Original Paper Received: January 5, 2015 Accepted: March 12, 2015 Published online: April 30, 2015
Fetal Diagn Ther DOI: 10.1159/000381640
Maternal Anxiety and the SecondTrimester Prenatal Screening: A Prospective Cohort Study Sanaz Mousavi a, b Sedigheh Hantoushzadeh a Mahdi Sheikh a, b Mamak Shariat a
Maternal, Fetal and Neonatal Research Center and b Breast-Feeding Research Center, Vali-Asr Hospital, Tehran University of Medical Sciences, Tehran, Iran
Key Words Anxiety · Estriol · Fetoprotein · Human chorionic gonadotropin · Quadruple screening · Inhibin · Pregnancy · Stress
Abstract Objective: Assessing the effects of maternal anxiety on the markers and results of quadruple screening and on maternal anxiety after receiving positive results. Methods: This prospective cohort study evaluated 1,595 pregnant women referred for prenatal visits. Maternal state/trait anxiety levels were measured, then quadruple screening was performed by measuring serum α-fetoprotein (AFP), β-human chorionic gonadotropin, inhibin A, and unconjugated estriol (UE3). After receiving the results, the state/trait anxiety was remeasured. Amniocentesis was performed for screening-positive mothers. Results: High prescreening maternal anxiety was associated with lower rates of elevated AFP (OR, 0.27; 95% CI, 0.1–0.74) and elevated inhibin A (OR, 0.38; 95% CI, 0.15– 0.98). High maternal anxiety was associated with higher rates of decreased UE3 (OR, 1.8; 95% CI, 1.06–3.08). There were no significant associations between prescreening maternal anxiety and the final screening or amniocentesis results. Among the screening-positive mothers, those who
© 2015 S. Karger AG, Basel 1015–3837/15/0000–0000$39.50/0 E-Mail [email protected] www.karger.com/fdt
had high state/trait anxiety before screening had higher anxiety scores after receiving positive results compared to those with low prescreening anxiety levels (52.9 ± 10.8 vs. 43.7 ± 10.3). Conclusion: High prescreening maternal anxiety is associated with lower rates of elevated AFP and inhibin A and higher rates of decreased UE3. However, maternal anxiety does not affect the final screening or amniocentesis result. High maternal state/trait anxiety before screening is associated with significantly higher maternal anxiety after the receipt of positive results. © 2015 S. Karger AG, Basel
Introduction
The quadruple screening test was introduced in 1996; it screens for chromosomal abnormalities and is conducted during the second trimester with a detection rate of 79% [1, 2]. Quadruple screening remains the most common approach to assessing chromosomal abnormality risks in the United States [2]. This screening test involves the measurements of α-fetoprotein (AFP), β-human chorionic gonadotropin (β-hCG), unconjugated estriol (UE3), and inhibin A, in maternal serum [1, 2].
Mahdi Sheikh, MD, PhD Maternal, Fetal and Neonatal Research Center Vali-Asr Teaching Hospital, Imam Khomeini Hospital Complexes Keshavarz Boulevard, Tehran 1419733141 (Iran) E-Mail mahdisheikh @ gmail.com
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a
Materials and Methods Study Population and Study Design This prospective cohort study evaluated pregnant women who were referred for prenatal visits to a tertiary referral hospital with an annual birth rate of 2,200 births, between February 2012 and April 2014. Pregnant women were considered eligible for this study if they met the following criteria: a maternal age of 20–35 years, a gestational age of 15–20 weeks, a singleton pregnancy, normal blood pressure upon enrollment, nonsmoker and nonalco-
2
Fetal Diagn Ther DOI: 10.1159/000381640
holic statuses, no history of substance abuse, no history of fever or antibiotic use and/or any infection in the previous 2 weeks, and no vaginal bleeding during gestation. A total of 1,675 pregnant women agreed to participate in the study, and 80 were excluded because of the presence of one or more of the following criteria: major stressful events in the recent month according to the Holmes and Rahe Stress Scale (HRSS), any maternal medical or psychological disease, and any hypertensive disorder that was detected till the performance of amniocentesis. A total of 1,595 women ranging from 20 to 35 years of age at 15–20 weeks of gestation completed this study after providing informed consent. This study was approved by the Research Deputy and Ethics Committee of our institute (reference No.: 1733260109). Data Collection Upon enrollment, ultrasound imaging was performed for all the participants to determine gestational age. Then, maternal state and trait anxiety levels were measured by the Spielberger StateTrait Anxiety Inventory (STAI) questionnaire for every participant before quadruple screening was performed [11]. The STAI questionnaire consists of two self-reporting scales for measuring state and trait anxiety levels. Each scale contains 20 items, and each item is scored from 1 to 4. The scores obtained on this questionnaire range from 20 to 80. A score of more than 40 indicates high anxiety. All participants also completed an inventory of stressful life events (HRSS) to assess the occurrence of major stressful events during the past month, and a score of 300 or more was considered indicative of major stressful events [12]. During the following week, the quadruple screening test was performed for all participants. This test was performed by measuring the serum levels of the following four markers in maternal blood: AFP, which was measured by enzyme immunoassay; β-hCG, which was measured by radioimmunoassay (CIS Bio International, Bagnols, France), and inhibin A and UE3, which were measured by solid-phase, two-site sequential chemiluminescent immunometric assay (Immulite, Diagnostic Products Corporation, Los Angeles, Calif., USA). The values were expressed as multiples of the median (MoMs) for gestational age. AFP, β-hCG and inhibin A were considered abnormally high if they were at or above 2.5 MoMs. UE3 was considered abnormally low at less than 0.5 MoM. AFP and β-hCG were considered abnormally low at less than 0.4 MoMs. A calculated risk of greater than 1 in 270 was designated as a positive screen and was considered an indication for amniocentesis. One week after the results of the quadruple screening test were received, the STAI questionnaire was completed again by each participant to reassess the state and trait anxiety levels. Then, amniocentesis was performed for mothers who screened positive, and the results were recorded. Statistical Analysis All statistical analyses were performed using SPSS statistical software (version 18.0.0: PASW, Chicago, Ill., USA). The Pearson correlation coefficient, χ2 analysis, Fisher’s exact test, independent-samples t test, and one-way ANOVA were used to analyze the correlations and relationships among the variables. Sample size was calculated for a power of 80% and an α error of 0.05. Estimated odds ratios with 95% confidence intervals and p values were used to evaluate the statistical significance of the associations and correlations between the variables.
