Obstetrics & Gynecology:
Contents: Original Research
Obstetric, Perinatal, and Fetal Outcomes in Pregnancies With False-Positive Integrated Screening Results
Baer, Rebecca J. MPH; Currier, Robert J. PhD; Norton, Mary E. MD; Flessel, Monica C. PhD; Goldman, Sara MPH; Towner, Dena MD; Jelliffe-Pawlowski, Laura L. PhD
Genetic Disease Screening Program, California Department of Public Health, Richmond, and the Division of Maternal Fetal Medicine, University of California, San Francisco, and the Department of Epidemiology and Biostatistics, University of California San Francisco School of Medicine, San Francisco, California; and the Division of Maternal Fetal Medicine, University of Hawaii, Honolulu, Hawaii.
Corresponding author: Rebecca J. Baer, MPH, Genetic Disease Screening Program, California Department of Public Health, 850 Marina Bay Parkway, Room F175, Richmond, CA 94804; e-mail: Rebecca.Baer@cdph.ca.gov.
The authors thank Susan Green and Marie-Thérèse Mitchell of the California Department of Public Health for their diligent efforts collecting the outcome of pregnancy data used for this study.
Financial Disclosure The authors did not report any potential conflicts of interest.
OBJECTIVE: To assess the risk of adverse obstetric, perinatal, and fetal outcomes for pregnant women participating in prenatal sequential integrated screening through the California Prenatal Screening Program who had a false-positive screening result.
METHODS: Women who underwent first- and second-trimester prenatal integrated screening plus nuchal translucency measurement with outcome information available were included. Fetuses and neonates with chromosomal or neural tube defects were excluded. We compared the risk of adverse outcomes for all women with a positive screening result compared with a 10% random sample of women with a negative screening result. Logistic binomial regression was used to compare adverse outcomes in screen-positive compared with screen-negative women.
RESULTS: We identified 9,051 screen-positive and 30,928 screen-negative pregnancies with outcome information available. Compared with screen-negative pregnancies, screen-positive women were more likely to be diagnosed with preeclampsia, placenta previa, or abruption (7.6% screen-positive, 3.8% screen-negative; relative risk 1.7, 95% confidence interval [CI] 1.6–1.8) or experience fetal loss before 20 weeks of gestation (1.9% screen-positive, 0.2% screen-negative; relative risk 3.5, 95% CI 3.2–3.8). Women with positive results for more than one screened condition were at substantially greater risk of fetal and neonatal mortality (relative risks 33.6–156.7, 95% CIs 21.8–194.4).
CONCLUSION: Among pregnancies without chromosomal or neural tube defects, prenatal sequential integrated screening provides information regarding risk across a variety of adverse pregnancy outcomes.
LEVEL OF EVIDENCE: II
Prenatal screening using maternal serum samples drawn in the first- and second-trimester has been effectively used worldwide to identify women at risk for trisomy 21, trisomy 18, and neural tube defects.1–3
In California, prenatal sequential integrated screening has been in place since 2009 and includes screening for trisomy 21, trisomy 18, neural tube defects, and Smith-Lemli-Opitz Syndrome using maternal serum pregnancy-associated plasma protein-A, total chorionic gonadotropin (hCG) plus nuchal translucency measurement in the first trimester and α-fetoprotein, hCG, unconjugated estriol, and dimeric inhibin-A in the second trimester.3 Regulations require that health care providers offer screening to all women seen before the 20th gestational week and screening is covered by Medi-Cal (California's low-income health coverage) and most private insurance companies.
Positive prenatal screening results have been associated with aneuploidy other than trisomy 21 and trisomy 18 as well as abdominal wall defects and congenital defects.4–10 In addition, screen-positive pregnancies are at increased risk for poor perinatal outcomes including fetal demise and preterm birth.4,11,12 Women who screen positive for more than one condition (eg, have positive results for trisomy 21 and neural tube defects) have been shown to be at particularly high risk for poor birth outcomes.10,13
This study assesses the risk of adverse obstetric, perinatal, and fetal outcomes in a large sample of California pregnant women with false-positive prenatal sequential integrated screening results.
