Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Epidemiology and Population Health

Periconceptional maternal body mass index and the impact on post-implantation (sex-specific) embryonic growth and morphological development

International Journal of Obesity volume 45, pages 2369–2376 (2021)Cite this article

Subjects

Abstract

Objective

Women with obesity have an increased risk of pregnancy complications. Although complications generally present in the second and third trimester of pregnancy, most of them develop in the periconception period. Moreover, fetal sex also impacts pregnancy course and outcome. Therefore, our aim is to study (sex-specific) associations between periconceptional maternal body mass index (BMI) and embryonic growth and morphological development.

Methods

A total of 884 women with singleton pregnancies were selected from the Rotterdam Periconception Cohort, comprising 15 women with underweight, 483 with normal weight, 231 with overweight and 155 with obesity. Longitudinal three-dimensional ultrasound examinations were performed at 7, 9, and 11 weeks of gestation for offline measurements of crown-rump length (CRL), embryonic volume (EV), and Carnegie stages. Analyses were adjusted for maternal age, parity, ethnicity, education, and periconceptional lifestyle.

Results

A negative trend was observed for embryos of women with obesity (βEV −0.03, p = 0.086), whereas embryonic growth and developmental trajectories in women with overweight were comparable to those with normal weight. Maternal underweight was associated with faster morphological development (βCarnegie 0.78, p = 0.004). After stratification for fetal sex, it was demonstrated that female embryos of underweight women grow and morphologically develop faster than those of normal weight women (βEV 0.13, p = 0.008; βCarnegie 1.39, p < 0.001), whereas female embryos of women with obesity grow slower (βEV −0.05, p = 0.027).

Conclusion

We found that periconceptional maternal underweight is associated with faster embryonic growth, especially in females. In contrast, female embryos of women with obesity grow slower than female embryos of women with normal weight. This may be the result of altered female adaptation to the postnatal environment. Future research should focus on strategies for optimizing preconceptional maternal weight, to reduce BMI-related pregnancy complications and improve the health of future generations.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Flowchart of the study population.
Fig. 2: Embryonic trajectories of embryonic volumes (EV) and Carnegie stages for maternal underweight (red), normal weight (yellow), overweight (purple), and obesity (blue).

Similar content being viewed by others

Code availability

The code underlying this article can be shared on reasonable request to the corresponding author.

References

  1. Mokdad AH, Ford ES, Bowman BA, Dietz WH, Vinicor F, Bales VS, et al. Prevalence of obesity, diabetes, and obesity-related health risk factors, 2001. JAMA. 2003;289:76–9.

    Article  PubMed  Google Scholar 

  2. Wright SM, Aronne LJ. Causes of obesity. Abdom Imaging. 2012;37:730–2.

    Article  PubMed  Google Scholar 

  3. Redinger RN. The pathophysiology of obesity and its clinical manifestations. Gastroenterol Hepatol. 2007;3:856–63.

    Google Scholar 

  4. Double burden of malnutrition. In: World Health Organization, https://www.who.int/news-room/factsheets/detail/malnutrition. Accessed on 1 July 2020.

  5. Guelinckx I, Devlieger R, Beckers K, Vansant G. Maternal obesity: pregnancy complications, gestational weight gain and nutrition. Obes Rev. 2008;9:140–50.

    Article  CAS  PubMed  Google Scholar 

  6. Metwally M, Li TC, Ledger WL. The impact of obesity on female reproductive function. Obes Rev. 2007;8:515–23.

    Article  CAS  PubMed  Google Scholar 

  7. van der Steeg JW, Steures P, Eijkemans MJ, Habbema JD, Hompes PG, Burggraaff JM, et al. Obesity affects spontaneous pregnancy chances in subfertile, ovulatory women. Hum Reprod. 2008;23:324–8.

    Article  PubMed  Google Scholar 

  8. Aune D, Saugstad OD, Henriksen T, Tonstad S. Maternal body mass index and the risk of fetal death, stillbirth, and infant death: a systematic review and meta-analysis. JAMA. 2014;311:1536–46.