Mousavi/Hantoushzadeh/Sheikh/Shariat
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Despite the high detection rate of quadruple screening, studies have shown that this test has a false-positive rate of 5–7.5% [2, 3]. Mothers who receive positive results experience high anxiety levels during pregnancy, which may increase their risks of preterm birth and low birth weight delivery [4, 5]. To minimize these consequences, studies are needed to identify the maternal and fetal factors that could falsely change the results of the quadruple screening. In some studies, maternal anxiety has been associated with changes in serum levels of some of the markers used in quadruple screening. Maltau et al. [6] have shown that maternal anxiety is associated with reduced concentrations of estriol in maternal plasma. In addition, it has been documented that high maternal anxiety increases cortisol in maternal serum and also in fetal cord blood [7]. Other studies have reported that higher cortisol levels affect the syntheses or the serum levels of estriol, AFP, and inhibin [8–10]. Although the markers evaluated in the quadruple screening could be affected by maternal anxiety, an extensive literature search revealed a lack of studies assessing the associations of state/trait anxiety levels before screening with the final results of the quadruple screening. It is unclear whether a higher maternal anxiety level could cause a false-positive or false-negative result on the quadruple screening. Whether a higher state/trait anxiety level before this test affects the severity of maternal anxiety after a positive screening result remains unknown. This information could aid in the improved use and interpretation of the quadruple screening. It could also help with earlier identification and management of women who are at risk of experiencing higher anxiety after a positive screening result to minimize the detrimental effects of anxiety on pregnancy outcome. We conducted this study to evaluate the effects of the level of maternal state/trait anxiety on the serum levels of the markers assessed in the quadruple screening, on the final results of the quadruple screening, and on the severity of maternal anxiety after receiving positive results.
Table 1. Association of maternal state anxiety level before the quadruple screening and different serum markers
of the quadruple screening Maternal serum marker
Elevated AFP (n = 27) Decreased AFP (n = 5 ) Elevated β-HCG (n = 41) Decreased β-HCG (n = 97) Elevated inhibin A (n = 25) Decreased UE3 (n = 58) Positive screening (n = 81)
Mothers with high state anxiety (n = 709)
low state anxiety (n = 886)
5 (0.7) 2 (0.2) 14 (2) 40 (5.6) 6 (0.8) 34 (4.7) 31 (4.3)
22 (2.4)* 3 (0.3) 27 (3) 57 (6.4) 19 (2.1)* 24 (2.7)* 50 (5.6)
OR
95% CI
0.27 0.81 0.63 0.85 0.38 1.8 0.76
0.1 – 0.74 0.13 – 4.9 0.33 – 1.22 0.56 – 1.3 0.15 – 0.98 1.06 – 3.08 0.48 – 1.21
Data expressed as number with percent in parentheses. OR = Odds ratio; 95% CI = 95% confidence interval. * p < 0.05 for the comparison between two groups with and without the specified characteristic.
Table 2. Association of maternal trait anxiety level before the quadruple screening and different serum markers of the quadruple screening
Maternal serum marker
Elevated AFP (n = 27) Decreased AFP (n = 5 ) Elevated β-HCG (n = 41) Decreased β-HCG (n = 97) Elevated inhibin A (n = 25) Decreased UE3 (n = 58) Positive screening (n = 81)
Mothers with high trait anxiety (n = 664)
low trait anxiety (n = 931)
8 (1.2) 2 (0.3) 13 (1.9) 43 (6.4) 6 (0.9) 26 (3.9) 30 (4.5)
19 (2) 3 (0.3) 28 (3) 54 (5.8) 19 (2) 32 (3.4) 51 (5.4)
OR
95% CI
0.58 0.92 0.64 1.11 0.43 1.14 0.81
0.25 – 1.34 0.15 – 5.56 0.33 – 1.26 0.73 – 1.68 0.17 – 1.1 0.67 – 1.94 0.51 – 1.29
Data expressed as number with percent in parentheses. OR = Odds ratio; 95% CI = 95% confidence interval.
Descriptive Statistics A total of 1,675 pregnant women participated in the study, of which 80 were excluded. Of them, 16 had experienced major stress in the past month and 64 had a medical or psychological disease. The mean ± standard deviation for gestational age was 16.2 ± 1.3 weeks. The trait anxiety score before screening was 38.4 ± 9.9. The state anxiety score before screening was 38.4 ± 10.6. The AFP MoM was 1.2 ± 2.6. The β-hCG MoM was 1.2 ± 6.3. The inhibin A MoM was 1.1 ± 6.9. The UE3 MoM was 1 ± 0.4. The trait anxiety score after screening was 38.2 ± 9.1. Finally, the state anxiety score after screening was 32.1 ± 11.6. Maternal Anxiety and Quadruple Screening
A total of 931 women had low (58.3%) and 664 had high (41.6%) trait anxiety before screening, while 886 women had low (55.5%) and 709 had high (44.4%) state anxiety before screening. Of the participants, 1,563 had normal (97.9%), 27 had high (1.6%) and 5 had low (0.3%) serum AFP levels. A total of 1,457 women had normal (91.3%), 41 had high (2.5%) and 97 had low (6%) serum β-hCG levels. In addition, 1,570 had normal (98.4%) and 25 had high (1.5%) serum inhibin A levels. Finally, 1,532 women had normal (96%) and 58 had low (3.6%) serum UE3 levels. Overall, 1,514 pregnant women (94.9%) had a negative screening result, and 81 (5%) had a positive result.
Fetal Diagn Ther DOI: 10.1159/000381640
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Results
Postscreening state anxiety score
0.6 0.4 0.2
0
0.2
0.4
0.6
0.8
1.0
1 – specificity
70 60 50 40 30 20 High
Low
Prescreening state anxiety
Fig. 1. The sensitivity and specificity of the quadruple screening in detecting chromosomal abnormalities in the fetus. Diagonal segments are produced by ties.
