A real-world simulation of the fertility trend among women with endometriosis in Italy

Introduction

In February 2024, a narrative review on the issue of infertility and endometriosis¹ was published by Italian authors. The paper concluded that patients with endometriosis are more prone to infertility than those without endometriosis, due to various potential factors directly and indirectly affect fertility. Although this association is widely recognized,^2-5 the evidence supporting the impact of endometriosis on fertility is not robust from an epidemiological perspective. Whilst endometriosis itself may directly worsen pregnancy outcomes and live birth rates,⁶ fertility is also a continuous variable that decreases with age⁷ and is influenced by women’s reproductive desires⁸. Regarding live birth rates, Vercellini et al.⁹ found a slight increase in adverse pregnancy outcomes in endometriotic patients, which could potentially affect the number of births among these patients. Furthermore, endometriotic patients often experience various health issues that can impact their quality of life^10,11 and influence their desire to conceive and give birth. Additionally, treatments for endometriosis, such as contraceptive medications and surgical procedures,¹² can affect the ability to conceive and give birth. Finally, endometriosis is an evolutive disease,¹³ which makes it challenging to definitively determine a patient’s fertility potential if she does not attempt to conceive at a young age and instead choose to pursue pregnancy later in her life.
In conclusion, further epidemiological studies on fertility and endometriosis are needed to help endometriotic patients plan their pregnancies and determine the optimal timing for conception and childbirth.
The objective of this study is to model a real-world probability curve of fertility rates in non-endometriotic and endometriotic women using demographic data and information from Italy, along with findings from the existing literature. The authors state that the primary information will be provided by trends rather than by probabilistic values, as the latter will be derived from multiple estimates that may be questioned as potentially biased.

Design and setting

Calculating of the probability of conceiving and giving birth in a real-world scenario would involve considering a reference population and its demographic characteristics, along with specific issues related to endometriosis within that population. The key factors influencing the chances of pregnancy include: 1. the actual desire for pregnancy within that female population; 2. the infertility rate in that population and the outcomes of assisted reproductive technologies (ART); 3. the age at which endometriosis is diagnosed in that population and the impact of endometriosis treatments on fertility; 4. the infertility rate in endometriotic patients in that population and the outcomes of ART in these endometriotic patients; 5. the natural decline in fertility with age in women.

Reference population

This study focused on the Italian population and gathered data covering the period from 2020 to 2023, as this was the most recent timeframe available at the time of writing. Detailed demographic information for probability estimates is shown in Table 1. Epidemiological data on endometriosis were obtained from Italian healtcare institutions and the scientific literature; each value and its source are listed in Table 1. Furthermore, Table 1 includes some recalculated values.

Estimating mean age of surgery for endometriosis

To estimate the mean age of surgery for various causes in endometriotic patients, means with standard deviations or ranges from studies referenced at ^21-30,  included in the metanalysis by Bafort et al.³¹, were extracted. The studies referenced at ^21-30 are high-quality papers acknowledged by Bafort et al.³¹ In study arms where standard deviations were missing, these were recalculated from limit ranges. The study arms by Jarrel et al.²³ lacked limits and standard deviations, so missing standard deviations were imputed using the mean of standard deviations from the other studies,^21,22,24-30 to avoid omitting the information on mean age at surgery reported in Jarrell 2005²³, thereby introducing a potential bias. The overall mean age and standard deviation were calculated by pooling and weighting the data from the above-mentioned study arms using a random-effects model.

