Skip to main content

No evidence for a diminished ovarian reserve among patients with hypertensive disorders of pregnancy: a case control study



Existing evidence suggests a relation between cardiovascular dysfunction and diminished ovarian reserve. While it is known that pre-existent cardiovascular dysfunction is also associated with the development of preeclampsia (PE) during pregnancy, we hypothesize that signs of diminished ovarian reserve may occur more frequently among women with a history of hypertensive disorders of pregnancy (HDP). The aim of our study was therefore to analyse if women with a history of HDP show signs of diminished ovarian reserve, represented by lower anti-Mullarian hormone (AMH) levels, compared to controls. For this retrospective observational case control study, patients included women with a history of HDP, whereas controls constituted of women with a history of an uncomplicated pregnancy. The study was conducted in a tertiary referral centre in which all women underwent a one-time cardiovascular and metabolic assessment. Ovarian reserve and markers of cardiovascular function were evaluated, adjusted for age and body mass index (BMI) using linear regression analyses.


163 patients and 81 controls were included over a time span of 3 years. No signs of diminished ovarian reserve i.e. lower AMH level were observed in the patient group versus controls. A subgroup analysis even showed higher AMH levels in late onset HDP as compared to controls (2.8 vs. 2.0 µg/L, p = 0.025). As expected, cardiovascular function markers were significantly less favourable in the patient group compared to controls; higher levels of systolic blood pressure (BP) (5%), diastolic BP (4%), triglycerides (29%), glucose (4%) and insulin levels (81%) (all p < 0.05), whereas high density lipid (HDL) cholesterol was 12% lower (NS).


Despite unfavourable cardiovascular risk profile, the present study does not substantiate the hypothesis that women with HDP show accelerated ovarian ageing as compared to healthy parous controls. Although HDP patients should be warned about their cardiovascular health, they shouldn’t be concerned about unfavourable ovarian reserve status.


Prior research showed that decreased ovarian reserve, represented by low oocyte yield during in-vitro fertilization (IVF) treatment or low Anti-Müllerian hormone (AMH), could be associated with an increased risk of developing preeclampsia (PE) during pregnancy [1]. PE, classically defined by hypertension and proteinuria after the 20th week of pregnancy, relates to foetal and maternal morbidity and mortality in 2–8% of all pregnancies [2, 3]. In line with these findings, Yarde et al. observed 10% lower AMH among women with a history of PE [4]. These findings may suggest an association between decreased ovarian reserve and PE, which may have consequences for future reproductive plans and preventive care. However, this association has not been confirmed to date.

Serum AMH levels show a consistent decline that correlates with the age dependent depletion of the primordial and antral follicle pool [5]. Furthermore, it was also shown that the decline of AMH levels is independently and inversely associated with the risk of cardiovascular disease (CVD) [6], even when adjusted for age. Therefore, it can be hypothesised that AMH reflects cardiovascular status in women of childbearing age. As such, women with low AMH levels during pregnancy show an increased risk of gestational hypertension and CVD markers [7, 8] as well as other hypertensive disorders of pregnancy (HDP), placental malperfusion lesions and miscarriage [9,10,11]. Decreased ovarian reserve is also associated with a lower rate of pregnancy and live birth [12]. Women with a history of PE are at risk for CVD, especially with ageing [13]. Interestingly, the prevalence of PE is highly associated with pre-existing attenuated cardiovascular function [14]. Based on this knowledge, we expect that women with a history of any HDP show a less favourable cardiovascular status.

The possible link between cardiovascular health and ovarian function can be studied from a different perspective as well. A genome-wide association study for age at natural menopause identified several common genetic variants that play a role in timing of ovarian aging [15]. Most of these loci appear to be involved in DNA damage response processes [16]. In line with this finding, it is suggested that ovarian ageing and early menopause may result from processes of general ageing, through DNA damage and genetic susceptibility [17].

We speculate that common denominators of cardiovascular health, such as, but not limited to, genetic variance and/or cardiovascular dysfunction may play a role in the predisposition for both HDP and ovarian reserve capacity. This can be further substantiated by the observation that the ovaries are highly vascularized organs, so impaired blood flow can induce oxidative stress and thereby increase follicular demise [4]. It is expected that different rates of ovarian follicle pool depletion can contribute to wide variation in fecundity among fertile women [18, 19]. Unravelling underlying mechanisms may increase our understanding of reproductive health and lifespan.