MATERIALS AND METHODS
Study participants were pregnant with singletons and had expected dates of delivery of June 2009 through May 2012. All women included in the study were participants in the California Prenatal Screening Program administered by the Genetic Disease Screening Program within the California Department of Public Health and had sequential integrated screening, which included first- and second-trimester serum analysis and nuchal translucency measurement when fetal crown rump length was 45–84 mm.14 Analytes measured included pregnancy-associated plasma protein-A and hCG in the first trimester and α-fetoprotein, hCG, unconjugated estriol and dimeric inhibin-A in the second trimester. They were reported as multiples of the median adjusted for gestational age, maternal weight, race or ethnicity, smoking status, and preexisting diabetes.3 Second-trimester risk assessment was provided for trisomy 21, trisomy 18, neural tube defects, and Smith-Lemli-Opitz-Syndrome. Positive interpretation was determined by risk calculation: risk one or greater in 200 resulted in positive screening for trisomy 21, one or more in 100 for trisomy 18, a maternal serum α-fetoprotein multiples of the median 2.5 or greater (singletons) for neural tube defect, and one or more in 250 for Smith-Lemli-Opitz Syndrome (based on a published algorithm15). Screen-positive interpretation qualified women for state facilitated follow-up services (eg, genetic counseling, obstetric ultrasonography, chorionic villus sampling).
Although preliminary risk assessment is provided in the first trimester for trisomy 21 and trisomy 18 for patients who undergo first-trimester serum screening and nuchal translucency measurement, this study included only women who participated in both first- and second-trimester screening, because our intention was to focus on pregnancies with completed sequential integrated screening.
Information about chromosomal abnormalities and neural tube defects are gathered by Genetic Disease Screening Program Chromosome and Neural Tube Defect registry personnel who collect this information on all California births.16 Registry ascertainment sources include physicians, laboratories, hospitals, and prenatal diagnostic centers. All of these sources are mandated by California law to report these diagnoses to the Genetic Disease Screening Program. Pregnancies with chromosomal or neural tube defects identified in the fetus or neonate were excluded from this study.
To track adverse obstetric, perinatal, and fetal outcomes among the participants in the California Prenatal Screening Program, outcome of pregnancy surveys are routinely sent to prenatal providers within 120 days of the estimated date of delivery for all screen positive pregnancies regardless of screening scenario (eg, sequential integrated or second-trimester serum only) and for a random 10% sample of pregnancies that have had sequential integrated screening.3,14 Outcome of pregnancy surveys ask health care providers about maternal diagnoses, birth outcome, and structural birth defects (defined as International Classification of Diseases, 9th Revision, Clinical Modification codes 740.0–746.9 and 747.1–759.917). Multiple attempts are made by program staff to gather complete information on outcomes from prenatal providers and birth hospitals.8,9 To assess the representativeness of the study participants, pregnancies with complete questionnaires (included in the study) were compared with those without questionnaires with respect to maternal characteristics using the χ2 test (Poisson distribution). Logistic binomial regression was used to examine the relationship between obstetric complications including placenta previa, placental abruption, and preeclampsia; adverse perinatal outcomes including miscarriage (defined as fetal death before 20 weeks of gestation), fetal demise (defined as fetal death at 20 weeks of gestation or after), neonatal death (defined as death at 28 days of age or before), preterm birth (defined as delivery before 37 weeks of gestation), small for gestational age (birth weight for gestational age based on smooth U.S. birth norms,18 small for gestational age defined as 10th percentile or lower), and structural birth defects in screen-positive pregnancies (overall and by screen-positive result [eg, trisomy 21 only]) compared with screen-negative pregnancies.
All analyses were done using Statistical Analysis Software 9.3. Methods and protocols were approved by the Committee for the Protection of Human Subjects within the Health and Human Services Agency of the State of California. All analyses were based on data received by the Genetic Disease Screening Program personnel as of May 31, 2013.
Of the 318,163 singleton pregnancies with sequential integrated screening (first- and second-trimester serum analysis plus nuchal translucency measurement) and estimated dates of delivery between June 2009 and May 2012, outcome of pregnancy surveys were sent for 41,059 screen-negative (13.4%) and 12,031 screen-positive (100%) pregnancies. Complete outcome of pregnancy surveys were received for 75.4% of the screen-negative and 78.2% of the screen-positive women. Included in the study were 30,928 screen-negative and 9,051 screen-positive pregnancies with complete outcome of pregnancy surveys and no indication of a chromosome or neural tube defect in the Genetic Disease Screening Program registry.
