FACTS Mental Health Awareness Series
Association of PCOS with Psychiatric and Neurodevelopmental Disorders in Offspring
By Leah Beth VanBlaricum
Editor’s note: Given May is Mental Health Awareness month, we are continuing to feature summaries of research related to the various ways fertility and infertility intersect with psychiatric, mental and emotional wellbeing — in this instance the intergenerational health of children born to mothers with polycystic ovary syndrome (PCOS). Leah Beth VanBlaricum, a recent medical school graduate and former FACTS electiive student, summarized an article, Association of polycystic ovary syndrome or anovulatory infertility with offspring psychiatric and mild neurodevelopmental disorders: a Finnish population-based cohort study, published in Human Reproduction in 2020.
Join us at our FACTS 2022 Virtual Conference THIS Saturday, May 21st for a presentation by Dr. Joe Stanford to learn more about intergenerational health and the importance of taking care of women long before they get pregnant to improve the health outcomes of their children. Tomorrow, Tuesday, the 17th, is the LAST DAY to register to ensure you receive access to this Saturday’s session in real time!
Polycystic ovarian syndrome (PCOS) is a condition characterized by excess androgens, anovulatory cycles, and insulin resistance. Excessive androgen exposure in utero due to PCOS has been associated with the future development of neurodevelopmental or psychiatric disorders. In a study published in 2020 in Human Reproduction, Chen et al examined the association between maternal PCOS and development of neurodevelopmental or psychiatric disorders in offspring . Pregnancy complications associated with PCOS, such as obesity, preterm birth, gestational diabetes, and small for gestational age (SGA), were also studied to assess their potential impact on the development of psychiatric or neurodevelopmental disorders in children born to mothers with PCOS.
The study population, along with information on maternal conditions, was derived from live births in Finland from 1996 to 2014 recorded in the Drugs and Pregnancy Database and Medical Birth Register. Maternal diagnoses of PCOS or anovulatory infertility and offspring neurodevelopmental and psychiatric disorder diagnoses were derived from International Classification of Diseases (ICD) codes on the Finnish Care Register for Health Care. Researchers analyzed a total of 1,097,753 births from 590,939 mothers. The offspring were followed until December 31, 2018, with some up to 22 years old. PCOS and anovulatory infertility were considered one diagnosis, as the results with the two as separate conditions yielded similar results. The combined impacts of PCOS plus additional risk factors — including maternal BMI, gestational diabetes, cesarean delivery, preterm birth, SGA, and fertility treatments — were also analyzed for contribution to neurodevelopmental and psychiatric disorder development in offspring. During analysis, data were adjusted for maternal demographic factors, psychiatric disorders, parity, smoking, psychotropic prescriptions, and systemic inflammatory diseases.
Children born to those with PCOS had an increased risk of being diagnosed with every neuropsychiatric disorder that was tested (Hazard ratio – HR – 1.32; 95% CI 1.27 – 1.38). Researchers found that when maternal PCOS was present, there was a 30 to 50 percent increased risk of the offspring developing mood disorders, anxiety disorders, eating disorders, sleep disorders, personality disorders, intellectual disabilities, specific developmental disorders, autism spectrum disorder, attention-deficit/hyperactivity disorders, conduct disorders, tic disorders, and other behavioral and emotional disturbances. This was true for women with PCOS who had normal BMI (HR 1.92; 95% CI 1.65–2.23). But women with PCOS who were moderately or severely obese had offspring who demonstrated an increasingly greater risk of neurodevelopmental or psychiatric disorder development (HR 2.11; 95% CI 1.76–2.53).
“When maternal PCOS was present, there was a 30 to 50 percent increased risk of the offspring developing mood disorders, anxiety disorders, eating disorders, sleep disorders and a wide range of other neuropsychiatric disorders.”
Additionally, children born to women with PCOS demonstrated an increased risk of neurodevelopmental or psychiatric disorders when perinatal problems were present, such as SGA or preterm birth. The hazard ratio (HR) increased from 1.28; CI 1.22–1.34 in absence of perinatal problems to 1.99; 1.84–2.16. Offspring of women with both PCOS and gestational diabetes also had a higher risk than offspring born to mothers with gestational diabetes only (HR 1.70; 95% CI 1.53–1.88 compared to HR 1.30; 95% CI 1.25–1.36). A similar pattern was observed when considering those who had a cesarean delivery (HR 1.29; 95% CI 1.23– 1.35 compared to HR 1.71; 95% CI 1.58–1.84).
Finally, fertility treatments in conjunction with PCOS did not appear to increase the risk of neurodevelopmental or psychiatric disorders in offspring.
PCOS is the most common endocrine disorder in reproductive aged women. Diagnosing this disease and recognizing the association between maternal PCOS and the onset of neurodevelopmental or psychiatric disorders in their children provides women greater autonomy over their reproductive health and that of their offspring. PCOS affects 6 to 12% of women , but for many, the diagnosis and treatment are often delayed . Up to 70% of women with PCOS remain undiagnosed, according to some estimates [,]. The use of fertility awareness-based methods (FABMs) to systematically track cycle patterns could help more women recognize the symptoms of PCOS sooner and provide earlier access to treatment, maximizing their health prior to conception. Women with PCOS would then be able to take additional proactive measures to monitor their children for any neurodevelopmental or psychiatric disorders.
“The use of fertility awareness-based methods (FABMs) to systematically track cycle patterns could help more women recognize the symptoms of PCOS sooner and provide earlier access to treatment, maximizing their health prior to conception.”
Given that weight is also positively correlated with increased risk, women with PCOS and an elevated BMI can implement weight management strategies prior to conception to minimize the likelihood of their children developing neurodevelopmental or psychiatric disorders. Incorporating a healthy diet and regular exercise and abstaining from smoking, drug use, and excessive caffeine consumption are also beneficial as they can protect against pregnancy complications like preterm birth, gestational diabetes, and SGA, which conflates the risk.
The strengths of this study include its inclusion of a large population size and consequently the generalizability of its findings. However, this study did have several limitations. First, the observed incidence of PCOS was lower than the general population, which could indicate that the results from this study analyze only the most severe cases of PCOS. This might create a false sense of increased risk if PCOS severity and the risk of neurodevelopmental or psychiatric disorders in offspring are positively correlated. Secondly, this study only utilized inpatient diagnoses even as it included adjustment for maternal psychiatric disorders. Additionally, familial factors and paternal psychiatric comorbidities were not considered. Given the heritability of some neurodevelopmental and psychiatric disorders , failure to investigate all maternal and paternal psychiatric comorbidities could inflate the effects of PCOS on the offsprings’ development of these disorders.
Furthermore, only births recorded from 1996 to 2014 were included in offspring analysis — with analysis ending in 2018. Not all of the subjects reached the maximum age of 22, limiting a full cohort analysis. Lastly, the study does not comment on the severity of these disorders in the offspring. Considering mood and anxiety disorders are typically grouped broadly, the affected children could experience a wide range of psychiatric symptoms — a range that is not considered in the study’s results. The urgency for determining a mechanism of PCOS and neurodevelopmental and psychiatric disorders is contingent upon how severe and/or manageable these conditions may be.
Further research is needed to determine the mechanism responsible for the association between maternal PCOS and the development of these disorders in their children. While some studies have demonstrated that female offspring born to mothers with PCOS are at greater risk for neurodevelopmental and psychiatric disorders because of increased exposure to opposite hormones, the stratification of offspring in this study based on sex showed similar development between the male and female offspring [,]. Elicitation of the mechanism will also shed light on whether management of PCOS symptoms can reduce the risk in children. If understood more, women would have additional opportunities to reach their reproductive goals.
 Chen X, Kong L, Piltonen TT, Gissler M, Lavebratt C. Association of polycystic ovary syndrome or anovulatory infertility with offspring psychiatric and mild neurodevelopmental disorders: a Finnish population-based cohort study. Hum Reprod. 2020;35(10):2336-2347. doi:10.1093/humrep/deaa192
 Accessed 5-15-22. https://www.cdc.gov/diabetes/basics/pcos.html#:~:text=PCOS%20is%20one%20of%20the,beyond%20the%20child%2Dbearing%20years.
 Gibson-Helm M, Teede H, Dunaif A, Dokras A. Delayed Diagnosis and a Lack of Information Associated With Dissatisfaction in Women With Polycystic Ovary Syndrome. J Clin Endocrinol Metab. 2017;102(2):604-612. doi:10.1210/jc.2016-2963
 Tomlinson, J. A., Pinkney, J. H., Evans, P., Millward, A., & Stenhouse, E. (2013). Screening for diabetes and cardiometabolic disease in women with polycystic ovary syndrome. The British Journal of Diabetes & Vascular Disease, 13(3), 115–123. doi:10.1177/1474651413495571
 March WA, Moore VM, Willson KJ, Phillips DI, Norman RJ, Davies MJ. The prevalence of polycystic ovary syndrome in a community sample assessed under contrasting diagnostic criteria. Hum Reprod. 2010 Feb;25(2):544-51. doi: 10.1093/humrep/dep399. Epub 2009 Nov 12. PMID: 19910321
 Bray, N. J., & O’Donovan, M. C. (2019). The genetics of neuropsychiatric disorders. Brain and neuroscience advances, 2, 2398212818799271. https://doi.org/10.1177/2398212818799271.
 Palomba S, Marotta R, Di Cello A, Russo T, Falbo A, Orio F, Tolino A, Zullo F, Esposito R, La Sala GB. Pervasive developmental disorders in children of hyperandrogenic women with polycystic ovary syndrome: a longitudinal case-control study. Clin Endocrinol (Oxf) 2012;77:898–904.
 Cesta CE, Oberg AS, Ibrahimson A, Yusuf I, Larsson H, Almqvist C, D’Onofrio BM, Bulik CM, Fernandez de la Cruz L, Mataix-Cols D et al. Maternal polycystic ovary syndrome and risk of neuropsychiatric disorders in offspring: prenatal androgen exposure or genetic confounding? Psychol Med 2019;50:1–9.
ABOUT THE AUTHOR
Leah Beth VanBlaricum
Leah Beth VanBlaricum will begin her psychiatry residency at Indiana University-Vincennes in the summer of 2022. Her interests include rural medicine and women’s mental health. She keeps busy caring for her 4-month old son and helping her husband and extended family on the farm.