We hypothesize that there is a concomitant association between lower AMH levels—reflecting a diminished ovarian reserve—and a higher rate of cardiovascular dysfunction is observed in women with a history of HDP. The aim of this study is to evaluate cardiovascular function and ovarian reserve among women with a history of HDP and healthy controls.


Study population, baseline characteristics

163 patients and 81 controls were included. There was a small but significant difference in age between patients and controls (31.7 vs. 34.1 years, respectively, p < 0.001). We observed 6.9% higher body weight (p = 0.002) and 9.3% higher BMI (p < 0.001) among patients. Parity was significantly lower for patients (1 vs. 2, p < 0.001). As expected, duration of pregnancy was significantly shorter in patients (241 vs. 279 days, p < 0.001) and their children had lower birth weight (2105 vs. 3432 g, p < 0.001). Controls were significantly longer postpartum at time of investigation (191 vs. 74 weeks, p < 0.001). Baseline characteristics are summarized in Table 1.

Table 1 Baseline characteristics and obstetric history

Ovarian reserve and cardiovascular function

Ovarian reserve, represented by AMH, was 20% higher among patients compared to controls (2.4 vs. 2.0 µg/L). This difference remained significant after correction for age (p = 0.045). There was a significant inverse relation between age and AMH (B=–0.143, p = 0.002). No significant correlations between AMH and BMI or other cardiovascular function parameters were found. Cardiovascular function parameters showed less favourable results among patients; higher fasting glucose (4%, p = 0.016), insulin (81%, p < 0.001), systolic BP (5%, p = 0.001), diastolic BP (4%, p < 0.001), MAP (6%, p < 0.001) and triglycerides (29%, p = 0.002). Ovarian reserve and cardiovascular function are summarized in Table 2.

Table 2 Ovarian reserve and cardiovascular function, corrected for age and BMI

A correlation matrix of AMH and age, blood pressure and BMI is shown in Appendix 1, to show the associations between these measurements.

Subgroup analysis

For the subgroup analysis, patients were divided in early (< 34 weeks) and late (≥ 34 weeks) onset of HDP. In comparison to controls, significant differences in age, weight, BMI, gravidity, parity, birth weight, gestational age at delivery and time postpartum at measurement were observed in both subgroups. No difference in AMH was observed in the early onset group compared to controls. However, significant higher AMH levels were observed in the late onset group, compared to controls (2.8 vs. 2.0 µg/L, p = 0.025).

In the early onset group, significantly higher fasting glucose levels (4%, p = 0.014) than controls were observed. Both subgroups showed comparable differences with higher insulin (98% in early and 70% in late onset, respectively, p < 0.001), systolic BP (6% and 5%, p < 0.05), diastolic BP (4% and 3%, p < 0.01), MAP (6% and 5%, p = 0.004) and triglycerides (both 29%, p < 0.05) than controls.

The comparison between the subgroups shows significantly higher BMI and borderline lower triglycerides in the early onset group. Birth weight and gestational age at delivery were lower among early onset cases, as could be expected. Results of the subgroup analysis are summarized in Table 3.

Table 3 Subgroup analysis of early and late onset HDP, corrected for age and BMI


The present study shows no association between patients with a history of HDP and diminished ovarian reserve. Our findings are in line with a prospective observational study by Bhide et al. who also observed that ovarian reserve parameters were not diminished among women with a history of PE [20]. Another matched control study by van Disseldorp et al. found no significant difference in prevalence of gestational hypertension or PE comparing pregnancies of women with advanced ovarian ageing to pregnant women with normal IVF response [21].

In contrast to our findings, Yarde et al. did observe lower AMH levels in women with a history of PE compared to women with a previous uncomplicated pregnancy [4]. This outcome may be attributed to the fact that AMH levels in that study were measured approximately 10 years after the complicated pregnancy, in contrast to a mean follow up time of 2 years in our study. The mean age of our study population (31.7 ± 4.1 vs. 34.1 ± 4.7) is lower than the study population of Yarde et al. (38.8 ± 4.9 vs. 39.3 ± 4.3). Variable age related decline of AMH during reproductive life span might account for different findings between the studies, even though we did not find a difference in age related decline within our patient population.

Similarly, a retrospective cohort study analysing obstetric outcomes in IVF pregnancies in patients with diminished ovarian reserve observed a higher incidence of PE and placental foetal vascular lesions when compared to controls [22], underlining the conflicting evidence concerning this subject. A possible explanation might be the difference in study design, as Herman et al. specifically observe patients with diminished ovarian reserve according to a cut-off point, in contrast to our study which analyses AMH levels in HDP patients and controls as a continuous outcome measure.