Fig. 2. Box plot graph showing the postscreening state anxiety scores after the receipt of positive screening results in mothers with prescreening high vs. low state anxiety levels.
Association between Maternal Anxiety before Screening and Serum Levels of Quadruple Screening Markers Using Pearson correlation, there was no significant correlation between maternal state and trait anxiety scores before screening and maternal serum AFP, β-hCG, UE3 or inhibin levels. High maternal state anxiety (a state anxiety score of more than 40) before the quadruple screening was associated with significantly lower rates of elevated AFP and inhibin levels (p = 0.006, p = 0.04, respectively). In addition, maternal anxiety was associated with significantly higher rates of decreased UE3 levels (p = 0.03). We could not find a significant association between maternal anxiety and elevated or decreased β-hCG (table 1). High maternal trait anxiety (a trait anxiety score of more than 40) before pregnancy had a borderline association with the reduced detection of elevated inhibin (p = 0.05). There were no significant associations between trait anxiety before screening and elevated or decreased AFP, β-hCG and UE3 levels (table 2).
Regardless of the maternal anxiety state, quadruple screening was able to detect chromosomal abnormalities in the fetus with a sensitivity of 77% and a specificity of 96.2% (fig. 1). The prescreening state and trait anxiety levels had no significant associations with chromosomal abnormalities in the fetus as tested by amniocentesis.
Association between Maternal Anxiety before Screening and Results of Quadruple Screening There was no significant association between high maternal state anxiety and the final screening results (p = 0.2, table 1). We did not find a significant association between high maternal trait anxiety and the final screening results (p = 0.2, table 2). 4
Fetal Diagn Ther DOI: 10.1159/000381640
Association between Quadruple Screening Results and Maternal Anxiety after Screening Using Pearson correlation, significant correlations were detected between the state anxiety score after screening and maternal serum AFP (r = 0.21, p = 0.002), β-hCG (r = 0.37, p = 0.000), and inhibin (r = 0.18, p = 0.009). There was a significant association between a positive screening result and high maternal state anxiety after screening (p = 0.000). There was no association between positive screening results and high maternal trait anxiety after screening (p = 0.3). Among the mothers with positive screening results, those who had high state anxiety before screening had significantly higher state anxiety scores after receiving positive screening results compared with the mothers with low state anxiety before screening (52.9 ± 10.8 vs. 43.7 ± 10.3, p = 0.000, fig. 2). In addition, the mothers with high trait anxiety before screening had significantly higher state anxiety scores after receiving positive screening results compared with the mothers with low trait anxiety before screening (51.5 ± 10 vs. 44.9 ± 11.5, p = 0.009, fig. 3). Mousavi/Hantoushzadeh/Sheikh/Shariat
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Sensitivity
0.8
0
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1.0
Maternal Anxiety and Quadruple Screening
Fetal Diagn Ther DOI: 10.1159/000381640
Postscreening state anxiety score
70 60 50 40 30 20 High
Low
Prescreening trait anxiety
Fig. 3. Box plot graph showing the postscreening state anxiety scores after the receipt of positive screening results in mothers with prescreening high vs. low trait anxiety levels.
Discussion
Main Findings In this study, high maternal state anxiety was associated with the lower rates of elevated AFP and inhibin A levels. High maternal state anxiety was also associated with higher rates of decreased UE3 levels. However, when β-hCG levels in addition to these factors were considered together in the quadruple screening test, maternal anxiety was not found to be significantly associated with the final results of the quadruple screening. In addition, regardless of anxiety state, the quadruple screening remained highly specific and sensitive for the detection of chromosomal abnormalities in the fetus. After the quadruple screening, the mothers who received positive screening results had significantly higher anxiety scores. Among the mothers with positive results, those who had higher anxiety levels before screening had significantly higher anxiety levels after receiving their positive screening results. These findings may aid in the earlier detection of mothers who are at increased risk of experiencing higher anxiety levels after receiving positive results and who need more social and psychological support to prevent the detrimental effects of anxiety on pregnancy outcome.
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Color version available online
Interpretation In the current study, anxious mothers had lower AFP, inhibin A and UE3 levels. This could be due to the effects
of maternal anxiety on placental function. It has been documented that maternal anxiety can alter placental function through several mechanisms, potentially leading to excess glucocorticoid action on the fetoplacental unit as follows [13–15]: first, levels of cortisol become elevated in these mothers [15]. Second, the expression of 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) is down-regulated in the placenta [14]. This enzyme catalyzes the conversion of the active form of cortisol to its inactive form in the placenta, protecting the fetus from high levels of maternal glucocorticoids [14]. Maternal anxiety is associated with a reduction in placental 11β-HSD2, leading to the increased transfer of active cortisol from the maternal to the fetal compartment [14]. This finding has also been demonstrated in other studies. Glover et al. [13] have shown a stronger correlation between maternal and fetal cortisol among more anxious pregnant women. In addition, Keshavarzi et al. [7] have reported that higher maternal anxiety is associated with an increase in fetal cord blood cortisol. Results from animal studies have suggested that cortisone may induce the marked suppression of AFP synthesis. Gitlin and Boesman [16] have shown that the subcutaneous injection of cortisone into pregnant rats suppresses fetal AFP synthesis in utero. In addition, a modest elevation in fetal plasma cortisol causes the negative feedback inhibition of fetal adrenocorticotropic hormone (ACTH) secretion [17]. A decrease in fetal ACTH secretion caused by cortisol seems to play a key role in the pathophysiology of changes in maternal serum markers. This hormone has been shown to stimulate the expression of both the α and βA mRNAs and proteins by fetal adrenal cells, thereby stimulating the secretion of inhibin by fetal adrenocortical cells [18, 19]. Therefore, the depression of ACTH release in the fetus can lead to the decreased secretion of inhibin. In addition, the depression of ACTH release has been shown to cause a decreased production of estriol precursors, which are mainly produced in the fetal adrenal glands [20], potentially leading to reduced maternal serum estriol [21]. In our study, despite the effects of maternal anxiety on some of the serum markers used in the quadruple screening, when the serum levels of all these markers were considered and interpreted together for this test, maternal anxiety was not found to be associated with the final results. Regardless of the maternal anxiety state, quadruple screening was able to detect chromosomal abnormalities in the fetus with a sensitivity of 77% and a specificity of 96.2%. A review by Wald et al. [1] has also reported that the evaluation of AFP alone leads to the detection of 35% of fetal
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Strengths and Limitations Our study is the first report of the association between the severity of state anxiety before screening and the serum levels of the quadruple screening markers. In addition, our assessment of the influence of maternal state and trait anxiety before screening on the final screening results, the amniocentesis results, and the severity of anxiety after receiving positive results in addition to the large sample size used were the main strengths of this study.