Estimating live birth rate and pregnancy rate

Figure 1 illustrates the estimated trend in live birth rates based on women’s age. The estimates were derived combining several trends and rates obtained from samples drawn from different populations, presumably not using contraception. The samples were collected non systematically by reading full texts from relevant references found in PubMed and SCIELO.^14,15,32-50 These samples include rates of conception after intra-uterine insemination in women with only male infertility (from which the live birth rates were calculated according to van Noord-Zaadstra et al.)³⁴ and live birth rates women not using effective contraception. These rates were extracted from texts, tables or figures. In the latter case, the software Digitizelt 2.3.3 (© I. Bormann 2001-2016) was used. Rates were normalized by converting them into natural logarithmic values and then averaged according to each age group. The mean logit values were converted back into rates (thinner black line of the Figure 1). A polynomial trend line of the mean values rate (thicker black shape) was fitted to estimate the live birth rate according to female age (f(a)) (Figure 1). The cumulative pregnancy rate was then re-calculated based on this trend line, applying corrections reported by van Noord-Zaadstra et al.³⁴(f(b)).

Estimating punctual probabilities

Table 2 presents derived variables used for calculating punctual probabilities normalized for the Italian population. The formulas for these probabilities are also provided in Table 2.

Estimating punctual fertility rate after surgery for endometriosis

It is impossible to estimate the actual fertility rate (cumulative pregnancy rate and live birth rate) across all the different proportions of the female population undergoing several surgical approaches, follow-up, additional therapies, and treatments in a real-world setting, as no relevant data are available. Therefore, to estimate the fertility rate (cumulative pregnancy rate and live birth rate) following any surgical procedure for endometriosis, the aim is to recalculate the cumulative pregnancy rate based on meta-analyses. On 26 January 2025, a search was conducted in PubMed using the terms “endometriosis + surgery + fertility” with the limit “meta-analysis” (no additional limits were set). The search yielded 56 items, from which studies that reported the outcome “clinical pregnancy rate” were selected. Full-text articles of meta-analyses^61-86 and two additional articles^87,88 that provided relevant data were included. These latter two articles were discovered during the bibliographic research for drafting the present paper. Figure 2 illustrates a PRISMA-like flowchart describing the data extraction and calculation steps to determine the final estimate of the mean cumulative pregnancy rate. Metanalyses report data on study arms including the number of events of cumulative pregnancy rates, along with the total number of patients observed in individual studies on patients who underwent surgery for endometriosis (excluding diagnostic surgeries), compared with a contrast group. The contrast group may include patients who underwent other kinds of surgeries, pharmacologic treatments, a combination of additional therapies, or no treatment. Eligible series have to include any type of surgical procedures for endometriosis (excluding series with only diagnostic laparoscopy and diagnostic laparotomy), with pregnancies occurring either after ART or spontaneously. Additional treatments administered before or after surgeries were not considered significant in the final estimate of cumulative pregnancy rate, nor was the post-operative follow-up period. On the contrary, the expected heterogeneity of pooled series would be more useful in describing the real-world behaviour of cumulative pregnancy rates following any surgical procedure for endometriosis. Each arm of the study with surgery (excluding diagnostic laparoscopy and diagnostic laparotomy) reported in each meta-analysis, regardless of other treatments and follow-up time, was assessed to calculate the cumulative pregnancy rate from events used to calculate the odds ratios.

In the first step of data synthesis, cumulative pregnancy rates calculated in each arm included in the meta-analyses were combined and averaged (weighted pooled estimates, employing a random-effects model if the Q-statistic indicated heterogeneity, or a fixed model in the absence of heterogeneity). Duplicate data from the same articles included by different authors in their meta-analyses were retained, as the Authors believed that considering multiple authors’ perspectives would provide a more accurate overall estimate of the pregnancy rate in the subsequent stage of data synthesis.
In the second step of data synthesis, all previously-obtained weighted cumulative pregnancy rates from each individual series of every meta-analysis were re-pooled and re-averaged (Figure 3). The final estimate of the cumulative pregnancy rate includes endometriotic patients treated surgically alone  (various types of surgery), endometriotic patients who underwent surgery and also received various pharmacological therapies, followed for different durations, with or without subsequent ART, as would occour in a real-world scenario.