    Article  CAS  PubMed  Google Scholar 

  9. Di Renzo GC, Rosati A, Sarti RD, Cruciani L, Cutuli AM. Does fetal sex affect pregnancy outcome? Gend Med. 2007;4:19–30.

    Article  PubMed  Google Scholar 

  10. de Zegher F, Devlieger H, Eeckels R. Fetal growth: boys before girls. Horm Res. 1999;51:258–9.

    PubMed  Google Scholar 

  11. Steegers-Theunissen RP, Twigt J, Pestinger V, Sinclair KD. The periconceptional period, reproduction and long-term health of offspring: the importance of one-carbon metabolism. Hum Reprod Update. 2013;19:640–55.

    Article  CAS  PubMed  Google Scholar 

  12. Power C, Atherton K, Thomas C. Maternal smoking in pregnancy, adult adiposity and other risk factors for cardiovascular disease. Atherosclerosis. 2010;211:643–8.

    Article  CAS  PubMed  Google Scholar 

  13. Reynolds RM, Allan KM, Raja EA, Bhattacharya S, McNeill G, Hannaford PC, et al. Maternal obesity during pregnancy and premature mortality from cardiovascular event in adult offspring: follow-up of 1 323 275 person years. BMJ. 2013;347:f4539.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Metwally M, Ong KJ, Ledger WL, Li TC. Does high body mass index increase the risk of miscarriage after spontaneous and assisted conception? A meta-analysis of the evidence. Fertil Steril. 2008;90:714–26.

    Article  PubMed  Google Scholar 

  15. Blomberg MI, Kallen B. Maternal obesity and morbid obesity: the risk for birth defects in the offspring. Birth Defects Res A Clin Mol Teratol. 2010;88:35–40.

    CAS  PubMed  Google Scholar 

  16. Gordon GH, Antony KM, Sampene E, Iruretagoyena JI. Maternal obesity is not associated with increased crown-rump length in first-trimester ultrasounds of singleton gestations. J Matern Fetal Neonatal Med. 2019;32:2393–9.

    Article  PubMed  Google Scholar 

  17. Thagaard IN, Krebs L, Holm JC, Christiansen M, Møller H, Lange T, et al. The effect of obesity on early fetal growth and pregnancy duration: a cohort study. J Matern Fetal Neonatal Med. 2018;31:2941–6.

    Article  PubMed  Google Scholar 

  18. Rousian M, Koning AH, van Oppenraaij RH, Hop WC, Verwoerd-Dikkeboom CM, van der Spek PJ, et al. An innovative virtual reality technique for automated human embryonic volume measurements. Hum Reprod. 2010;25:2210–6.

    Article  CAS  PubMed  Google Scholar 

  19. Verwoerd-Dikkeboom CM, Koning AH, Hop WC, Rousian M, Van Der Spek PJ, Exalto N, et al. Reliability of three-dimensional sonographic measurements in early pregnancy using virtual reality. Ultrasound Obstet Gynecol. 2008;32:910–6.

    Article  CAS  PubMed  Google Scholar 

  20. Verwoerd-Dikkeboom CM, Koning AH, van der Spek PJ, Exalto N, Steegers EA. Embryonic staging using a 3D virtual reality system. Hum Reprod. 2008;23:1479–84.

    Article  CAS  PubMed  Google Scholar 

  21. Steegers-Theunissen RP, Verheijden-Paulissen JJ, van Uitert EM, Wildhagen MF, Exalto N, Koning AH. et al. Cohort Profile: The Rotterdam Periconceptional Cohort (Predict Study). Int J Epidemiol. 2016;45:374–81.

    Article  PubMed  Google Scholar 

  22. van Uitert EM, Exalto N, Burton GJ, Willemsen SP, Koning AH, Eilers PH, et al. Human embryonic growth trajectories and associations with fetal growth and birthweight. Hum Reprod. 2013;28:1753–61.

    Article  PubMed  Google Scholar 

  23. Rousian M, Koning AH, van der Spek PJ, Steegers EA, Exalto N. Virtual reality for embryonic measurements requiring depth perception. Fertil Steril. 2011;95:773–4.

    Article  PubMed  Google Scholar 

  24. O’Rahilly R, Muller F. Developmental stages in human embryos: revised and new measurements. Cells Tissues Organs. 2010;192:73–84.

    Article  PubMed  Google Scholar 

  25. Gaillard R, de Ridder MA, Verburg BO, Witteman JC, Mackenbach JP, Moll HA, et al. Individually customised fetal weight charts derived from ultrasound measurements: the Generation R Study. Eur J Epidemiol. 2011;26:919–26.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Papageorghiou AT, Ohuma EO, Altman DG, Todros T, Cheikh Ismail L, Lambert A, et al. International standards for fetal growth based on serial ultrasound measurements: the Fetal Growth Longitudinal Study of the INTERGROWTH-21st Project. Lancet. 2014;384:869–79.

    Article  PubMed  Google Scholar 

  27. Hoftiezer L, Hof MHP, Dijs-Elsinga J, Hogeveen M, Hukkelhoven C, van Lingen RA. From population reference to national standard: new and improved birthweight charts. Am J Obstet Gynecol. 2019;220:e17.

    Article  Google Scholar 

  28. Yu Z, Han S, Zhu J, Sun X, Ji C, Guo X. Pre-pregnancy body mass index in relation to infant birth weight and offspring overweight/obesity: a systematic review and meta-analysis. PLoS One. 2013;8:e61627.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Burton GJ, Hempstock J, Jauniaux E. Nutrition of the human fetus during the first trimester-a review. Placenta. 2001;22:S70–7.

    Article  PubMed  Google Scholar 

  30. Velazquez MA, Fleming TP, Watkins AJ. Periconceptional environment and the developmental origins of disease. J Endocrinol. 2019;242:T33–T49.

    Article  CAS  PubMed  Google Scholar 

  31. Nahar A, Maki S, Kadokawa H. Suppressed expression of granulocyte macrophage colony-stimulating factor in oviduct ampullae of obese cows. Anim Reprod Sci. 2013;139:1–8.

    Article  CAS  PubMed  Google Scholar 

  32. Ducker GS, Rabinowitz JD. One-carbon metabolism in health and disease. Cell Metab. 2017;25:27–42.

    Article  CAS  PubMed  Google Scholar 

  33. Tobi EW, Goeman JJ, Monajemi R, Gu H, Putter H, Zhang Y, et al. DNA methylation signatures link prenatal famine exposure to growth and metabolism. Nat Commun. 2014;5:5592.

    Article  CAS  PubMed  Google Scholar 

  34. Langley-Evans SC. Nutrition in early life and the programming of adult disease: a review. J Hum Nutr Diet. 2015;28:1–14.

    Article  PubMed  Google Scholar 

  35. Lubchenco LO, Hansman C, Dressler M, Boyd E. Intrauterine growth as estimated from liveborn birth-weight data at 24 to 42 weeks of gestation. Pediatrics. 1963;32:793–800.

    Article  CAS  PubMed  Google Scholar 

  36. Bermejo-Alvarez P, Rizos D, Rath D, Lonergan P, Gutierrez-Adan A. Sex determines the expression level of one third of the actively expressed genes in bovine blastocysts. Proc Natl Acad Sci USA. 2010;107:3394–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Gutiérrez-Adán A, Perez-Crespo M, Fernandez-Gonzalez R, Ramirez MA, Moreira P, Pintado B, et al. Developmental consequences of sexual dimorphism during pre-implantation embryonic development. Reprod Domest Anim. 2006;41:54–62.

