations in the screened population, reducing the number of defects identified at birth. The effect of this “screening bias” would be to increase the number of infant abnormalities among younger mothers in studies that did not account for defects in abortuses.

The studies cited in this paper made attempts to exclude defects in fetuses with chromosomal abnormalities. If the identification of fetuses with abnormal karyotypes is incomplete, the association between advancing maternal age and karyotypic abnormalities could increase the number of cardiac abnormalities among infants of older mothers (because cardiac defects often accompany karyotypic abnormalities).

Apart from these errors, there are potential mechanisms that could account for a real increase in defects in younger and older mothers. Nutritional factors have been proposed as contributors.7 Multivitamin use and micronutrient intake are lowest among young pregnant women.13,14 Other exposures related to birth defects also vary by maternal age, including smoking, alcohol use, illicit drug use, and environmental exposures.5,7 Further research may help to clarify the factors associated with increasing risks, and lead to interventions to reduce these risks.

PATIENT COUNSELING POINTS

Birth defects occur in about 3% to 5% of pregnancies. Women who are pregnant before age 20 and after age 35 have a higher risk of birth defects—chromosomal and nonchromosomal. The reasons that women at the ends of the reproductive age spectrum have a higher chance of having a baby with a birth defect are not completely understood. For older women, some of the birth defects occur because the baby has a chromosomal problem. Although the risk of having a baby with birth defects is higher for younger and older women, the overall absolute increase in the number of babies with birth defects is low.

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DETECTION

There are a variety of serum screening tests—with and without measurement of nuchal translucency (NT)—that are in current use for the detection of aneuploidy and other problems. Detection rates for Down syndrome range from 64% (NT alone) to 96% (integrated testing).15 The α-fetoprotein (AFP) component of maternal serum screening is useful for the detection of open NTDs and abdominal wall defects, in addition to other, rarer abnormalities.

About 65% of pregnant women in the United States typically undergo an ultrasonographic evaluation during gestation.16 Depending in part on the gestational age at the time of the scan, the detection rate for congenital anomalies varies widely, ranging from 16% to 85%.17 In addition to the known link between NT and aneuploidy, increased NT has also been associated with cardiac defects. In a large, multicenter study, however, the sensitivity of NT measurements for identifying cardiac defects was very low, suggesting that this would not be a good screening tool for congenital heart disease in the general population.

Numerous studies have evaluated the cost-effectiveness of “screening” second-trimester ultrasonography performed to identify fetal abnormalities, and the results are conflicting.16 Generally speaking, screening in a high-risk population will be more cost-effective than screening in the general population. Many women over 35 years of age are currently offered second-trimester ultrasonographic evaluation as an adjunct to other screening studies to detect fetuses with chromosomal abnormalities. Despite a significant relative increase in the risk of abnormalities, the absolute increase in abnormal fetuses among mothers aged less than 20 years is low. Because of the low absolute risk, screening ultrasonography to detect birth defects for mothers aged less than 20 years is unlikely to be cost-effective, but this has not been specifically addressed.

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CONCLUSION

Young maternal age and advanced maternal age are both associated with an increase in the risk of fetal structural abnormalities overall, and for abnormalities that are not associated with abnormal fetal karyotypes. Using the estimates provided here, patients can be counseled that the absolute increase in the number of fetuses with structural defects is low. The biologic mechanisms that explain the increase in the risk of nonchromosomal abnormalities at the extremes of maternal age are unclear. Additional research may help to identify intervention strategies to reduce the prevalence of these defects among women at risk.

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Ambica Garg, MBBS, MS, is First Year Resident; Claire Connolly, BS, is Medical Student; and Lisa M. Hollier, MD, MPH, is Associate Professor; all in the Department of Obstetrics, Gynecology & Reproductive Sciences, University of Texas Houston Medical School and LBJ General Hospital, Houston.

References

1. Centers for Disease Control and Prevention. Improved national prevalence estimates for 18 selected major birth defects—United States, 1999-2001. MMWR Morb Mortal Wkly Rep. 2006;54(51&52):1301-1305.
2. Mathews TJ, Hamilton BE. Mean age of mother, 1970-2000. Natl Vital Stat Rep. 2002;51(1):1-13.
3. Frejka T, Sardon JP. First birth trends in developed countries: persisting parenthood postponement. Demographic Res. 2006;15(6):147-180.
4. Hamilton BE, Martin JA, Ventura SJ. Births: preliminary data for 2006. Natl Vital Stat Rep. 2007;56(7):1-18.
5. Hollier LM, Leveno KJ, Kelly MA, McIntire DD, Cunningham FG. Maternal age and malformations in singleton births. Obstet Gynecol. 2000; 96(5):701-706.
6. Croen LA, Shaw GM. Young maternal age and congenital malformations: a population-based study. Am J Public Health. 1995;85(5):710-713.
7. Reefhuis J, Honein MA. Maternal age and non-chromosomal birth defects, Atlanta—1968-2000: teenager or thirty-something, who is at risk? Birth Defects Res A Clin Mol Teratol. 2004;70(9):572-579.
8. Tan KH, Tan TY, Tan J, Tan I, Chew SK, Yeo GS. Birth defects in Singapore: 1994-2000. Singapore Med J. 2005;46(10):545-552.
9. Baird PA, Sadovnick AD, Yee IM. Maternal age and birth defects: a population study. Lancet. 1991;337(8740):527-530.
10. Hay S, Barbano H. Independent effects of maternal age and birth order on the incidence of selected congenital malformations. Teratology. 1972;6(3):271-279.
11. Martin JA, Hamilton BE, Sutton PD, et al. Births: final data for 2005. Natl Vital Stat Rep. 2007; 56(6):1-103.
12. Loane M, Dolk H, Bradbury I; EUROCAT Working Group. Increasing prevalence of gastroschisis in Europe 1980-2002: a phenomenon restricted to younger mothers? Paediatr Perinat Epidemiol. 2007;21(4):363-369.
13. Centers for Disease Control and Prevention (CDC). Knowledge and use of folic acid among women of reproductive age—Michigan 1998. MMWR Morb Mortal Wkly Rep. 2001;50(10): 185-189.
14. Mathews F, Yudkin P, Smith RF, Neil A. Nutrient intakes during pregnancy: the influence of smoking status and age. J Epidemiol Community Health. 2005;4(1):17-23.
15. ACOG Committee on Practice Bulletins. ACOG Practice Bulletin No. 77: screening for fetal chromosomal abnormalities. Obstet Gynecol. 2007; 109(1):217-227.
16. Martin JA, Hamilton BE, Sutton PD, Ventura SJ, Menacker F, Munson ML. Births: final data for 2002. Natl Vital Stat Rep. 2003;52(10):1-113.
17. ACOG Committee on Practice Bulletins. ACOG Practice Bulletin No. 58. Ultrasonography in pregnancy. Obstet Gynecol. 2004;104(6):1449-1458.

DISCLAIMER
The opinions expressed herein are those of the author and do not necessarily represent the views of the sponsor or the publisher. Please review complete prescribing information of specific drugs or combination of drugs, including indications, contraindications, warnings, and adverse effects before administering pharmacologic therapy to patients.

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