The majority of the screened population was Hispanic or white not Hispanic (44.4% and 32.4%, respectively) and was between 18 and 34 years of age (70.1%; Table 1). Of the women who screened positive, most screened positive for trisomy 21 (78.9%) and neural tube defects (14.2%). Women with screen-positive results were at increased risk of placental abruption, preeclampsia, or a combination of the obstetric complications we examined (relative risks [RRs] 1.7–2.5) (Table 2). One in 13 women who screened positive had one of these complications compared with 1 in 26 women who screened negative. One in 27 women who screened positive experienced a miscarriage, fetal demise, or neonatal death compared with 1 in 156 screen-negative women (miscarriage RR 3.5, 95% confidence interval [CI] 3.2–3.8; fetal demise RR 2.4, 95% CI 2.2–2.7; neonatal death RR 2.8, 95% CI 2.1–3.6). The rate of preterm birth in the screen-positive population was nearly twice the rate of the screen-negative population (12.2% compared with 6.3%; RR 1.7, 95% CI 1.6–1.8). In addition, screen-positive pregnancies were more likely to be carrying a fetus with a nonneural tube defect structural birth defect. The highest observed risk was for abdominal wall defects (RR 4.1, 95% CI 3.7–4.5), and a twofold risk was demonstrated for central nervous system, circulatory, and respiratory structural birth defects (RRs 2.1–2.2, 95% CIs 1.5–3.1) (Table 3).
When adverse outcomes were examined by positive screening result, risks across outcomes were highest for women with positive screening results for more than one screened condition (eg, trisomy 21 and neural tube defects) (Fig. 1). Of the 247 women who fell into this category, the risk of a miscarriage was 36.0% compared with 0.2% in the screen-negative population (RR 156.7, 95% CI 126.4–194.4) and 8.5% for fetal demise compared with 0.4% in the screen-negative population (RR 33.6, 95% CI 21.8–51.9). Of those surviving to birth, 2.0% of the live-born neonates with multiple positive screening results died within 28 days of age compared with 0.1% in the screen-negative population (RR 64.9, 95% CI 30.0–140.5). Women with positive results for neural tube defects only were at nearly 25-fold increased risk of a fetus with an abdominal wall defect (Table 4).
Table 4-a Risk of Ad...Image Tools
Risk of adverse obst...Image Tools
Table 4-b Risk of Ad...Image Tools
We found that women with false-positive sequential integrated screening results were at greater risk for nearly all of the adverse outcomes measured including fetal loss, preterm birth, and structural birth defects. Pregnancies that screened positive for more than one condition (eg, trisomy 21 and neural tube defects) were at particularly high risk for adverse outcomes.
Women at greatest risk were screen-positive for neural tube defects or for more than one screened condition; in other words, an elevated maternal serum α-fetoprotein conferred the greatest risk. Only 20% of screen-negative pregnancies had any adverse outcome compared with 51% of those who screened positive for neural tube defects (fourfold risk) and 79% of women who screened positive for more than one condition (15-fold risk). The most striking finding was the fetal and neonatal mortality among women with screen-positive results for multiple conditions. These women had a rate of miscarriage of 36%, a risk that was 157-fold higher than the screen-negative population (0.2%). Likewise, the rate of fetal demise was 1 in 12, or 34-fold above the screen-negative population risk, and the neonatal death rate of 1 in 49 was 65-fold increased risk. Our findings are consistent with others who have examined adverse outcomes and elevated maternal serum α-fetoprotein.12,19–23 Using a maternal serum α-fetoprotein multiples of the median cutoff of 2.0 (compared with our cutoff of 2.5), the First and Second Trimester Evaluation of Risk for Fetal Aneuploidy trial also demonstrated an association between elevated maternal serum α-fetoprotein and preterm birth, small for gestational age, preeclampsia, and fetal loss at 24 weeks of gestation or before.21
For nearly all adverse outcomes analyzed, women who screened positive for more than one condition were at greater risk than those who screened positive for neural tube defects only; this risk assessment is based solely on elevated maternal serum α-fetoprotein. Approximately 51% of women who screened positive for neural tube defects only had an adverse outcome compared with 79% of women who screened positive for more than one condition (RRs 3.8 compared with 14.5), indicating that the more abnormal analytes, the greater the risk of an adverse outcome.
