To investigate the effects of maternal smoking during pregnancy on newborn infants’ anogenital distance (AGD).
Fifty-six female and sixty-four male newborn infants from mothers who smoked during pregnancy were included in this study. A control group for each sex was selected from infants whose mothers had no active or passive (in either the household or the workplace) smoke exposure before or during pregnancy. Questionnaire data on maternal demographic characteristics and information about cigarette use were collected. We assessed genital anthropometry which included AGD for both male and female neonates, and stretched penile length (SPL), penile girth for males within the first 48 h after birth. AGD measurements were also normalized according to birth weight (AGD/weight in grams), length (AGD/height in millimeters), and ponderal index [AGD/(weight in grams/height in cubic centimeters)]. Anogenital index (AGI) was calculated by dividing the AGD by cube root of birth weight.
In female infants, prenatal smoke exposure was associated with significantly increased weight-adjusted AGD (p=0.03). There was also a significant correlation between mothers’ daily smoking rates and weight-adjusted AGD (r=0.27/p=0.03). In male infants, fetal smoke exposure was not associated with any AGD measurements, SPL and penile girth.
A significant increase in weight-adjusted AGD in female infants exposed to maternal smoking may be an indicator of antenatal androgen exposure and may pose a risk for short and long-term endocrine, metabolic and behavioral problems.
The authors would like to thank Prof. Dr. Tülay Güran (Department of Pediatric Endocrinology and Diabetes, Marmara University, School of Medicine, Istanbul, Turkey) for a great deal of support and her valuable guidance. We would like to thank Prof. Dr. Beyhan Cengiz (Department of Public Health, Faculty of Medicine, Celal Bayar University, Manisa, Turkey) and Dr. Cigdem Selli (MRC Centre for Reproductive Health, The Queen’s Medical Research Institute, The University of Edinburgh) for helping statistical analysis of the study. We thank Dr. Louise Bath (Consultant of Pediatric Endocrinology and Diabetes in Royal Hospital for Sick Children, Edinburgh, Scotland) for English language editing of this manuscript.
Research funding: We have no direct or indirect commercial financial incentive associated with publishing the article. This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
Authors’ contribution: D.Ö.K. contributed in study design, conducting training sessions, analyzing and interpreting the data, and taking the lead in writing and revision of the manuscript. C.A. performed the measurements, contributed in collecting and inputting the data. A.P.A informed the participants about the study, obtained consent and organized the questionnaires. H.Ü.T participated in study design and critical reading. Ö.O participated in conducting training sessions, collecting and interpreting the data, supervised the manuscript and provided critical feedback.
Conflict of interest: The authors declare there was no any conflict of interest. All authors declare no competing interests.
Ethical approval: The study was approved by the Behçet Uz Children's Hospital Ethics committee and adhered to the Declaration of Helsinki for Medical Research involving Human Subjects.