    Article  PubMed  Google Scholar 

  38. Gabory A, Roseboom TJ, Moore T, Moore LG, Junien C. Placental contribution to the origins of sexual dimorphism in health and diseases: sex chromosomes and epigenetics. Biol Sex Differ. 2013;4:5.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Eriksson JG, Kajantie E, Osmond C, Thornburg K, Barker DJ. Boys live dangerously in the womb. Am J Hum Biol. 2010;22:330–5.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Mao J, Zhang X, Sieli PT, Falduto MT, Torres KE, Rosenfeld CS. Contrasting effects of different maternal diets on sexually dimorphic gene expression in the murine placenta. Proc Natl Acad Sci USA. 2010;107:5557–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Lecoutre S, Deracinois B, Laborie C, Eberlé D, Guinez C, Panchenko PE, et al. Depot- and sex-specific effects of maternal obesity in offspring’s adipose tissue. J Endocrinol. 2016;230:39–53.

    Article  CAS  PubMed  Google Scholar 

  42. Dobbs KB, Gagné D, Fournier E, Dufort I, Robert C, Block J, et al. Sexual dimorphism in developmental programming of the bovine preimplantation embryo caused by colony-stimulating factor 2. Biol Reprod. 2014;91:80.

    Article  PubMed  CAS  Google Scholar 

  43. Albouy-Llaty M, Thiebaugeorges O, Goua V, Magnin G, Schweitzer M, Forhan A, et al. Influence of fetal and parental factors on intrauterine growth measurements: results of the EDEN mother-child cohort. Ultrasound Obstet Gynecol. 2011;38:673–80.

    Article  CAS  PubMed  Google Scholar 

  44. Ay L, Kruithof CJ, Bakker R, Steegers EA, Witteman JC, Moll HA, et al. Maternal anthropometrics are associated with fetal size in different periods of pregnancy and at birth. The Generation R Study. BJOG. 2009;116:953–63.

    Article  CAS  PubMed  Google Scholar 

  45. Lopes KRM, Souza ASR, Figueiroa JN, Alves JGB. Correlation between pre-pregnancy body mass index and maternal visceral adiposity with fetal biometry during the second trimester. Int J Gynaecol Obstet. 2017;138:133–7.

    Article  PubMed  Google Scholar 

  46. Canavan TP, Deter RL. The effect of maternal body mass index on fetal growth: use of individualized growth assessment and two-level linear modeling. J Clin Ultrasound. 2014;42:456–64.

    Article  PubMed  Google Scholar 

  47. Zhang C, Hediger ML, Albert PS, Grewal J, Sciscione A, Grobman WA, et al. Association of maternal obesity with longitudinal ultrasonographic measures of fetal growth: findings from the NICHD Fetal growth studies-singletons. JAMA Pediatr. 2018;172:24–31.

    Article  PubMed  Google Scholar 

  48. Farrell T, Holmes R, Stone P. The effect of body mass index on three methods of fetal weight estimation. BJOG. 2002;109:651–7.

    Article  PubMed  Google Scholar 

  49. Sebire NJ, Jolly M, Harris J, Regan L, Robinson S. Is maternal underweight really a risk factor for adverse pregnancy outcome? A population-based study in London. BJOG. 2001;108:61–6.

    CAS  PubMed  Google Scholar 

  50. Siega-Riz AM, Adair LS, Hobel CJ. Maternal underweight status and inadequate rate of weight gain during the third trimester of pregnancy increases the risk of preterm delivery. J Nutr. 1996;126:146–53.

    Article  CAS  PubMed  Google Scholar 

  51. Mitchell MC, Lerner E. Weight gain and pregnancy outcome in underweight and normal weight women. J Am Diet Assoc. 1989;89:634–8.

    Article  CAS  PubMed  Google Scholar 

  52. Kramer MS, Coates AL, Michoud MC, Dagenais S, Hamilton EF, Papageorgiou A. Maternal anthropometry and idiopathic preterm labor. Obstet Gynecol. 1995;86:744–8.