In our study, ovarian reserve was not diminished in HDP patients compared to controls, also after correction for age and BMI. Subgroup analysis showed that specifically late onset HDP was associated with significantly higher AMH levels. This finding emphasizes the possibility that early and late onset HDP have a different aetiology. I.e. early onset HDP patients show higher BMI and might have more cardiovascular damage. One can speculate that late onset HDP patients might be more represented by anovulatory subfertility that is often accompanied by higher AMH levels [23]. While the prevalence of PCOS, time to pregnancy or use of fertility medication is not known in our study it is important to stress that the study was not conducted in a subfertile population.

As expected, there was clear evidence for attenuated cardiovascular function among former HDP patients i.e., higher systolic and diastolic BP, MAP, BMI, triglycerides, glucose and insulin levels and lower HDL cholesterol, indicative for a more atherogenic profile. However, since HDP is known to induce long-term cardiovascular dysfunction, the follow-up time between pregnancy and analysis might influence the cardiovascular parameters as well, especially because lifestyle and environmental factors can be adjusted throughout the years. It is known that higher maternal age increases chance of HDP, however this is only a small attribution and since age is adjusted for, we do not expect this to influence our results.

Strengths of the present study are that all measurements were performed by trained staff with the use of standardized questionnaires and protocols to provide high precision data. Furthermore, all AMH serum samples were analysed in the same ISO accredited laboratory, as were all other laboratory measurements. Limitations include a relatively small patient population, especially in the control group. However, post hoc sample size calculation shows it to be sufficient to detect a 2-years increase of ovarian ageing in patients with a power of 80% and an α of 5%. Next to the limitations stated above, it should be noted that extrapolation of the conclusions of this observational case control study to all subjects of the general population should be done with care.


In conclusion, the present study shows that a history of HDP is not associated with diminished ovarian reserve, as quantified by lower AMH concentration. Our results do substantiate the close relationship between cardiovascular risk factors and HDP.


Study design

For this retrospective observational case control study with the aim to evaluate cardiovascular function and ovarian reserve among women with a history of HDP and healthy controls, patients aged 18 to 41 years old were recruited at the tertiary outpatient clinic at the Maastricht University Medical Centre+ (MUMC+). They were at least six months postpartum which allows hormonal markers to normalize. All patients had a history of HDP (gestational hypertension or PE), diagnosed according to the criteria specified in 2018 by the International Society for the Study of Hypertension in Pregnancy (ISSHP) [24]. Gestational hypertension is defined as new onset hypertension after 20 weeks of gestation in the absence of proteinuria and without biochemical or haematological abnormalities, with a systolic blood pressure (BP) ≥ 140 mmHg and/or diastolic BP ≥ 90 mmHg. PE is defined as gestational hypertension with proteinuria and/or evidence of maternal acute kidney injury (AKI), liver dysfunction, neurological features, haemolysis or thrombocytopenia, or foetal growth restriction. The control group consisted of healthy women aged 18 to 41 years with a history of an uncomplicated, naturally conceived pregnancy. Controls were recruited through local advertisements and internet. Exclusion criteria for both groups were current pregnancy, breastfeeding, hormonal medication and ovarian surgery.

A post hoc power analysis was conducted using the OpenEpi statistics program. Based the included number of patients and controls, the mean AMH levels and standard deviations in our data and using α of 5%, the actual power is approximated to be 91,14%.


All women underwent cardiovascular and metabolic assessment. Physical examination was performed by a trained research physician, and included measurement of height (meters), body weight (kilograms) and BP (systolic, diastolic and mean arterial pressure (MAP); mmHg). The latter was measured in sitting position after 10 min of rest, every 3 min for a time period of 30 min. The median of eleven consecutive measurements was taken as representative. Body mass index (BMI) was calculated by weight/height2 (kg/m2).

Fasting blood samples were collected for measurement of AMH, lipid profile, insulin and glucose levels. AMH levels were analysed at the clinical chemical laboratory of the Erasmus MC, Rotterdam, the Netherlands. All samples were stored at -20˚C until assayed. AMH levels were determined by ELISA (GenII Beckman Coulter, Inc., Webster, Texas). For analysis, serum AMH levels below 0.1 µg/L were valued at 0.0. Other measurements were analysed at the central diagnostic laboratory of the MUMC+. Serum total cholesterol, high density lipoprotein (HDL) cholesterol, triglycerides and glucose were analysed using an enzymatic colorimetric assay (Cobas 8000 instrument, Roche Diagnostics, Mannheim, Germany). Serum insulin was determined using a chemiluminescent immunometric assay (XPi instrument, Siemens Medical Solutions Diagnostics, LA).