References
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The main limitation of the study was that the duration of maternal anxiety before screening was not known. Although we attempted to exclude causes of acute major stress and anxiety, we do not exactly know how long the mothers were anxious before undergoing quadruple screening. Another limitation of our study was that maternal serum cortisol levels were not measured before and after the quadruple screening was performed. This information could have allowed for a better understanding of the basic pathophysiology of the obtained results.
Conclusion
High maternal anxiety before the second-trimester screening is associated with lower rates of elevated AFP and inhibin A, and higher rates of decreased UE3. However, maternal anxiety does not seem to affect the final screening or amniocentesis results. These results need to be confirmed in other studies; more studies are needed to assess the effect of chronic versus acute anxiety on the screening results, since the duration of anxiety might play an important role on the placental function. Also measuring maternal serum cortisol levels should be considered in other studies to reveal more aspects of the pathophysiology behind the obtained results. In addition, high maternal state and trait anxiety before screening is associated with significantly higher maternal anxiety after the receipt of a positive screening result. These findings could aid in the earlier detection of mothers who require strong social and psychological support to minimize the detrimental effects of anxiety on pregnancy outcome.
Disclosure Statement None declared.
1 Wald NJ, Kennard A, Hackshaw A, McGuire A: Antenatal screening for Down’s syndrome. J Med Screen 1997;4:181–246. 2 Malone FD, Canick JA, Ball RH, Nyberg DA, Comstock CH, Bukowski R, et al: First-trimester or second-trimester screening, or both, for Down’s syndrome. N Engl J Med 2005;353:2001–2011. 3 Benn PA, Ying J, Beazoglou T, Egan JF: Estimates for the sensitivity and false-positive rates for second trimester serum screening for Down syndrome and trisomy 18 with ad-
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justment for cross-identification and double-positive results. Prenat Diagn 2001; 21: 46–51. 4 Jorgensen FS: User acceptability of an alphafetoprotein screening programme. Dan Med Bull 1995;42:100–105. 5 Ding XX, Wu YL, Xu SJ, Zho RP, Jia XM, Zhang SF, Huang K, Zhu P, Hao JH, Tao FB: Maternal anxiety during pregnancy and adverse birth outcomes: a systematic review and meta-analysis of prospective cohort studies. J Affect Disord 2014;159:103–110.
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chromosomal abnormalities, while AFP and hCG together are able detect 59%, AFP, hCG and UE3 are able to detect 69%, and the collective consideration of AFP, hCG, UE3, and inhibin A in the quadruple screening test results in the detection of 76%, with a false-positive rate of 5%. In the current study, the mothers who had high state or trait anxiety levels before the quadruple screening experienced significantly higher state anxiety after receiving their positive screening results compared with the mothers with low anxiety before the screening. One of the main disadvantages of antenatal screening is the high level of anxiety experienced by mothers who receive positive results [4, 22]. This high anxiety puts the mother at an increased risk of adverse pregnancy outcomes, especially preterm birth and low birth weight delivery [5]. Some studies have suggested that social and psychological counseling and support effectively decrease the anxiety levels of mothers who receive positive screening results [22–24]. The results of this study are supported by the aforementioned studies [4, 5, 22–24], indicating that the assessment of maternal anxiety before the quadruple screening test, especially for high-risk mothers, could help in the early identification of mothers who are at increased risk of experiencing high anxiety levels and are thus at increased risks of adverse pregnancy outcomes. This early identification could help to provide better and earlier psychological and social support to these mothers, which may help to minimize their anxiety levels and improve pregnancy outcome.
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12 Holmes TH, Rahe RH: The Social Readjustment Rating Scale. J Psychosom Res 1967;11: 213–218. 13 Glover V, Bergman K, Sarkar P, O’Connor TG: Association between maternal and amniotic fluid cortisol is moderated by maternal anxiety. Psychoneuroendocrinology 2009;34: 430–435. 14 O’Donnell KJ, Bugge Jensen A, Freeman L, Khalife N, O’Connor T, Glover V: Maternal prenatal anxiety and downregulation of placental 11β-HSD2. Psychoneuroendocrinology 2012;37:818–826. 15 Kane HS, Dunkel Schetter C, Glynn LM, Hobel CJ, Sandman CA: Pregnancy anxiety and prenatal cortisol trajectories. Biol Psychol 2014;100:13–19. 16 Gitlin D, Boesman M: Serum α-fetoprotein synthesis in the human and rat fetus and its inhibition in the rat. Pediatr Res 1967;1:216– 217. 17 Wood CE: Negative-feedback inhibition of fetal ACTH secretion by maternal cortisol. Am J Physiol 1987;252:R743–R748. 18 Vanttinen T, Kuulasmaa T, Liu J, Voutilainen R: Expression of activin/inhibin receptor and binding protein genes and regulation of activin/inhibin peptide secretion in human adrenocortical cells. J Clin Endocrinol Metab 2002;87:4257–4263.
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19 Spencer SJ, Rabinovici J, Mesiano S, Goldsmith PC, Jaffe RB: Activin and inhibin in the human adrenal gland. Regulation and differential effects in fetal and adult cells. J Clin Invest 1992;90:142–149. 20 Maltau JM, Stokke KT, Moe N: Effects of betamethasone on plasma levels of estriol, cortisol and HCS in late pregnancy. Acta Obstet Gynecol Scand 1979;58:235–238. 21 Zachmann M, Girard J, Duc G, Illig R, Prader A: Low urinary estriol during pregnancy caused by isolated fetal ACTH-deficiency. Acta Paediatr Scand Suppl 1979;277:26–31. 22 Smedler AC, Bremme K: Pregnant women participating in screening must be helped with anxiety generated by alarming information (in Swedish). Lakartidningen 1992; 89: 652–653. 23 Field T, Diego M, Delgado J, Medina L: Yoga and social support reduce prenatal depression, anxiety and cortisol. J Bodyw Mov Ther 2013;17:397–403. 24 Keenan KL, Basso D, Goldkrand J, Butler WJ: Low level of maternal serum alpha-fetoprotein: its associated anxiety and the effects of genetic counseling. Am J Obstet Gynecol 1991;164:54–56.