This value is reported in Table 2 (variable s_i) and was used to calculate the variables t_i and w_i (Table 2). The live birth rate following surgery was calculated based on the previous punctual estimates of pregnancy rates, as shown in Table 2 (variables u_i and v_i).

Estimating the probability trend for the desire of pregnancy

The expected probability trend of the desire for pregnancy in the Italian population was determined by using the normal curve formula with a mean age of 31.7 (approximately 32) and a standard deviation of ±6.99 (f(c))⁵⁷ (Table 1).
Estimating the probability trend for the age at the diagnosis of endometriosis
The expected probability trend of the age at the diagnosis of endometriosis was determined by applying the normal curve formula with a mean age of 30 and a standard deviation of ±2.551 (f(d))¹⁹ (Table 1).

Estimating the probability trend for the mean age of surgery for endometriosis

The expected probability trend of the age at the surgery for endometriosis was determined by applying the normal curve formulas to the punctual estimates obtained from high-quality studies reported in the metanalysis by Bafort et al.,³¹ as previously described: weighted overall mean age of 28.3 and weighted standard deviation of ±5.744 (f(e)) (Table 1).

Software

The calculations and plots were performed by using LibreOffice Calc version 7.0.3.1, copyright© 2000-2020.

Results

Relevant punctual estimates

Table 2 reports the results of punctual normalized rates of fertility (cumulative pregnancy rates and live birth rates) in different groups of Italian women:

• non-endometriotic women: cumulative pregnancy rate 0.995946 (I_i), live birth rate 0.934349 (L_i), comprising both spontaneous conception and ART outcomes;
• endometriotic women before 30 years of age: cumulative pregnancy rate 0.384000 (M_i), live birth rate 0.330782 (N_i), assuming similar rates of contraception, voluntary abortion, and first pregnancy desire as non-endometriotic Italian women; no surgery and the same chance of pregnancy as non-endometriotic women were also assumed;
• endometriotic women between 30 and 32 years of age: assumed 0.001 for both cumulative pregnancy rate and live birth rate, representing the probability of contraceptive pill failure;
• endometriotic women after 32 years of age: cumulative pregnancy rate 1.0 (Q_i), live birth rate 0.861412 (R_i), including both spontaneous conception and ART outcomes;
• endometriotic women undergoing operative surgery: cumulative pregnancy rate 0.465007 (Z_i), live birth rate 0.400586 (AA_i), normalized for the mean of previous cumulative pregnancy rates (Q_i, M_i, 0.001), and live birth rates (R_i, N_i, 0.001) and weighted for the proportion of Italian women under 32 years, over 32 years and for the rate of patients using contraception in both age groups (61.6%, variable s in Table 1, according to Istat 2017⁵⁶).

Plotting punctual estimates

Non-endometriotic patients’ punctual estimates were plotted for f(a), f(b)-f(b*s), f(c)-f(c*s). Punctual estimates for endometriotic patients under 30 years of age were plotted for f(a), f(b)-f(b*s), f(c)-f(c*s), f(d). The 0.001 estimate was plotted for f(a) and f(b). Punctual estimates for endometriotic women over 32 years of age were calculated and plotted for f(a), f(b), f(c), f(d). Endometriotic women undergoing operative surgery had punctual estimates calculated and plotted for f(a), f(b)-f(b*s), f(c)-f(c*s), f(d), and f(e).

Combining plotted estimates

The final estimates of the trend of cumulative pregnancy rate and live birth rate by age in endometriotic patients are an average composition weighted for the proportion of Italian patients under 30 years, between 30 and 32 years, over 32 years, and for the rate of surgery (variable z, from Kiser 2025⁶⁰) for each plotted value reported above.