Statistical analysis

Data were checked for a normal distribution with Shapiro-Wilk test. Baseline characteristics were summarized as mean and standard deviations and compared using Student t-test. Gravidity and parity were compared using chi-square test. Ovarian reserve and cardiovascular function were summarized as median and interquartile range (IQR). All data were corrected for age and BMI and compared with linear regression analysis. Correlation coefficients between ovarian reserve and cardiovascular function parameters were computed with Spearman’s rho test. Data in the subgroup analysis with early onset (< 34 weeks gestational age) and late onset (≥ 34 weeks gestational age) cases were summarized as median and IQR. Correction for age and BMI was again performed with linear regression analysis. A two-tailed p-value ≤ 0.05 was considered as significant. Statistical analyses were performed using the statistical software SPSS (version 25).

Availability of data and materials

The datasets used and analysed during the current study are available from the corresponding author on reasonable request.



Acute kidney injury


Anti-Mullarian hormone


Body mass index


Blood pressure


Confidence interval


Cardiovascular disease


High density lipoprotein


Hypertensive disorders of pregnancy


Interquartile range


International Society for the Study of Hypertension in Pregnancy


In-vitro fertilization


Mean arterial pressure


Polycystic ovary syndrome




  1. Woldringh GH, Frunt MH, Kremer JA, Spaanderman ME. Decreased ovarian reserve relates to pre-eclampsia in IVF/ICSI pregnancies. Hum Reprod. 2006;21(11):2948–54.

    Article  PubMed  CAS  Google Scholar 

  2. Sibai B, Dekker G, Kupferminc M. Pre-eclampsia. Lancet. 2005;365(9461):785–99.

    Article  PubMed  Google Scholar 

  3. Steegers EA, von Dadelszen P, Duvekot JJ, Pijnenborg R. Pre-eclampsia. Lancet. 2010;376(9741):631–44.

    Article  PubMed  Google Scholar 

  4. Yarde F, Maas AH, Franx A, Eijkemans MJ, Drost JT, van Rijn BB, et al. Serum AMH levels in women with a history of preeclampsia suggest a role for vascular factors in ovarian aging. J Clin Endocrinol Metab. 2014;99(2):579–86.

    Article  PubMed  CAS  Google Scholar 

  5. Yarde F, Voorhuis M, Dólleman M, Knauff EA, Eijkemans MJ, Broekmans FJ. Antimüllerian hormone as predictor of reproductive outcome in subfertile women with elevated basal follicle-stimulating hormone levels: a follow-up study. Fertil Steril. 2013;100(3):831–8.

    Article  PubMed  CAS  Google Scholar 

  6. de Kat AC, Verschuren WM, Eijkemans MJ, Broekmans FJ, van der Schouw YT. Anti-Müllerian hormone trajectories are Associated with Cardiovascular Disease in women: results from the Doetinchem Cohort Study. Circulation. 2017;135(6):556–65.

    Article  PubMed  Google Scholar 

  7. Shand AW, Whitton K, Pasfield A, Nassar N, McShane M, Han X, et al. Evaluation of anti-mullerian hormone in the first trimester as a predictor for hypertensive disorders of pregnancy and other adverse pregnancy outcomes. Aust N Z J Obstet Gynaecol. 2014;54(3):244–9.

    Article  PubMed  Google Scholar 

  8. Verit FF, Akyol H, Sakar MN. Low antimullerian hormone levels may be associated with cardiovascular risk markers in women with diminished ovarian reserve. Gynecol Endocrinol. 2016;32(4):302–5.

    Article  PubMed  CAS  Google Scholar 

  9. Han S, Zhai Y, Guo Q, Qin Y, Liu P. Maternal and neonatal Complications in patients with diminished Ovarian Reserve in In-Vitro Fertilization/Intracytoplasmic sperm injection cycles. Front Endocrinol. 2021;12:648287.

    Article  Google Scholar 

  10. Ganer Herman H, Volodarsky-Perel A, Ton Nu TN, et al. Diminished ovarian reserve is a risk factor for preeclampsia and placental malperfusion lesions. Fertil Steril. 2023;119(5):794–801.