    Article  CAS  PubMed  Google Scholar 

  53. Torloni MR, Betrán AP, Daher S, Widmer M, Dolan SM, Menon R, et al. Maternal BMI and preterm birth: a systematic review of the literature with meta-analysis. J Matern Fetal Neonatal Med. 2009;22:957–70.

    Article  PubMed  Google Scholar 

  54. McDonald SD, Han Z, Mulla S, Beyene J. Knowledge Synthesis G. Overweight and obesity in mothers and risk of preterm birth and low birth weight infants: systematic review and meta-analyses. BMJ. 2010;341:c3428.

    Article  PubMed  PubMed Central  Google Scholar 

  55. O’Brien TE, Ray JG, Chan WS. Maternal body mass index and the risk of preeclampsia: a systematic overview. Epidemiology. 2003;14:368–74.

    Article  PubMed  Google Scholar 

  56. Torloni MR, Betrán AP, Horta BL, Nakamura MU, Atallah AN, Moron AF, et al. Prepregnancy BMI and the risk of gestational diabetes: a systematic review of the literature with meta-analysis. Obes Rev. 2009;10:194–203.

    Article  CAS  PubMed  Google Scholar 

  57. Smith GC, Smith MF, McNay MB, Fleming JE. First-trimester growth and the risk of low birth weight. N Engl J Med. 1998;339:1817–22.

    Article  CAS  PubMed  Google Scholar 

  58. Jaddoe VW, de Jonge LL, Hofman A, Franco OH, Steegers EA, Gaillard R. First trimester fetal growth restriction and cardiovascular risk factors in school age children: population based cohort study. BMJ. 2014;348:g14.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Barker DJ. The fetal and infant origins of adult disease. BMJ. 1990;301:1111.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Van Dijk MR, Borggreven NV, Willemsen SP, Koning AHJ, Steegers-Theunissen RPM, Koster MPH. Maternal lifestyle impairs embryonic growth: the rotterdam periconception cohort. Reprod Sci. 2018;25:916–22.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank the Rotterdam Periconception Cohort team for data acquisition and the participating couples and gynecologists for their contributions. We also thank Dr. Anton Koning for his contributions by assisting in the acquisition and accessibility of VR data and Mitch Vleghert for his support in data analyses. This research was funded by the Erasmus MC Medical Research Advisor Committee’s ‘Health Care Efficiency Research’ program and the department of Obstetrics and Gynaecology of the Erasmus University Medical Center, Rotterdam, The Netherlands.

Author information

Authors and Affiliations

  1. Departments of Obstetrics and Gynecology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands

    Linette van Duijn, Melek Rousian & Régine P. M. Steegers-Theunissen

  2. Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands

    Joop S. E. Laven

Authors
  1. Linette van Duijn
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Melek Rousian
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Joop S. E. Laven
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Régine P. M. Steegers-Theunissen
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

JL and RST initiated the research question and supervised all aspects of the study. LvD and JL contributed to data acquisition. MR and RST initiated and supervised the statistical procedures of the manuscript. LvD and MR wrote the first draft. All authors contributed to the writing and the critical revisions of the manuscript and all authors approved the final version of the manuscript and authorized the submitted version.

Corresponding author

Correspondence to Régine P. M. Steegers-Theunissen.

Ethics declarations

Competing interests

JL reports grants and personal fees from Ferring and Titus Healthcare, grants and personal fees from Ansh Labs, grants from NIH, the Dutch Heart Association, and ZonMW, outside the submitted work. None of the other authors have a conflict of interest to disclose.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

van Duijn, L., Rousian, M., Laven, J.S.E. et al. Periconceptional maternal body mass index and the impact on post-implantation (sex-specific) embryonic growth and morphological development. Int J Obes 45, 2369–2376 (2021). https://doi.org/10.1038/s41366-021-00901-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41366-021-00901-7

This article is cited by

Search

Advanced search

Quick links