Our findings of increased risk for women who screened positive for trisomy 21, trisomy 18, and Smith-Lemli-Opitz Syndrome, however, indicate that maternal serum α-fetoprotein is not the only analyte that confers perinatal risk, because these positive screening results are not associated with elevated maternal serum α-fetoprotein. Although 20% of screen-negative pregnancies had any adverse outcome, 26–47% of women who screened positive for trisomy 21, trisomy 18, or Smith-Lemli-Opitz Syndrome had an adverse outcome (1.3-fold to 3.6-fold increased risk). The trisomy 21 and trisomy 18 positive screening results typically include low pregnancy-associated plasma protein-A and unconjugated estriol, which have also previously been associated with adverse outcomes.19–22,24 Notably, we found that women with a positive screening result for Smith-Lemli-Opitz Syndrome had a 54-fold risk of miscarriage and nearly ninefold risk of fetal demise, likely driven by low unconjugated estriol, which is required for Smith-Lemli-Opitz Syndrome-positive interpretation.17
Although the strengths of the present study include its large, diverse population, one limitation is the incomplete outcome data, which was available for 75.4% of the screen-negative population and 78.3% of the screen-positive population. The comparable response rate in the two groups indicates that there is not a bias toward reporting outcomes in screen-positive patients. If health care providers are more likely to report adverse outcomes than normal outcomes, this would likely make the absolute risks of adverse outcomes appear higher in both groups and would therefore likely not change the relative risks. Similarly, we noted several statistically significant differences between maternal characteristics in the population participating in the study compared with the rest of the screened population as a result of frequency of survey response. In addition, our study is limited by its retrospective nature. We had incomplete data regarding other perinatal risk factors in the maternal history or findings that may have evolved during pregnancy. We were unable to assess the affect of interventions that might have been used such as ultrasonography or other means of antenatal surveillance.
Our study focuses on women who completed sequential integrated screening. Most (53%) women with first trimester-positive screening do not continue with second-trimester screening, but rather choose diagnostic testing.3 Therefore, this current analysis is restricted to pregnancies that are viable at 15 weeks of gestation (the minimum gestation for second-trimester screening) and may not be generalizable to the total screened population.
This study demonstrates that prenatal sequential integrated false-positive results can provide assessment of obstetric and fetal risk beyond the targeted conditions. Although the appropriate management for such screen-positive pregnancies continues to be debated, these data can be helpful in considering the fate of current screening methodologies.
1. Chitayat D, Langlois S, Wilson RD; Genetics Committee of the Society of Obstetricians and Gynaecologists of Canada; Prenatal Diagnosis Committee of the Canadian College of Medical Geneticists. Prenatal screening for fetal aneuploidy in singleton pregnancies. J Obstet Gynaecol Can 2011;33:736–50.
2. Saller DN Jr, Canick JA. Current methods of prenatal screening for Down syndrome and other fetal abnormalities. Clin Obstet Gynecol 2008;51:24–36.
3. Currier R, Wu N, van Meter K, Goldman S, Lorey F, Flessel M. Integrated and first trimester prenatal screening in California: program implementation and patient choice for follow-up services. Prenat Diagn 2012;32:1077–83.
4. Barrett SL, Bower C, Hadlow NC. Use of the combined first-trimester screen result and low PAPP-A to predict risk of adverse fetal outcomes. Prenat Diagn 2008;28:28–35.
5. Alamillo CM, Krantz D, Evans M, Fiddler M, Pergament E. Nearly a third of abnormalities found after first-trimester screening are different than expected: 10-year experience from a single center. Prenat Diagn 2013;33:251–6.
6. Breathnach FM, Malone FD, Lambert-Messerlian G, Cuckle HS, Porter TF, Nyberg DA, et al.. First- and second-trimester screening: detection of aneuploidies other than down syndrome. Obstet Gynecol 2007;110:651–7.