    Article  PubMed  Google Scholar 

  11. Busnelli A, Somigliana E, Cirillo F, Levi-Setti PE. Is diminished ovarian reserve a risk factor for miscarriage? Results of a systematic review and meta-analysis. Hum Reprod Update. 2021;27(6):973–88.

    Article  PubMed  Google Scholar 

  12. Hu S, Xu B, Jin L. Perinatal outcome in young patients with diminished ovarian reserve undergoing assisted reproductive technology. Fertil Steril. 2020;114(1):118–124e1.

    Article  PubMed  Google Scholar 

  13. van Rijn BB, Nijdam ME, Bruinse HW, Roest M, Uiterwaal CS, Grobbee DE, et al. Cardiovascular Disease risk factors in women with a history of early-onset preeclampsia. Obstet Gynecol. 2013;121(5):1040–8.

    Article  PubMed  Google Scholar 

  14. Bernstein IM, Shapiro RE, Whitsel A, Schonberg AL. Relationship of plasma volume to sympathetic tone in nulliparous women. Am J Obstet Gynecol. 2003;188(4):938–42.

    Article  PubMed  Google Scholar 

  15. Stolk L, Zhai G, van Meurs JBJ, Verbiest MMPJ, Visser JA, Estrada K, et al. Loci at chromosomes 13, 19 and 20 influence age at natural menopause. Nat Genet. 2009;41(6):645–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Ruth KS, Day FR, Hussain J, Martínez-Marchal A, Aiken CE, Azad A, et al. Genetic insights into biological mechanisms governing human ovarian ageing. Nature. 2021;596(7872):393–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Laven JSE. Early menopause results from instead of causes premature general ageing. Reprod Biomed Online. 2022;45(3):421–4.

    Article  PubMed  CAS  Google Scholar 

  18. Collins JA, Crosignani PG. Unexplained infertility: a review of diagnosis, prognosis, treatment efficacy and management. Int J Gynaecol Obstet. 1992;39(4):267–75.

    Article  PubMed  CAS  Google Scholar 

  19. Evers JL. Female subfertility. Lancet. 2002;360(9327):151–9.

    Article  PubMed  Google Scholar 

  20. Bhide P, Vårtun Å, Aune B, Flo K, Basnet P, Acharya G. Ovarian reserve in women with a previous history of severe pre-eclampsia. Arch Gynecol Obstet. 2017;295(1):233–8.

    Article  PubMed  Google Scholar 

  21. van Disseldorp J, Eijkemans R, Fauser B, Broekmans F. Hypertensive pregnancy Complications in poor and normal responders after in vitro fertilization. Fertil Steril. 2010;93(2):652–7.

    Article  PubMed  Google Scholar 

  22. Ganer Herman H, Volodarsky-Perel A, Ton Nu TN, Machado-Gedeon A, Cui Y, Shaul J, et al. Diminished ovarian reserve is a risk factor for preeclampsia and placental malperfusion lesions. Fertil Steril. 2023;119(5):794–801.

    Article  PubMed  Google Scholar 

  23. Iliodromiti S, Kelsey TW, Anderson RA, Nelson SM. Can Anti-Müllerian hormone predict the diagnosis of polycystic ovary syndrome? A systematic review and Meta-analysis of extracted data. J Clin Endocrinol Metabolism. 2013;98(8):3332–40.

    Article  CAS  Google Scholar 

  24. Brown MA, Magee LA, Kenny LC, Karumanchi SA, McCarthy FP, Saito S, et al. Hypertensive Disorders of Pregnancy Hypertension. 2018;72(1):24–43.

    CAS  Google Scholar 

Download references


Not applicable.


There was no additional funding performing this study.

Author information

Authors and Affiliations



All authors fulfil the criteria for authorship; B.B. and O.V. wrote and edited the manuscript. D.P., M.S. and R.G. initiated the study. B.B., L.J. and D.P. collected the data. B.B. analysed the data. B.B., O.V., M.S. and R.G. interpreted the data. All authors commented on the draft, and have seen and approved the final version.

Corresponding author

Correspondence to Bo E. van Bree.

Ethics declarations

Ethical approval and consent to participate

All participants gave written informed consent, approval was obtained from the ethical committee of MUMC+ (MEC 13-2-001.10/pl).

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s Note

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

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary Material 1

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

van Bree, B.E., Jorissen, L.M., Pattinaja, D.A. et al. No evidence for a diminished ovarian reserve among patients with hypertensive disorders of pregnancy: a case control study. J Ovarian Res 17, 5 (2024).

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: