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Hum. Reprod. Advance Access originally published online on September 2, 2006
Human Reproduction 2006 21(11):2948-2954; doi:10.1093/humrep/del155
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© The Author 2006. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Decreased ovarian reserve relates to pre-eclampsia in IVF/ICSI pregnancies

G.H. Woldringh1, M.H.A. Frunt, J.A.M. Kremer and M.E.A. Spaanderman

Department of Obstetrics and Gynaecology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

1 To whom correspondence should be addressed at: Huispost 791, Postbus 9101, Nijmegen 6500HB, The Netherlands. E-mail: g.woldringh{at}obgyn.umcn.nl


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgement
 References
 
BACKGROUND: Pre-eclampsia affects 2–10% of all pregnancies and is a major cause of maternal and fetal morbidity and mortality. As compared with the general population, IVF pregnancies are associated with a 2.7-fold risk of pre-eclampsia. An advanced age and associated subfertility in the IVF group reflects a general decrease in ovarian reserve, which itself has been linked to cardiovascular disease. We tested the hypothesis that decreased ovarian reserve is associated with pre-eclampsia as a vascular complication in IVF/ICSI pregnancies. METHODS: In this retrospective case–control study, 41 cases with a history of pre-eclampsia were compared to 82 matched controls without hypertension or (pre)eclampsia. All pregnancies were established after IVF or ICSI. Several indicators of ovarian reserve such as variables related to basal ovarian function and response to hyperstimulation were compared in both the groups by multivariate analysis. The condition of the neonates was evaluated as well. RESULTS: A higher amount of total administered FSH and FSH per day, together with a lower number of obtained oocytes during IVF treatment, were associated with an increased risk to pre-eclampsia in a subsequent pregnancy. The administered FSH per follicle and per obtained oocyte showed even stronger relationships, the latter having the best predictive value. Neonatal outcome was comparable between the groups. CONCLUSION: Diminished responsiveness of the ovaries to FSH stimulation in an IVF cycle, reflecting decreased ovarian reserve, is associated with an increased risk of developing pre-eclampsia in a subsequent pregnancy.

Key words: FSH/ICSI/IVF/ovarian reserve/pre-eclampsia


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 Acknowledgement
 References
 
Pre-eclampsia is a major cause of maternal and fetal morbidity and mortality worldwide. The severity of the disease ranges from a mild disorder with transient hypertension and proteinuria in the later part of pregnancy to a life-threatening disease with seizures and severe fetal distress (Sibai et al., 2005Go). Overall, pre-eclampsia affects 2–10% of all pregnancies and accounts for as much as 15–20% of maternal mortality in developed countries (Anonymous, 2000Go). Identifying pregnancies at risk for pre-eclampsia is of great value, because close monitoring is helpful in preventing some adverse events (Farag et al., 2004Go). Numerous studies have tried to identify risk factors or have searched for screening tests to diagnose the disease at an early preclinical stage (Duckitt and Harrington, 2005Go). However, to date, this pursuit has not resulted in any suitable test for routine use in clinical practice (Conde-Agudelo et al., 2004Go).

As compared with the general population, IVF pregnancies are associated with a 2.7-fold risk of pre-eclampsia (Shevell et al., 2005Go) and a two-fold increased incidence of small for gestational age (Koudstaal et al., 2000Go). Several reasons have been brought up to explain this phenomenon, such as multiple gestation and advanced age at first ongoing pregnancy (Tanbo et al., 1995Go). However, these cannot fully clarify the observed association. The advanced age and associated subfertility in this group also reflect a general decrease in ovarian reserve, which itself has been linked with cardiovascular risk as well (Chu et al., 2003Go; Kalantaridou et al., 2004Go). Consequently, indicators of decreased ovarian reserve, such as elevated basal FSH levels or a diminished response to stimulation by exogenous FSH (Nikolaou et al., 2002Go), may point out those women at risk for development of vascular complications in their subsequent pregnancies.

In this study, we hypothesize that decreased ovarian reserve in women is associated with pre-eclampsia as a vascular complication in pregnancy. To this end, we conducted a retrospective case–control study amongst IVF and ICSI pregnancies. Cases that developed pre-eclampsia were compared to matched controls without hypertension or (pre)eclampsia in pregnancy. Ovarian reserve was assessed by basal levels of FSH and estradiol (E2) and by the response to hyperstimulation with exogenous FSH during IVF/ICSI treatment. These characteristics and subsequent pregnancy outcome variables were compared between the study groups.


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 Acknowledgement
 References
 
Patients
In this retrospective case–control study, data were obtained from two databases: (i) objective information on fertility treatment and pregnancy outcome and (ii) self-reported data on demographic features and pregnancy complications based on an earlier performed questionnaire study. Verification of reported complications during pregnancy and examination of other data were performed by studying the individual medical record.

A total of 1130 women who were successfully treated by IVF or ICSI in the Radboud University Nijmegen Medical Centre between October 1994 and April 2004 were enrolled in this study. Pregnancies established after transfer of frozen embryos and pregnancies that did not result in a live birth were not included. Of these 1130 eligible women, 201 were excluded because of insufficient data in the database of the questionnaire study (Figure 1). Of the remaining 929, 41 (4.4%) women reported pre-eclampsia during pregnancy, which was confirmed by checking the individual medical records. These women served as cases. For each case, two control women were selected out of a group of 526 women without any reported vascular complication in pregnancy (Figure 1). These 82 controls were matched according to the type of fertility treatment and several characteristics known to influence the risk of pre-eclampsia in pregnancy (Duckitt and Harrington, 2005Go): the number of fetuses, parity, maternal age at the time of delivery, pre-pregnant BMI (kg/m2), race and smoking. Smoking was evaluated as three subgroups, referred to ‘no smoking’, ‘smoking but not during pregnancy’ and ‘smoking also during pregnancy’. In case of more patients matching with the same treatment, the number of fetuses, parity and smoking group, the four patients with the best match for age at the time of delivery were checked for the two best matches for BMI. Because the indication for assisted reproduction treatment (ART) and the duration of subfertility might also have an effect on the development of pre-eclampsia (Pandian et al., 2001Go), we studied these variables as well, the latter being defined as the time evolved between the reported date of child wish and the date of ovum pick up minus 14 days.


Figure 1
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  		Figure 1. Determination of case and control groups.

 
IVF and ICSI treatment
Baseline FSH (IU/l) and baseline E2 (pmol/l) were measured on day 3 (±1) of a menstrual cycle before fertility treatment.

All IVF and ICSI cycles were performed according to a standardized ovarian stimulation protocol with pituitary down-regulation with a GnRH-agonist (leuproreline or triptoreline) followed by daily injections with urinary HMG or recombinant FSH (rFSH). At the moment of down-regulation, checked by ultrasound, daily injections with 150 units of FSH were started. Women older than 38 years, those who had a baseline FSH above 10 IU/l or had a poor response (less than four follicles with a diameter >15 mm) in a treatment cycle before, started with a higher daily dose up to 300 units of FSH. Women known to have polycystic ovary syndrome (PCOS), or with overstimulation in a previous cycle, started with a lower dose of FSH. The total amount of administered FSH was defined as the product of the dose of administered FSH per day and the total number of days of administration. An injection of 10 000 units of hCG was given 36 h before oocyte retrieval. The luteal phase was supported by injections of hCG or vaginally administered progesterone. The maximal achieved E2 concentration represented the highest level of E2 measured during FSH stimulation in the cycle leading to conception and was determined by measuring the serum E2 concentration on the day of hCG-injection, 2 days before oocyte retrieval. Maximal endometrial thickness (mm) was the greatest thickness of the triple-layer intracavitary-lined endometrium reached during stimulation. The number of follicles with a diameter >9 mm was determined on the day of hCG injection. The fertility laboratory determined the number of obtained oocytes and the number of embryos usable for transfer. An embryo usable for transfer was defined as an embryo with two pronuclei on day 1 and which had reached the 2- to 8-cell stage on day 3.

From these data, the administered FSH units per follicle and per obtained oocyte were calculated, defined as the total amount of administered FSH divided by the number of follicles and the number of obtained oocytes, respectively. The number of the treatment cycles in which the women conceived was examined as well.

Pregnancy course and outcome
Pre-eclampsia was defined according to the criteria of the Report of the National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy (2000), which included gestational hypertension (repeated blood pressure measurements of >140 mm Hg systolic or >90 mm Hg diastolic) and proteinuria (urine protein creatinine ratio of ≥0.3 g/10 mmol or dipstick test ≥1+ for protein) after 20 weeks of gestation. Gestational age at delivery was defined as the difference between the date of oocyte retrieval and the date of delivery with 14 days added. Birthweight was measured, and for determination of the birthweight centile, we used the Dutch national reference curve, which adjusts for parity, gestation and sex of the infant (Kloosterman, 1970Go). Apgar score and sex of the children were evaluated as well.

Statistics
Statistical analysis was carried out using the Statistics Package for Social Sciences (SPSS) 12.0.1 for Windows. Variables, detailed as median and range or as percentage, were evaluated non-parametrically by using Mann–Whitney U-test and Fisher’s exact test, where appropriate. We considered a difference statistically significant when P < 0.05. If applicable, correlations were evaluated by Spearman’s Rho correlation analysis. To identify actual independent factors, we performed a multivariate backward stepwise logistic regression analysis that included as covariates those variables that were found to be correlated with the study variables. Receiver operation characteristic (ROC) curves were constructed from the possible predictors to explore their predictive values. We calculated the Mantel–Haenszel common odds ratios and 95% CI at the threshold points that yielded to a reasonable value in sensitivity and specificity.


   Results
Top
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 Acknowledgement
 References
 
The demographic characteristics of the women with pre-eclampsia and the control group are summarized in Table I. Both the subgroups were comparable with respect to duration of subfertility, indication for IVF or ICSI and all matching criteria, such as maternal age at delivery, pre-pregnant BMI, maternal smoking status, parity, number of fetuses and type of fertility treatment. There were no pregnancies with more than two fetuses in the study population, and in case of multiparity, it was always a pregnancy of the second child of the woman. All women were Caucasians. In the both groups, the median treatment number of the conception cycle was 2 [range: 1–6].


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  		Table I. Demographic characteristics of the study groups

 
Leuproreline versus triptoreline, urinary HMG versus rFSH and the used medication during the luteal phase were comparable between the group of women with pre-eclampsia and the control group.

Data of the baseline, stimulation and response variables are summarized in Table II. There was no difference in baseline FSH and E2 levels between the two groups. As compared with the controls, more pre-eclamptic women received an increased daily dose of FSH (Figure 2), although the median in both the groups was the same. There were 19 (47.5%) women in the pre-eclamptic group, who received >150 units of FSH daily as compared with 22 (26.8%) women in the control group (P = 0.027). The first group also received a higher total dose of FSH. A lower number of oocytes was obtained in this group. After assessment of a multivariate backward stepwise logistic regression analysis on the baseline, stimulation and response variables, two independent variables—the total dose of administered FSH and the number of obtained oocytes—remained. Consequently, the calculated administered FSH per obtained oocyte was higher in the pre-eclamptic group as compared with the controls. Considering the effect of age on the incidence of pre-eclampsia, as well as an observed correlation between age and dose of administered FSH, we performed a multivariate analysis including maternal age as covariate as well. Moreover, another multivariate analysis was carried out to examine the possible influence of the used FSH and GnRH-agonists and the medication for luteal support. The results showed that maternal age, as well as the medication used in cycle control and for support in the luteal phase, had not influenced the results (data not shown).


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  		Table II. Baseline, stimulation and response variables of the study groups

 

Figure 2
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  		Figure 2. Box plot of administered FSH in dose per day.

 
With respect to responsiveness, there were no differences in the maximally reached E2 levels, endometrial thickness, number of follicles with a diameter >9 mm and usable embryos. Yet, in line with our findings in FSH per obtained oocyte, the FSH administered per follicle was also higher in the pre-eclamptic subgroup as compared with controls.

The results of the univariate analysis of predictive variables at given threshold points as assessed after ROC construction are summarized in Table III. At these threshold points, the administered FSH per obtained oocyte had the best, yet the modest, predictive power. The ROC curve of this variable is shown in Figure 3.


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  		Table III. Univariate analysis of variables associated with the occurrence of pre-eclampsia

 

Figure 3
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  		Figure 3. Receiver operation characteristic (ROC) curve of administered FSH per obtained oocyte related to the development of pre-eclampsia.

 
The pregnancy outcomes of the study groups are summarized in Table IV. For singleton as well as for twin pregnancies, the gestational age at delivery and birthweight of all children were lower in the pre-eclamptic subgroup. Between the two subgroups, there were no differences in observed sex, birthweight centile and umbilical arterial pH at birth and Apgar score after 5 min.


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  		Table IV. Pregnancy outcomes of the study groups

 

   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
Acknowledgement
 References
 
Pre-eclampsia affects 2–10% of all pregnancies and relates to substantial maternal and fetal morbidity and mortality (Wilson et al., 2003Go). Women conceiving through treatment by ART seem to more likely develop pre-eclampsia (Kallen et al., 2005Go; Shevell et al., 2005Go). In our study, we explored a possible association between ovarian reserves, as measured by basal ovarian function and response capacity to FSH stimulation on one hand and the development of pre-eclampsia as pregnancy-related vascular complication on the other. We observed that a decreased responsiveness of the ovaries to FSH stimulation, as indicated by the need for a higher amount of total administered FSH and FSH per day and a lower number of obtained oocytes during an IVF or ICSI cycle, was associated with an increased risk to develop pre-eclampsia in a subsequent pregnancy. The administered FSH per follicle and FSH per obtained oocyte showed an even stronger relation, with the latter being the most powerful predictor of all variables studied.

Patients with PCOS have a higher risk of pre-eclampsia (de Vries et al., 1998Go). Because PCOS patients generally have a high ovarian response to FSH (Heijnen et al., 2006Go), these women may be overrepresented in the group with low FSH dosages per obtained oocyte. This may have biased our results. However, the number of patients with PCOS in our group was too small to draw conclusions on this possible bias.

In our study, basal ovarian function, as assessed by baseline FSH and E2 concentrations, did not relate to the development of pre-eclampsia. Although basal FSH is a frequently used marker for ovarian reserve, its value in clinical practice is argued (Jain et al., 2004Go). The response of the ovaries to hyperstimulation might be superior in reflecting ovarian reserve as compared with basal functions (Lass, 2001Go). This seems to be in line with our findings with respect to the relation with pre-eclampsia.

To our knowledge, this is the first study examining a relation between ovarian reserve and vascular complications in pregnancy. Although we found no similar studies to compare our results with, several authors have examined the response to hyperstimulation in ART in relation with treatment success. An association between diminished responsiveness of the ovaries and decreased pregnancy rates has been found (Kailasam et al., 2004Go). There is also a higher chance of pregnancy loss found as correlation with diminished ovarian reserve (Levi et al., 2001Go). This high loss rate was likely to be because of fetal aneuploidy, which was higher among women with elevated FSH concentrations (Nasseri et al., 1999Go), but there are also other possible factors affecting the chance of an ongoing pregnancy in patients with diminished ovarian reserve.

Pregnancies after oocyte donation are associated with an increased risk of pregnancy-induced hypertension compared with pregnancies after IVF with own oocytes (Soderstrom-Anttila et al., 1998Go). On the one hand, this may be viewed upon as an immunological imbalance between ‘graft’ and ‘host’. On the other hand, the ovarian failure may also indicate a generalized ageing of the system, including vascular system, ultimately leading to the vascular disease of pre-eclampsia. This latter explanation is supported by the observation that patients with primary ovarian failure are at a higher risk for pre-eclampsia after oocyte donation (Pados et al., 1994Go).

An association between decreased ovarian reserve and an increased risk of pre-eclampsia may have implications for several patient groups. Women at risk for decreased ovarian reserve like those with a family history of a premature menopause, or having a history of chemotherapy, radiotherapy, pelvic surgery or infection (Nikolaou and Templeton, 2003Go), might be counselled for closer monitoring during pregnancy. Women without these risk factors but showing a low response to hyperstimulation could also be considered to be at increased risk for developing pre-eclampsia if pregnancy should occur. Unfortunately, at the chosen threshold point in the ROC curve, our most powerful variable showed only a modest discriminative power, which makes it hardly suitable for routine use in clinical practice. More research on these and other potential predictors is needed.

Because maternal vascular complications in pregnancy relate to neonatal morbidity as well (Sibai et al., 2005Go), we studied several variables associated with the condition of the newborn. Apgar score and umbilical arterial pH at birth did not differ between both the study groups. In accordance to other studies, we observed a shorter gestation at delivery in the pre-eclamptic subgroup, which was expected, considering the tendency to induce labor artificially in case of pre-eclampsia. Although these children had a lower birthweight, after adjustment for gestational age, parity and sex, the outcome between both the groups were comparable. This is in contrast with the findings of several other studies that state that birthweight even after adjustment for gestational age is lower in children born to mothers with pre-eclampsia (Odegard et al., 2000Go). Possibly we did not observe this in our study because of the limited number of cases.

The selection of cases in this study was based on reported complications during pregnancy, and although these were all verified in both cases and controls, the reported incidence of pre-eclampsia was low as compared with that of the general population, especially because pre-eclampsia is stated to occur more frequently in pregnancies resulting from ART (Shevell et al., 2005Go). Probably there were women who were not aware of their clinical condition before delivery, in that case we did not select them through their self-report. In addition, the low BMI amongst our studied population may also have affected the incidence of pre-eclampsia. This figure may have been biased by our local selection protocol before IVF, which excludes women when having a BMI above 32 kg/m2, because obesity is associated with lower changes for live birth after IVF and ICSI (Fedorcsak et al., 2004Go), increased rates of miscarriage, gestational diabetes, hypertension and mechanical problems during delivery (Balen et al., 2006Go). Despite the considerable number of women who initially enrolled in this study, the low number reporting pre-eclampsia resulted in a small case group that led to a modest power. Considering this, and because the used case–control design has the tendency to overestimate found relations, a larger prospective study is needed to verify our results.

In conclusion, diminished responsiveness of the ovaries to FSH stimulation in an IVF cycle, which reflects a decreased ovarian reserve, is associated with an increased risk of developing pre-eclampsia in a subsequent pregnancy. We speculate that reduced ovarian responsiveness also reflects diminished vascular reserve capacity, the latter giving rise to pregnancy-associated vascular complications.


   Acknowledgement
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgement
References
 
We thank Dr J.C.M. Hendriks for his valuable contribution to the statistical analysis.


   References
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgement
 References
 
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Submitted on February 7, 2006; resubmitted on April 6, 2006; accepted on April 11, 2006.


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