7. Kazerouni NN, Currier RJ, Hodgkinson C, Goldman S, Lorey F, Roberson M. Ancillary benefits of prenatal maternal serum screening achieved in the California program. Prenat Diagn 2010;30:981–7.
8. Jelliffe-Pawlowski LL, Walton-Haynes L, Currier RJ. Using second trimester ultrasound and maternal serum biomarker data to help detect congenital heart defects in pregnancies with positive triple-marker screening results. Am J Med Genet A 2008;146A:2455–67.
9. Jelliffe-Pawlowski LL, Walton-Haynes L, Currier RJ. Identification of second trimester screen positive pregnancies at increased risk for congenital heart defects. Prenat Diagn 2009;29:570–7.
10. Chitayat D, Farrell SA, Huang T, Meier C, Wyatt PR, Summers AM. Double-positive maternal serum screening results for down syndrome and open neural tube defects: an indicator for fetal structural or chromosomal abnormalities and adverse obstetric outcomes. Am J Obstet Gynecol 2002;187:758–63.
11. Summers AM, Huang T, Meier C, Wyatt PR. The implications of a false positive second-trimester serum screen for down syndrome. Obstet Gynecol 2003;101:1301–6.
12. Spencer K. Second-trimester prenatal screening for Down syndrome and the relationship of maternal serum biochemical markers to pregnancy complications with adverse outcome. Prenat Diagn 2000;20:652–6.
13. Summers AM, Huang T, Wyatt PR. Pregnancy outcomes of women with positive serum screening results for down syndrome and trisomy 18. Prenat Diagn 2002;22:269–71.
14. Wu N, Platt LD, Greene N, Currier RJ. Practitioner-specific medians for nuchal translucency to improve first-trimester screening performance. Obstet Gynecol 2012;119:785–94.
15. Palomaki GE, Bradley LA, Knight GJ, Craig WY, Haddow JE. Assigning risk for Smith-Lemli-Opitz syndrome as part of 2nd trimester screening for Down's syndrome. J Med Screen 2002;9:43–4.
16. Kazerouni NN, Currier B, Malm L, Riggle S, Hodgkinson C, Smith S, et al.. Triple-marker prenatal screening program for chromosomal defects. Obstet Gynecol 2009;114:50–8.
17. American Medical Association. International Classification of Diseases: ICD-9-CM 2008 physician. Chicago (IL); 2008.
18. Alexander GR, Himes JH, Kaufman RB, Mor J, Kogan M. A United States national reference for fetal growth. Obstet Gynecol 1996;87:163–8.
19. Dugoff L, Hobbins JC, Malone FD, Vidaver J, Sullivan L, Canick JA, et al.. Quad screen as a predictor of adverse pregnancy outcome. Obstet Gynecol 2005;106:260–7.
20. Huang T, Hoffman B, Meschino W, Kingdom J, Okun N. Prediction of adverse pregnancy outcomes by combinations of first and second trimester biochemistry markers used in the routine prenatal screening of Down syndrome. Prenat Diagn 2010;30:471–7.
21. Jelliffe-Pawlowski LL, Baer RJ, Currier RJ. Second trimester serum predictors of preterm birth in a population-based sample of low-risk pregnancies. Prenat Diagn 2010;30:727–33.
22. Jelliffe-Pawlowski LL, Shaw GM, Currier RJ, Stevenson DK, Baer RJ, O'Brodovich HM, et al.. Association of early-preterm birth with abnormal levels of routinely collected first- and second-trimester biomarkers. Am J Obstet Gynecol 2013;208:492–11.
23. Allen R, Marleen S, Velauthar L, Harrington K, Aquilina J. The relationship between second trimester alpha fetoprotein levels and adverse pregnancy outcome. Open J Obstet Gynecol 2013;3:262–6.
24. Dugoff L, Hobbins JC, Malone FD, Porter TF, Luthy D, Comstock CH, et al.. First-trimester maternal serum PAPP-A and free-beta subunit human chorionic gonadotropin concentrations and nuchal translucency are associated with obstetric complications: a population-based screening study (the FASTER Trial). Am J Obstet Gynecol 2004;191:1446–51.
© 2014 by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.
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