Main result

Figure 4 shows the final trends in the cumulative pregnancy rate (dotted lines) and live birth rate (solid lines) among Italian women without endometriosis (in black), Italian women with endometriosis who underwent treatments (surgeries and ovarian suppression, in red), and Italian women with endometriosis who did not receive any treatment (those who were diagnosed with endometriosis, in green, excluding the use of the contraceptive pill). The trends for treated and untreated women indicate a decline in fertility associated with female ageing, the age at which surgery for endometriosis is performed, and hormonal suppressive therapies. Treatments lead to a significant decrease in fertility rates in the subgroup of Italian women with endometriosis, while untreated women with endometriosis appear to follow a similar trend to that of women without endometriosis, with only a slight decrease in fertility compared to non-endometriotic women. This decrease is mainly due to poor pregnancy outcomes,⁹ which affect the live birth rate.

Discussion

This study aims to depict a real-world trend of fertility in women with endometriosis, based on demographic data for the Italian female population and current scientific knowledge. These trends have been derived from various estimates relating to the entire Italian female population. Estimates are only an approximation of reality. The estimation methods, the assumptions on which they are based, and the final results after an estimating process may be biased. Therefore, the estimates of this study may be subject to questioning due to their nature as estimates, and this is the main limit of the study. Additionally, these figures are calculated under the assumption that endometriotic patients without fertility problems have the same chance of conceiving as non-endometriotic women without infertility problems, as well as the same rate of voluntary termination of pregnancy. The assumptions are merely logical. This could constitute a bias, but it should be pointed out that the aim of this study is not to provide the actual fertility probabilities for the Italian population strata (with and without endometriosis), but rather to present the estimates as a trend. To the best of the Authors’ knowledge, there is a lack of knowledge or real-world data on endometriosis and fertility trends in the general population. This is due to the difficulty in determining the actual proportion of endometriotic patients who have not been diagnosed with the condition during their lifetime. Therefore, the calculated fertility probabilities in the Italian population presented here should be considered as an approximation of the actual fertility probabilities among endometriotic patients. In this sense, the trends would convey the majority of information about fertility in endometriotic patients, rather than the estimated rates, and this aspect is the main strength of this work.
Furthermore, the estimates provided are static and pertain to the period from 2020 to 2023, during which the data were primarily gathered. This time frame was chosen as it represents the most recent data available. It is important to note that the 2020-2023 period is a unique post-COVID-19 era, characterized by shifts in demographics and health concerns due to various practical factors. Therefore, the results obtained from this specific time period should not be extrapolated to previous years. Moreover, these findings should not be generalized to different populations. However, formulas and trends can be utilized to create models for fertility curves in other populations and in other time frames within the same population. Consequently, the fertility rate trends could serve as a valuable benchmark, with practical implications for family planning policies.
The key issue regarding fertility in Italy is closely linked to the tendency for women to delay their first pregnancy, which typically occurs around the age of 32 due to social and cultural attitudes. This timing often overlaps with the average age at which they undergo surgery for endometriosis or receive a diagnosis of the condition. Consequently, the window of opportunity for conception is postponed to a later stage in the life of an endometriotic woman’s life, when fertility naturally declines. Figure 4 effectively illustrates this pattern. Endometriotic patients who do not undergo any treatment experience a slight decrease in fertility compared to non-endometriotic women in terms of live birth rates. When treatments are taking into account, the data shows that fertility rates among endometriotic women are lower than both those of non-endometriotic women and those of women who do not undergo treatment. This suggests that women with endometriosis should aim to conceive as early as possible, ideally before being diagnosed with endometriosis.
In conclusion, a significant proportion of infertility in endometriotic patients is iatrogenic. Family planning at the age of 32, in 10% to 15% of women – those with endometriosis²⁰ –, could impact the birth rate in Western countries, necessitating a reassessment of national family planning policies for the subpopulation of endometriotic patients. Ideally, endometriotic patients should not be advised to use contraceptives at a young age in order to conceive as soon as possible. However, since it is not known which women are affected by endometriosis, it may be beneficial to encourage all women to conceive earlier to improve their own chances of fertility and fertility  at the population level. Otherwise, it is illogical to worry about Italian demographic winter.

Conflicts of interest: none declared.

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