1. Jauniaux, E, Gulbis, B, Acharya, G, Thiry, P, Rodeck, C. Maternal tobacco exposure and cotinine levels in fetal fluids in the first half of pregnancy. Obstet Gynecol 1999;93:25–9. https://doi.org/10.1016/s0029-7844(98)00318-4.Search in Google Scholar
2. Ernst, A, Kristensen, SL, Toft, G, Thulstrup, AM, Hakonsen, LB, Olsen, SF, et al. Maternal smoking during pregnancy and reproductive health of daughters: a follow-up study spanning two decades Hum Reprod. 2012;27:3593–600 https://doi.org/10.1093/humrep/des337.Search in Google Scholar PubMed
3. Strohsnitter, WC, Hatch, EE, Hyer, M, Troisi, R, Kaufman, RH, Robboy, SJ, et al. The association between in utero cigarette smoke exposure and age at menopause. Am J Epidemiol. 2008;167:727–33. https://doi.org/10.1093/aje/kwm351.Search in Google Scholar PubMed
4. Ye, X, Skjaerven, R, Basso, O, Baird, DD, Eggesbo, M, Cupul Uicab, LA, et al. In utero exposure to tobacco smoke and subsequent reduced fertility in females. Hum Reprod 2010;25:2901–6. https://doi.org/10.1093/humrep/deq235.Search in Google Scholar PubMed PubMed Central
5. Brouwers, MM, Feitz, WF, Roelofs, LA, Kiemeney, LA, de Gier, RP, Roeleveld, N. Risk factors for hypospadias. Eur J Pediatr 2007;166:671–8. https://doi.org/10.1007/s00431-006-0304-z.Search in Google Scholar PubMed
6. Ravnborg, TL, Jensen, TK, Andersson, AM, Toppari, J, Skakkebaek, NE, Jorgensen, N. Prenatal and adult exposures to smoking are associated with adverse effects on reproductive hormones, semen quality, final height and body mass index. Hum Reprod 2011;26:1000–11. https://doi.org/10.1093/humrep/der011.Search in Google Scholar PubMed
7. Mendiola, J, Stahlhut, RW, Jorgensen, N, Liu, F, Swan, SH. Shorter anogenital distance predicts poorer semen quality in young men in Rochester, New York. Environ Health Perspect 2011;119:958–63. https://doi.org/10.1289/ehp.1103421.Search in Google Scholar PubMed PubMed Central
8. Jensen, MS, Toft, G, Thulstrup, AM, Bonde, JP, Olsen, J. Cryptorchidism according to maternal gestational smoking. Epidemiology 2007;18:220–5. https://doi.org/10.1097/01.ede.0000254061.90686.9f.Search in Google Scholar PubMed
9. Hsieh, MH, Eisenberg, ML, Hittelman, AB, Wilson, JM, Tasian, GE, Baskin, LS. Caucasian male infants and boys with hypospadias exhibit reduced anogenital distance. Hum Reprod 2012;27:1577–80. https://doi.org/10.1093/humrep/des087.Search in Google Scholar PubMed PubMed Central
10. Thankamony, A, Lek, N, Carroll, D, Williams, M, Dunger, DB, Acerini, CL, et al. Anogenital distance and penile length in infants with hypospadias or cryptorchidism: comparison with normative data. Environ Health Perspect 2014;122:207–11. https://doi.org/10.1289/ehp.1307178.Search in Google Scholar PubMed PubMed Central
11. Bornehag, CG, Carlstedt, F, Jonsson, BA, Lindh, CH, Jensen, TK, Bodin, A, et al. Prenatal phthalate exposures and anogenital distance in Swedish boys. Environ Health Perspect 2015;123:101–7. https://doi.org/10.1289/ehp.1408163.Search in Google Scholar
12. Barrett, ES, Hoeger, KM, Sathyanarayana, S, Abbott, DH, Redmon, JB, Nguyen, RHN, et al. Anogenital distance in newborn daughters of women with polycystic ovary syndrome indicates fetal testosterone exposure. J Dev Orig Health Dis 2018;9:307–14. https://doi.org/10.1017/s2040174417001118.Search in Google Scholar
13. Wu, XY, Li, ZL, Wu, CY, Liu, YM, Lin, H, Wang, SH, et al. Endocrine traits of polycystic ovary syndrome in prenatally androgenized female Sprague-Dawley rats. Endocr J 2010;57:201–9. https://doi.org/10.1507/endocrj.k09e-205.Search in Google Scholar
14. Eisenberg, ML, Hsieh, MH, Walters, RC, Krasnow, R, Lipshultz, LI. The relationship between anogenital distance, fatherhood, and fertility in adult men. PLOS One. 2011;6:e18973. https://doi.org/10.1371/journal.pone.0018973.Search in Google Scholar
15. Mendiola, J, Roca, M, Minguez-Alarcon, L, Mira-Escolano, MP, Lopez-Espin, JJ, Barrett, ES, et al. Anogenital distance is related to ovarian follicular number in young Spanish women: a cross-sectional study. Environ Health. 2012;11:90. https://doi.org/10.1186/1476-069x-11-90.Search in Google Scholar
16. Eisenberg, ML, Jensen, TK, Walters, RC, Skakkebaek, NE, Lipshultz, LI. The relationship between anogenital distance and reproductive hormone levels in adult men. J Urol 2012;187:594–8. https://doi.org/10.1016/j.juro.2011.10.041.Search in Google Scholar
17. Callegari, C, Everett, S, Ross, M, Brasel, JA. Anogenital ratio: measure of fetal virilization in premature and full-term newborn infants. J Pediatr 1987;111:240–3. https://doi.org/10.1016/s0022-3476(87)80075-6.Search in Google Scholar
18. Portney, LG, Watkins, MP. Foundations of clinical research: applications to practice. New Jersey: Prentice-Hall; 2000.Search in Google Scholar
19. Fowler, PA, Bhattacharya, S, Flannigan, S, Drake, AJ, O’Shaughnessy, PJ. Maternal cigarette smoking and effects on androgen action in male offspring: unexpected effects on second-trimester anogenital distance. J Clin Endocrinol Metab 2011;96:E1502–6. https://doi.org/10.1210/jc.2011-1100.Search in Google Scholar PubMed
20. Fowler, PA, Filis, P, Bhattacharya, S, le Bizec, B, Antignac, JP, Morvan, ML, et al. Human anogenital distance: an update on fetal smoke-exposure and integration of the perinatal literature on sex differences. Hum Reprod 2016;31:463–72. https://doi.org/10.1093/humrep/dev323.Search in Google Scholar PubMed PubMed Central
21. Swan, SH, Sathyanarayana, S, Barrett, ES, Janssen, S, Liu, F, Nguyen, RH, et al. First trimester phthalate exposure and anogenital distance in newborns. Hum Reprod 2015;30:963–72. https://doi.org/10.1093/humrep/deu363.Search in Google Scholar PubMed PubMed Central
22. Thankamony, A, Ong, KK, Dunger, DB, Acerini, CL, Hughes, IA. Anogenital distance from birth to 2 years: a population study. Environ Health Perspect 2009;117:1786–90. https://doi.org/10.1289/ehp.0900881.Search in Google Scholar PubMed PubMed Central
23. Gilboa, Y, Kivilevitch, Z, Oren, M, Cohen, YP, Katorza, E, Achiron, R. Anogenital distance in male and female fetuses at 20 to 35 weeks of gestation: centile charts and reference ranges. Prenat Diagn 2014;34:946–51. https://doi.org/10.1002/pd.4399.Search in Google Scholar PubMed
24. Welsh, M, Saunders, PT, Fisken, M, Scott, HM, Hutchison, GR, Smith, LB, et al. Identification in rats of a programming window for reproductive tract masculinization, disruption of which leads to hypospadias and cryptorchidism. J Clin Invest 2008;118:1479–90. https://doi.org/10.1172/jci34241.Search in Google Scholar
25. Dean, A, Sharpe, RM. Clinical review: anogenital distance or digit length ratio as measures of fetal androgen exposure: relationship to male reproductive development and its disorders. J Clin Endocrinol Metab 2013;98:2230–8. https://doi.org/10.1210/jc.2012-4057.Search in Google Scholar PubMed
26. Jain, VG, Goyal, V, Chowdhary, V, Swarup, N, Singh, RJ, Singal, A, et al. Anogenital distance is determined during early gestation in humans. Hum Reprod 2018;33:1619–27. https://doi.org/10.1093/humrep/dey265.Search in Google Scholar PubMed
27. Sir-Petermann, T, Codner, E, Maliqueo, M, Echiburu, B, Hitschfeld, C, Crisosto, N, et al. Increased anti-Mullerian hormone serum concentrations in prepubertal daughters of women with polycystic ovary syndrome. J Clin Endocrinol Metab 2006;91:3105–9. https://doi.org/10.1210/jc.2005-2693.Search in Google Scholar PubMed
29. Fowler, PA, Cassie, S, Rhind, SM, Brewer, MJ, Collinson, JM, Lea, RG, et al. Maternal smoking during pregnancy specifically reduces human fetal desert hedgehog gene expression during testis development. J Clin Endocrinol Metab 2008;93:619–26. https://doi.org/10.1210/jc.2007-1860.Search in Google Scholar PubMed
31. Toriola, AT, Vaarasmaki, M, Lehtinen, M, Zeleniuch-Jacquotte, A, Lundin, E, Rodgers, KG, et al. Determinants of maternal sex steroids during the first half of pregnancy. Obstet Gynecol 2011;118:1029–36. https://doi.org/10.1097/aog.0b013e3182342b7f.Search in Google Scholar PubMed PubMed Central
32. Bernstein, L, Pike, MC, Lobo, RA, Depue, RH, Ross, RK, Henderson, BE. Cigarette smoking in pregnancy results in marked decrease in maternal hCG and oestradiol levels. Br J Obstet Gynaecol 1989;96:92–6. https://doi.org/10.1111/j.1471-0528.1989.tb01582.x.Search in Google Scholar
34. Kitawaki, J, Inoue, S, Tamura, T, Yamamoto, T, Honjo, H, Higashiyama, T, et al. Cigarette smoking during pregnancy lowers aromatase cytochrome P-450 in the human placenta. J Steroid Biochem Mol Biol 1993;45:485–91. https://doi.org/10.1016/0960-0760(93)90163-q.Search in Google Scholar
35. Sarasin, A, Schlumpf, M, Muller, M, Fleischmann, I, Lauber, ME, Lichtensteiger, W. Adrenal-mediated rather than direct effects of nicotine as a basis of altered sex steroid synthesis in fetal and neonatal rat. Reprod Toxicol 2003;17:153–62. https://doi.org/10.1016/s0890-6238(02)00119-3.Search in Google Scholar
36. Tanko, LB, Christiansen, C. An update on the antiestrogenic effect of smoking: a literature review with implications for researchers and practitioners. Menopause 2004;11:104–9. https://doi.org/10.1097/01.gme.0000079740.18541.db.Search in Google Scholar PubMed
37. Kuijper, EA, Ket, JC, Caanen, MR, Lambalk, CB. Reproductive hormone concentrations in pregnancy and neonates: a systematic review. Reprod Biomed Online 2013;27:33–63. https://doi.org/10.1016/j.rbmo.2013.03.009.Search in Google Scholar PubMed
38. Fowler, PA, Childs, AJ, Courant, F, MacKenzie, A, Rhind, SM, Antignac, JP, et al. In utero exposure to cigarette smoke dysregulates human fetal ovarian developmental signalling. Hum Reprod 2014;29:1471–89. https://doi.org/10.1093/humrep/deu117.Search in Google Scholar PubMed
39. Fowler, PA, Anderson, RA, Saunders, PT, Kinnell, H, Mason, JI, Evans, DB, et al. Development of steroid signaling pathways during primordial follicle formation in the human fetal ovary. J Clin Endocrinol Metab 2011;96:1754–62. https://doi.org/10.1210/jc.2010-2618.Search in Google Scholar PubMed
40. O’Shaughnessy, PJ, Monteiro, A, Bhattacharya, S, Fraser, MJ, Fowler, PA. Steroidogenic enzyme expression in the human fetal liver and potential role in the endocrinology of pregnancy. Mol Hum Reprod 2013;19:177–87. https://doi.org/10.1093/molehr/gas059.Search in Google Scholar PubMed
41. Vinggaard, AM, Joergensen, EC, Larsen, JC. Rapid and sensitive reporter gene assays for detection of antiandrogenic and estrogenic effects of environmental chemicals. Toxicol Appl Pharmacol 1999;155:150–60. https://doi.org/10.1006/taap.1998.8598.Search in Google Scholar PubMed
42. Mandrup, KR, Jacobsen, PR, Isling, LK, Axelstad, M, Dreisig, K, Hadrup, N, et al. Effects of perinatal ethinyl estradiol exposure in male and female Wistar rats. Reprod Toxicol 2013;42:180–91. https://doi.org/10.1016/j.reprotox.2013.09.001.Search in Google Scholar
43. Smith, LM, Cloak, CC, Poland, RE, Torday, J, Ross, MG. Prenatal nicotine increases testosterone levels in the fetus and female offspring. Nicotine Tob Res 2003;5:369–74. https://doi.org/10.1080/146222031000094196.Search in Google Scholar
44. Matta, SG, Fu, Y, Valentine, JD, Sharp, BM. Response of the hypothalamo-pituitary-adrenal axis to nicotine. Psychoneuroendocrinology 1998;23:103–13. https://doi.org/10.1016/s0306-4530(97)00079-6.Search in Google Scholar
45. Barbieri, RL, York, CM, Cherry, ML, Ryan, KJ. The effects of nicotine, cotinine and anabasine on rat adrenal 11 beta-hydroxylase and 21-hydroxylase. J Steroid Biochem 1987;28:25–8. https://doi.org/10.1016/0022-4731(87)90119-1.Search in Google Scholar
46. Matikainen, T, Perez, GI, Jurisicova, A, Pru, JK, Schlezinger, JJ, Ryu, HY, et al. Aromatic hydrocarbon receptor-driven Bax gene expression is required for premature ovarian failure caused by biohazardous environmental chemicals. Nat Genet 2001;28:355–60. https://doi.org/10.1038/ng575.Search in Google Scholar PubMed
47. Kandel, DB, Udry, JR. Prenatal effects of maternal smoking on daughters’ smoking: nicotine or testosterone exposure?. Am J Publ Health. 1999;89:1377–83. https://doi.org/10.2105/ajph.89.9.1377.Search in Google Scholar PubMed PubMed Central
48. Liu, C, Xu, X, Zhang, Y, Li, W, Huo, X. Associations between maternal phenolic exposure and cord sex hormones in male newborns. Hum Reprod 2016;31:648–56. https://doi.org/10.1093/humrep/dev327.Search in Google Scholar PubMed
49. Fluck, CE, Meyer-Boni, M, Pandey, AV, Kempna, P, Miller, WL, Schoenle, EJ, et al. Why boys will be boys: two pathways of fetal testicular androgen biosynthesis are needed for male sexual differentiation. Am J Hum Genet 2011;89:201–18. https://doi.org/10.1016/j.ajhg.2011.06.009.Search in Google Scholar PubMed PubMed Central
50. van de Beek, C, Thijssen, JH, Cohen-Kettenis, PT, van Goozen, SH, Buitelaar, JK. Relationships between sex hormones assessed in amniotic fluid, and maternal and umbilical cord serum: what is the best source of information to investigate the effects of fetal hormonal exposure? Horm Behav 2004;46:663–9. https://doi.org/10.1016/j.yhbeh.2004.06.010.Search in Google Scholar PubMed
51. Benowitz, NL, Bernert, JT, Caraballo, RS, Holiday, DB, Wang, J. Optimal serum cotinine levels for distinguishing cigarette smokers and nonsmokers within different racial/ethnic groups in the United States between 1999 and 2004. Am J Epidemiol 2009;169:236–48. https://doi.org/10.1093/aje/kwn301.Search in Google Scholar PubMed
52. Barrett, ES, Parlett, LE, Redmon, JB, Swan, SH. Evidence for sexually dimorphic associations between maternal characteristics and anogenital distance, a marker of reproductive development. Am J Epidemiol 2014;179:57–66. https://doi.org/10.1093/aje/kwt220.Search in Google Scholar PubMed PubMed Central
53. Singal, AK, Jain, VG. Maternal and infant characteristics influencing the anogenital distance and penile length in newborns. Andrologia 2016;48:708–13. https://doi.org/10.1111/and.12507.Search in Google Scholar PubMed
© 2020 Walter de Gruyter GmbH, Berlin/Boston