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6 Maltau JM, Eielsen OV, Stokke KT: Effect of stress during labor on the concentration of cortisol and estriol in maternal plasma. Am J Obstet Gynecol 1979;134:681–684. 7 Keshavarzi F, Farnia V, Yazdchi K, Najafi F, Brand S, Bajoghli H, Nankali A, Salmanzadeh H: Effect of maternal anxiety on maternal serum and fetal cord blood cortisol. Asia Pac Psychiatry 2014;6:435–439. 8 Patrick J, Challis J, Natale R, Richardson B: Circadian rhythms in maternal plasma cortisol, estrone, estradiol, and estriol at 34 to 35 weeks’ gestation. Am J Obstet Gynecol 1979; 135:791–798. 9 Chou JY, Mano T, Feldman M: Inhibition of synthesis of alpha-fetoprotein by glucocorticoids in cultured hepatoma cells. J Cell Biol 1982;93:314–317. 10 Mylonas I, Jeschke U, Winkler L, Makovitzky J, Richter DU, Briese V, Friese K: Immunohistochemical expression of inhibin-alpha in human endometrium and the in vitro secretion of inhibin, estradiol and cortisol in cultured human endometrial glandular cells. Arch Gynecol Obstet 2003;268:142–150. 11 Spielberger CD, Gorssuch RL, Lushene PR, Vagg PR, Jacobs GA: Manual for the StateTrait Anxiety Inventory. Palo Alto, Consulting Psychologists Press, 1983.
Fetal Diagn Ther DOI: 10.1159/000381640
Maternal Anxiety and the SecondTrimester Prenatal Screening: A Prospective Cohort Study Sanaz Mousavi a, b Sedigheh Hantoushzadeh a Mahdi Sheikh a, b Mamak Shariat a
Maternal, Fetal and Neonatal Research Center and b Breast-Feeding Research Center, Vali-Asr Hospital, Tehran University of Medical Sciences, Tehran, Iran
Key Words Anxiety · Estriol · Fetoprotein · Human chorionic gonadotropin · Quadruple screening · Inhibin · Pregnancy · Stress
Abstract Objective: Assessing the effects of maternal anxiety on the markers and results of quadruple screening and on maternal anxiety after receiving positive results. Methods: This prospective cohort study evaluated 1,595 pregnant women referred for prenatal visits. Maternal state/trait anxiety levels were measured, then quadruple screening was performed by measuring serum α-fetoprotein (AFP), β-human chorionic gonadotropin, inhibin A, and unconjugated estriol (UE3). After receiving the results, the state/trait anxiety was remeasured. Amniocentesis was performed for screening-positive mothers. Results: High prescreening maternal anxiety was associated with lower rates of elevated AFP (OR, 0.27; 95% CI, 0.1–0.74) and elevated inhibin A (OR, 0.38; 95% CI, 0.15– 0.98). High maternal anxiety was associated with higher rates of decreased UE3 (OR, 1.8; 95% CI, 1.06–3.08). There were no significant associations between prescreening maternal anxiety and the final screening or amniocentesis results. Among the screening-positive mothers, those who
© 2015 S. Karger AG, Basel 1015–3837/15/0000–0000$39.50/0 E-Mail [email protected] www.karger.com/fdt
had high state/trait anxiety before screening had higher anxiety scores after receiving positive results compared to those with low prescreening anxiety levels (52.9 ± 10.8 vs. 43.7 ± 10.3). Conclusion: High prescreening maternal anxiety is associated with lower rates of elevated AFP and inhibin A and higher rates of decreased UE3. However, maternal anxiety does not affect the final screening or amniocentesis result. High maternal state/trait anxiety before screening is associated with significantly higher maternal anxiety after the receipt of positive results. © 2015 S. Karger AG, Basel
Introduction
The quadruple screening test was introduced in 1996; it screens for chromosomal abnormalities and is conducted during the second trimester with a detection rate of 79% [1, 2]. Quadruple screening remains the most common approach to assessing chromosomal abnormality risks in the United States [2]. This screening test involves the measurements of α-fetoprotein (AFP), β-human chorionic gonadotropin (β-hCG), unconjugated estriol (UE3), and inhibin A, in maternal serum [1, 2].
Mahdi Sheikh, MD, PhD Maternal, Fetal and Neonatal Research Center Vali-Asr Teaching Hospital, Imam Khomeini Hospital Complexes Keshavarz Boulevard, Tehran 1419733141 (Iran) E-Mail mahdisheikh @ gmail.com
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a
Materials and Methods Study Population and Study Design This prospective cohort study evaluated pregnant women who were referred for prenatal visits to a tertiary referral hospital with an annual birth rate of 2,200 births, between February 2012 and April 2014. Pregnant women were considered eligible for this study if they met the following criteria: a maternal age of 20–35 years, a gestational age of 15–20 weeks, a singleton pregnancy, normal blood pressure upon enrollment, nonsmoker and nonalco-
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Fetal Diagn Ther DOI: 10.1159/000381640
holic statuses, no history of substance abuse, no history of fever or antibiotic use and/or any infection in the previous 2 weeks, and no vaginal bleeding during gestation. A total of 1,675 pregnant women agreed to participate in the study, and 80 were excluded because of the presence of one or more of the following criteria: major stressful events in the recent month according to the Holmes and Rahe Stress Scale (HRSS), any maternal medical or psychological disease, and any hypertensive disorder that was detected till the performance of amniocentesis. A total of 1,595 women ranging from 20 to 35 years of age at 15–20 weeks of gestation completed this study after providing informed consent. This study was approved by the Research Deputy and Ethics Committee of our institute (reference No.: 1733260109). Data Collection Upon enrollment, ultrasound imaging was performed for all the participants to determine gestational age. Then, maternal state and trait anxiety levels were measured by the Spielberger StateTrait Anxiety Inventory (STAI) questionnaire for every participant before quadruple screening was performed [11]. The STAI questionnaire consists of two self-reporting scales for measuring state and trait anxiety levels. Each scale contains 20 items, and each item is scored from 1 to 4. The scores obtained on this questionnaire range from 20 to 80. A score of more than 40 indicates high anxiety. All participants also completed an inventory of stressful life events (HRSS) to assess the occurrence of major stressful events during the past month, and a score of 300 or more was considered indicative of major stressful events [12]. During the following week, the quadruple screening test was performed for all participants. This test was performed by measuring the serum levels of the following four markers in maternal blood: AFP, which was measured by enzyme immunoassay; β-hCG, which was measured by radioimmunoassay (CIS Bio International, Bagnols, France), and inhibin A and UE3, which were measured by solid-phase, two-site sequential chemiluminescent immunometric assay (Immulite, Diagnostic Products Corporation, Los Angeles, Calif., USA). The values were expressed as multiples of the median (MoMs) for gestational age. AFP, β-hCG and inhibin A were considered abnormally high if they were at or above 2.5 MoMs. UE3 was considered abnormally low at less than 0.5 MoM. AFP and β-hCG were considered abnormally low at less than 0.4 MoMs. A calculated risk of greater than 1 in 270 was designated as a positive screen and was considered an indication for amniocentesis. One week after the results of the quadruple screening test were received, the STAI questionnaire was completed again by each participant to reassess the state and trait anxiety levels. Then, amniocentesis was performed for mothers who screened positive, and the results were recorded. Statistical Analysis All statistical analyses were performed using SPSS statistical software (version 18.0.0: PASW, Chicago, Ill., USA). The Pearson correlation coefficient, χ2 analysis, Fisher’s exact test, independent-samples t test, and one-way ANOVA were used to analyze the correlations and relationships among the variables. Sample size was calculated for a power of 80% and an α error of 0.05. Estimated odds ratios with 95% confidence intervals and p values were used to evaluate the statistical significance of the associations and correlations between the variables.
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Despite the high detection rate of quadruple screening, studies have shown that this test has a false-positive rate of 5–7.5% [2, 3]. Mothers who receive positive results experience high anxiety levels during pregnancy, which may increase their risks of preterm birth and low birth weight delivery [4, 5]. To minimize these consequences, studies are needed to identify the maternal and fetal factors that could falsely change the results of the quadruple screening. In some studies, maternal anxiety has been associated with changes in serum levels of some of the markers used in quadruple screening. Maltau et al. [6] have shown that maternal anxiety is associated with reduced concentrations of estriol in maternal plasma. In addition, it has been documented that high maternal anxiety increases cortisol in maternal serum and also in fetal cord blood [7]. Other studies have reported that higher cortisol levels affect the syntheses or the serum levels of estriol, AFP, and inhibin [8–10]. Although the markers evaluated in the quadruple screening could be affected by maternal anxiety, an extensive literature search revealed a lack of studies assessing the associations of state/trait anxiety levels before screening with the final results of the quadruple screening. It is unclear whether a higher maternal anxiety level could cause a false-positive or false-negative result on the quadruple screening. Whether a higher state/trait anxiety level before this test affects the severity of maternal anxiety after a positive screening result remains unknown. This information could aid in the improved use and interpretation of the quadruple screening. It could also help with earlier identification and management of women who are at risk of experiencing higher anxiety after a positive screening result to minimize the detrimental effects of anxiety on pregnancy outcome. We conducted this study to evaluate the effects of the level of maternal state/trait anxiety on the serum levels of the markers assessed in the quadruple screening, on the final results of the quadruple screening, and on the severity of maternal anxiety after receiving positive results.
Table 1. Association of maternal state anxiety level before the quadruple screening and different serum markers
of the quadruple screening Maternal serum marker
Elevated AFP (n = 27) Decreased AFP (n = 5 ) Elevated β-HCG (n = 41) Decreased β-HCG (n = 97) Elevated inhibin A (n = 25) Decreased UE3 (n = 58) Positive screening (n = 81)
Mothers with high state anxiety (n = 709)
low state anxiety (n = 886)
5 (0.7) 2 (0.2) 14 (2) 40 (5.6) 6 (0.8) 34 (4.7) 31 (4.3)
22 (2.4)* 3 (0.3) 27 (3) 57 (6.4) 19 (2.1)* 24 (2.7)* 50 (5.6)
OR
95% CI
0.27 0.81 0.63 0.85 0.38 1.8 0.76
0.1 – 0.74 0.13 – 4.9 0.33 – 1.22 0.56 – 1.3 0.15 – 0.98 1.06 – 3.08 0.48 – 1.21
Data expressed as number with percent in parentheses. OR = Odds ratio; 95% CI = 95% confidence interval. * p < 0.05 for the comparison between two groups with and without the specified characteristic.
Table 2. Association of maternal trait anxiety level before the quadruple screening and different serum markers of the quadruple screening
Maternal serum marker
Elevated AFP (n = 27) Decreased AFP (n = 5 ) Elevated β-HCG (n = 41) Decreased β-HCG (n = 97) Elevated inhibin A (n = 25) Decreased UE3 (n = 58) Positive screening (n = 81)
Mothers with high trait anxiety (n = 664)
low trait anxiety (n = 931)
8 (1.2) 2 (0.3) 13 (1.9) 43 (6.4) 6 (0.9) 26 (3.9) 30 (4.5)
19 (2) 3 (0.3) 28 (3) 54 (5.8) 19 (2) 32 (3.4) 51 (5.4)
OR
95% CI
0.58 0.92 0.64 1.11 0.43 1.14 0.81
0.25 – 1.34 0.15 – 5.56 0.33 – 1.26 0.73 – 1.68 0.17 – 1.1 0.67 – 1.94 0.51 – 1.29
Data expressed as number with percent in parentheses. OR = Odds ratio; 95% CI = 95% confidence interval.
Descriptive Statistics A total of 1,675 pregnant women participated in the study, of which 80 were excluded. Of them, 16 had experienced major stress in the past month and 64 had a medical or psychological disease. The mean ± standard deviation for gestational age was 16.2 ± 1.3 weeks. The trait anxiety score before screening was 38.4 ± 9.9. The state anxiety score before screening was 38.4 ± 10.6. The AFP MoM was 1.2 ± 2.6. The β-hCG MoM was 1.2 ± 6.3. The inhibin A MoM was 1.1 ± 6.9. The UE3 MoM was 1 ± 0.4. The trait anxiety score after screening was 38.2 ± 9.1. Finally, the state anxiety score after screening was 32.1 ± 11.6. Maternal Anxiety and Quadruple Screening
A total of 931 women had low (58.3%) and 664 had high (41.6%) trait anxiety before screening, while 886 women had low (55.5%) and 709 had high (44.4%) state anxiety before screening. Of the participants, 1,563 had normal (97.9%), 27 had high (1.6%) and 5 had low (0.3%) serum AFP levels. A total of 1,457 women had normal (91.3%), 41 had high (2.5%) and 97 had low (6%) serum β-hCG levels. In addition, 1,570 had normal (98.4%) and 25 had high (1.5%) serum inhibin A levels. Finally, 1,532 women had normal (96%) and 58 had low (3.6%) serum UE3 levels. Overall, 1,514 pregnant women (94.9%) had a negative screening result, and 81 (5%) had a positive result.
Fetal Diagn Ther DOI: 10.1159/000381640
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Results
Postscreening state anxiety score
0.6 0.4 0.2
0
0.2
0.4
0.6
0.8
1.0
1 – specificity
70 60 50 40 30 20 High
Low
Prescreening state anxiety
Fig. 1. The sensitivity and specificity of the quadruple screening in detecting chromosomal abnormalities in the fetus. Diagonal segments are produced by ties.
Fig. 2. Box plot graph showing the postscreening state anxiety scores after the receipt of positive screening results in mothers with prescreening high vs. low state anxiety levels.
Association between Maternal Anxiety before Screening and Serum Levels of Quadruple Screening Markers Using Pearson correlation, there was no significant correlation between maternal state and trait anxiety scores before screening and maternal serum AFP, β-hCG, UE3 or inhibin levels. High maternal state anxiety (a state anxiety score of more than 40) before the quadruple screening was associated with significantly lower rates of elevated AFP and inhibin levels (p = 0.006, p = 0.04, respectively). In addition, maternal anxiety was associated with significantly higher rates of decreased UE3 levels (p = 0.03). We could not find a significant association between maternal anxiety and elevated or decreased β-hCG (table 1). High maternal trait anxiety (a trait anxiety score of more than 40) before pregnancy had a borderline association with the reduced detection of elevated inhibin (p = 0.05). There were no significant associations between trait anxiety before screening and elevated or decreased AFP, β-hCG and UE3 levels (table 2).
Regardless of the maternal anxiety state, quadruple screening was able to detect chromosomal abnormalities in the fetus with a sensitivity of 77% and a specificity of 96.2% (fig. 1). The prescreening state and trait anxiety levels had no significant associations with chromosomal abnormalities in the fetus as tested by amniocentesis.
Association between Maternal Anxiety before Screening and Results of Quadruple Screening There was no significant association between high maternal state anxiety and the final screening results (p = 0.2, table 1). We did not find a significant association between high maternal trait anxiety and the final screening results (p = 0.2, table 2). 4
Fetal Diagn Ther DOI: 10.1159/000381640
Association between Quadruple Screening Results and Maternal Anxiety after Screening Using Pearson correlation, significant correlations were detected between the state anxiety score after screening and maternal serum AFP (r = 0.21, p = 0.002), β-hCG (r = 0.37, p = 0.000), and inhibin (r = 0.18, p = 0.009). There was a significant association between a positive screening result and high maternal state anxiety after screening (p = 0.000). There was no association between positive screening results and high maternal trait anxiety after screening (p = 0.3). Among the mothers with positive screening results, those who had high state anxiety before screening had significantly higher state anxiety scores after receiving positive screening results compared with the mothers with low state anxiety before screening (52.9 ± 10.8 vs. 43.7 ± 10.3, p = 0.000, fig. 2). In addition, the mothers with high trait anxiety before screening had significantly higher state anxiety scores after receiving positive screening results compared with the mothers with low trait anxiety before screening (51.5 ± 10 vs. 44.9 ± 11.5, p = 0.009, fig. 3). Mousavi/Hantoushzadeh/Sheikh/Shariat
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Sensitivity
0.8
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Maternal Anxiety and Quadruple Screening
Fetal Diagn Ther DOI: 10.1159/000381640
Postscreening state anxiety score
70 60 50 40 30 20 High
Low
Prescreening trait anxiety
Fig. 3. Box plot graph showing the postscreening state anxiety scores after the receipt of positive screening results in mothers with prescreening high vs. low trait anxiety levels.
Discussion
Main Findings In this study, high maternal state anxiety was associated with the lower rates of elevated AFP and inhibin A levels. High maternal state anxiety was also associated with higher rates of decreased UE3 levels. However, when β-hCG levels in addition to these factors were considered together in the quadruple screening test, maternal anxiety was not found to be significantly associated with the final results of the quadruple screening. In addition, regardless of anxiety state, the quadruple screening remained highly specific and sensitive for the detection of chromosomal abnormalities in the fetus. After the quadruple screening, the mothers who received positive screening results had significantly higher anxiety scores. Among the mothers with positive results, those who had higher anxiety levels before screening had significantly higher anxiety levels after receiving their positive screening results. These findings may aid in the earlier detection of mothers who are at increased risk of experiencing higher anxiety levels after receiving positive results and who need more social and psychological support to prevent the detrimental effects of anxiety on pregnancy outcome.
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Color version available online
Interpretation In the current study, anxious mothers had lower AFP, inhibin A and UE3 levels. This could be due to the effects
of maternal anxiety on placental function. It has been documented that maternal anxiety can alter placental function through several mechanisms, potentially leading to excess glucocorticoid action on the fetoplacental unit as follows [13–15]: first, levels of cortisol become elevated in these mothers [15]. Second, the expression of 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) is down-regulated in the placenta [14]. This enzyme catalyzes the conversion of the active form of cortisol to its inactive form in the placenta, protecting the fetus from high levels of maternal glucocorticoids [14]. Maternal anxiety is associated with a reduction in placental 11β-HSD2, leading to the increased transfer of active cortisol from the maternal to the fetal compartment [14]. This finding has also been demonstrated in other studies. Glover et al. [13] have shown a stronger correlation between maternal and fetal cortisol among more anxious pregnant women. In addition, Keshavarzi et al. [7] have reported that higher maternal anxiety is associated with an increase in fetal cord blood cortisol. Results from animal studies have suggested that cortisone may induce the marked suppression of AFP synthesis. Gitlin and Boesman [16] have shown that the subcutaneous injection of cortisone into pregnant rats suppresses fetal AFP synthesis in utero. In addition, a modest elevation in fetal plasma cortisol causes the negative feedback inhibition of fetal adrenocorticotropic hormone (ACTH) secretion [17]. A decrease in fetal ACTH secretion caused by cortisol seems to play a key role in the pathophysiology of changes in maternal serum markers. This hormone has been shown to stimulate the expression of both the α and βA mRNAs and proteins by fetal adrenal cells, thereby stimulating the secretion of inhibin by fetal adrenocortical cells [18, 19]. Therefore, the depression of ACTH release in the fetus can lead to the decreased secretion of inhibin. In addition, the depression of ACTH release has been shown to cause a decreased production of estriol precursors, which are mainly produced in the fetal adrenal glands [20], potentially leading to reduced maternal serum estriol [21]. In our study, despite the effects of maternal anxiety on some of the serum markers used in the quadruple screening, when the serum levels of all these markers were considered and interpreted together for this test, maternal anxiety was not found to be associated with the final results. Regardless of the maternal anxiety state, quadruple screening was able to detect chromosomal abnormalities in the fetus with a sensitivity of 77% and a specificity of 96.2%. A review by Wald et al. [1] has also reported that the evaluation of AFP alone leads to the detection of 35% of fetal
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Strengths and Limitations Our study is the first report of the association between the severity of state anxiety before screening and the serum levels of the quadruple screening markers. In addition, our assessment of the influence of maternal state and trait anxiety before screening on the final screening results, the amniocentesis results, and the severity of anxiety after receiving positive results in addition to the large sample size used were the main strengths of this study.
References
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The main limitation of the study was that the duration of maternal anxiety before screening was not known. Although we attempted to exclude causes of acute major stress and anxiety, we do not exactly know how long the mothers were anxious before undergoing quadruple screening. Another limitation of our study was that maternal serum cortisol levels were not measured before and after the quadruple screening was performed. This information could have allowed for a better understanding of the basic pathophysiology of the obtained results.
Conclusion
High maternal anxiety before the second-trimester screening is associated with lower rates of elevated AFP and inhibin A, and higher rates of decreased UE3. However, maternal anxiety does not seem to affect the final screening or amniocentesis results. These results need to be confirmed in other studies; more studies are needed to assess the effect of chronic versus acute anxiety on the screening results, since the duration of anxiety might play an important role on the placental function. Also measuring maternal serum cortisol levels should be considered in other studies to reveal more aspects of the pathophysiology behind the obtained results. In addition, high maternal state and trait anxiety before screening is associated with significantly higher maternal anxiety after the receipt of a positive screening result. These findings could aid in the earlier detection of mothers who require strong social and psychological support to minimize the detrimental effects of anxiety on pregnancy outcome.
Disclosure Statement None declared.
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chromosomal abnormalities, while AFP and hCG together are able detect 59%, AFP, hCG and UE3 are able to detect 69%, and the collective consideration of AFP, hCG, UE3, and inhibin A in the quadruple screening test results in the detection of 76%, with a false-positive rate of 5%. In the current study, the mothers who had high state or trait anxiety levels before the quadruple screening experienced significantly higher state anxiety after receiving their positive screening results compared with the mothers with low anxiety before the screening. One of the main disadvantages of antenatal screening is the high level of anxiety experienced by mothers who receive positive results [4, 22]. This high anxiety puts the mother at an increased risk of adverse pregnancy outcomes, especially preterm birth and low birth weight delivery [5]. Some studies have suggested that social and psychological counseling and support effectively decrease the anxiety levels of mothers who receive positive screening results [22–24]. The results of this study are supported by the aforementioned studies [4, 5, 22–24], indicating that the assessment of maternal anxiety before the quadruple screening test, especially for high-risk mothers, could help in the early identification of mothers who are at increased risk of experiencing high anxiety levels and are thus at increased risks of adverse pregnancy outcomes. This early identification could help to provide better and earlier psychological and social support to these mothers, which may help to minimize their anxiety levels and improve pregnancy outcome.
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6 Maltau JM, Eielsen OV, Stokke KT: Effect of stress during labor on the concentration of cortisol and estriol in maternal plasma. Am J Obstet Gynecol 1979;134:681–684. 7 Keshavarzi F, Farnia V, Yazdchi K, Najafi F, Brand S, Bajoghli H, Nankali A, Salmanzadeh H: Effect of maternal anxiety on maternal serum and fetal cord blood cortisol. Asia Pac Psychiatry 2014;6:435–439. 8 Patrick J, Challis J, Natale R, Richardson B: Circadian rhythms in maternal plasma cortisol, estrone, estradiol, and estriol at 34 to 35 weeks’ gestation. Am J Obstet Gynecol 1979; 135:791–798. 9 Chou JY, Mano T, Feldman M: Inhibition of synthesis of alpha-fetoprotein by glucocorticoids in cultured hepatoma cells. J Cell Biol 1982;93:314–317. 10 Mylonas I, Jeschke U, Winkler L, Makovitzky J, Richter DU, Briese V, Friese K: Immunohistochemical expression of inhibin-alpha in human endometrium and the in vitro secretion of inhibin, estradiol and cortisol in cultured human endometrial glandular cells. Arch Gynecol Obstet 2003;268:142–150. 11 Spielberger CD, Gorssuch RL, Lushene PR, Vagg PR, Jacobs GA: Manual for the StateTrait Anxiety Inventory. Palo Alto, Consulting Psychologists Press, 1983.
