Consanguineous marriages refer to the legal recognition of two people as spouses who are second-degree cousins or closer, and among Arabs, this includes double first cousins, first cousins, first cousins once removed, and second cousins (1, 2). Consanguineous marriages are common in countries where the extended family is the main social unit, and they developed from environmental and economic conditions prevalent in rural areas (3). Furthermore, they reflect the fundamental value system, as well as the identity of descent groups and the long-standing history of Arabian families. Contrary to prevailing beliefs in Western countries, consanguineous marriages are prevalent in many different parts of the world and are not limited to certain religious communities or rural areas, but are widely accepted in many populations (4, 5). Hence, they are more prevalent in the Middle East compared to other regions of the world (6). Interestingly, consanguineous marriages prevail in the Middle East despite urbanization and improvements in socioeconomic development, and have even increased in recent generations (3). Although, demographic studies indicate that these consanguineous unions are often linked to marginally smaller family sizes compared to non-consanguineous marriages (7). This pattern has been attributed to higher rates of reproductive loss, infant mortality, and subfertility observed among consanguineous couples (8, 9). Collectively, these findings emphasize that the reproductive impact of consanguinity extends beyond its well-established genetic risks.

Through their common ancestors, consanguine couples share genetic information: in case the spouses are first cousins, they share 1/8th of their genes and their children will be homozygous at 1/16th of all loci (10). The genetic risk for the offspring can be given by the inbreeding coefficient “F” (11) which denotes the fraction of loci at which the children of a consanguineous union are predicted to acquire identical gene copies from both parents. Consanguine spouses' offspring have a higher incidence and prevalence of autosomal recessive hereditary disorders, and, if multiple genes are affected, individuals may suffer from complex and overlapping symptoms (12, 13). Besides these often clearly obvious conditions, affecting the physical and mental development, it appears that female offspring of consanguineous marriages have a higher risk of reduced ovarian reserve compared to their peers from non-consanguine marriages with a pronounced effect in women below 35 years of age (14, 15); this condition, which might go unnoticed, could have a severe impact on the live and family planning of the affected individuals.

Infertility, caused by a reduced ovarian reserve, is usually considered physiologic in women of advanced age due to the age-related decline in the number and quality of the oocytes (16). However, reduced ovarian reserve causing infertility may be overlooked in young women due to the misconception that the ovarian reserve is only determined by age. Yet, current literature on this topic remains limited and fragmented, highlighting a significant gap in research that calls for further investigation. Therefore, the aim of this narrative review is to raise awareness about the implications of consanguineous marriages, more specifically with the increased risk of reduced ovarian reserve, in order to gain a better understanding of the multifactorial genetic disorder to minimize its impact on the female offspring and to take countermeasures to preserve fertility. With the goal of answering the overarching research question; How does parental consanguinity, compared with non-consanguinity, affect the ovarian reserve and fertility potential of women of a reproductive age in the Middle East?

The population of interest was women of a reproductive age with parental consanguinity, and the study populations consisted of clinical or community samples in any country. We included studies comparing women with “reduced ovarian reserve” and/or “ovarian deficit” to women with normal ovarian reserves. To reflect the wide range of outcomes in fertility research, we used multiple definitions for reduced ovarian reserves and consanguinity. The parameters used to define ovarian reserve were AMH and AFC, as these are the most accurate markers (17).

The exclusion criteria was as follows: (1) The study reported on non-human subjects only; (2) The study reported on male data only; (3) Consanguinity (CSG) was measured but there was no ovarian reserve outcome; (4) CSG and ovarian reserve were measured but the ovarian reserve outcome reported was not of interest; (5) Both CSG and ovarian reserve outcome measured but the association between them was not tested or reported; (6) No control group (not exposed to CSG); (7) CSG reported not of interest; (8) Only secondary data analysis; (9) Qualitative data only; (10) Related publication (same data set); and (11) Duplicate record (See Supplementary Appendix A). We did not impose any restrictions on language or publication date, and no restrictions on the types of study design eligible for inclusion.

The search was conducted for articles that were published up until the 10th of March 2022, (updated 11th March 2024). The MeSH terms “reduced ovarian reserve” and “ovarian deficit” were used to identify studies examining the outcome. MeSH terms relating to “consanguinity” (CSG) such as “consanguine”, “cousin marriage” and “consanguineous marriage” were identified and combined with “OR”. Search terms for CSG were combined with search terms for ovarian using “AND”. The search strategy was replicated in Embase, MEDLINE, Web of Science, see Supplementary Appendix B for search strategy. Excel was used to import searches from each database, and after removing duplicates, studies were selected based on eligibility criteria. Disagreements at all stages were resolved through discussions among the reviewers.

PRISMA Guidelines were adhered to while conducting the analysis and this manuscript was prospectively registered with PROSPERO (Registration ID: CRD42022300162). The extraction of data was conducted using a standard form. Information was extracted based on study design (cohort, case-controlled, cross-sectional), sample (location, size), the definition of risk factor, the primary outcome “reduced ovarian reserve”, confounders, data relevant to effect size calculation, and information required for quality assessment.

We assessed study quality using the modified version of the Newcastle-Ottawa Scale (NOS) (18). Studies were classified as high, medium, or low quality. The assessment aimed to determine if the risk factor “consanguinity” was adequately evaluated, if controls were properly assessed when their selection was comparable to the exposed cases, and whether consanguinity was appropriately excluded in the control population. Two reviewers extracted data from each paper in duplicate. Each included paper underwent an independent NOS assessment by the two reviewers. Discrepancies were evaluated by a third reviewer and resolved through consultation with other members of the review group.

A narrative review of the systematic evidence was conducted due to the insufficient number of primary studies to conduct a meta-analysis. The available evidence from the search and from known sources was summarized, and conclusions on the potential impact of the consanguinity on ovarian reserve was reported. A better understanding of the limited research in this area can be illustrated through a visual summary of the existing evidential data (See Figure 1).

Despite a worldwide occurrence of consanguineous marriages (21), our systematic literature review revealed only three studies which investigated the possible impact of parental consanguinity on the ovarian health of their female offspring. The studies included all together almost 3,000 women, recruited from fertility units in Kuwait (14), the United Arab Emirates (20) and Oman (19). Though all three studies included women from Middle Eastern countries, two publications (14, 20) described a reduced ovarian reserve in women from consanguineous parents; hence, the publication of Saeghi et al. (19) did not confirm these findings. Possible explanations for the discrepant findings are the use of different thresholds defining reduced ovarian reserve, the measurement of AMH only in part of the study population (19) and the inclusion of varying percentages of first- and second-degree parental consanguinity into the respective cohorts. A closer relationship (first-degree compared to second-degree) increases the pool of shared genes and sharing more genes implicitly increases the risk of undetected genetic abnormalities, some of which may have a deleterious impact on the ovarian reserve. Unfortunately, not all papers presented data on the distribution and their respective ovarian reserve of women with first- and second-degree parental consanguinity. For example, while Seher et al. (14) and Melado et al. (15) reported significant associations between parental consanguinity and reduced ovarian reserve, Saeghi et al. (19) did not, although this could be in relation to incomplete AMH measurements and underrepresented first-degree parental consanguinity. This heterogeneity across studies also resulted in complex comparisons, making it difficult to draw firm conclusions. Highlighting the need for more consistency in design rigor for future investigations.

The higher incidence of genetic diseases in offspring from consanguineous marriages due to elevated levels of homozygosity—which might lead to complete inactivation or dysfunction of genes—is widely recognized (7, 12, 13). However, the impact of consanguinity on the fertility of the offspring is still neglected. This is especially surprising given that societies in which consanguineous marriages prevail, are known for being pro-family, with strong family bonds and a desire for “big” families (8, 9). In Middle Eastern societies, childbearing is often considered essential for women (15), making the preservation of ovarian reserve a critical determinant of their fertility. Nevertheless, large-scale demographic surveys have reported that consanguineous couples tend to have fewer surviving children compared to non-consanguineous couples (8, 9). While this has traditionally been associated with higher rates of neonatal mortality and congenital disorders, it is also plausible that underlying reproductive factors, including reduced ovarian reserve in female offspring, contribute to this difference. These observations are consistent with the findings of our review, suggesting that the biological effects of consanguinity extend across generations, including both reproductive capacity and family size.

Aside from age and ethnicity (22–25), a variety of factors (e.g., environmental, iatrogenic, hormonal) can influence a woman's ovarian reserve. Recently, advanced genetic testing has revealed an increasing number of pathogenic mutations associated with premature ovarian insufficiency (POI) in women with and without parental consanguinity (26–29). With the current diagnostic tools, genetic factors seem to account for roughly 20 to 25% of POI cases (30). Whereas POI is an obvious condition as the affected woman's cycle will cease at a young age (<40 years), the presence of diminished ovarian reserve may go unnoticed, especially if the woman does not experience cycle irregularities, a history of/present infertility, or if she does not seek an assessment of her ovarian reserve. The “hidden” character of reduced ovarian reserve might also contribute to the—so far—limited identification of genetic factors involved in the pathophysiology of this condition.

It is important to acknowledge that parental consanguinity not only has a detrimental impact on female fertility, but also seems to cause male infertility (31–33). To shed further light on genetic factors that might influence the health of offspring of consanguineous marriages, some researchers support the notion of extending genetic studies in consanguineous populations to subjects without any clinical phenotypes (34). The need for this kind of study is supported by the fact that the data presented here are derived from women who attended fertility units, either because of an existing infertility or since they were interested in evaluating their ovarian reserve, which introduces the possibility of selection biases and limits generalizability. This raises concerns regarding external validity, as the findings may not be generalizable to women in the general population who do not attend fertility clinics (31). To obtain a more complete picture of the impact of parental consanguinity on male and female fertility, genetic testing should be expanded to a wider and potentially fertile population.

Another limitation pertains to measurement variability in both AMH and AFC levels that are subject to inherent sources of heterogeneity that may affect the accuracy and comparability of findings across studies (35). For AMH, values can differ substantially between the type of assay used, as variations in antibody specificity, calibration standards and analytical sensitivity can yield discrepant results from identical samples (36). Moreover, AMH concentrations are not entirely stable within individuals indicating intercycle fluctuations are influenced by age, reproductive stage and the menstrual phase (36–38). Similarly, AFC measurement is influenced by intercycle variability in follicle number and operator dependent factors such as equipment quality and examiner expertise (39). As a result, the variation within the included studies can limit the reliability and generalizability of the reported associations. Future research should aim to follow a “gold standard” of measures and rigorous methodological practices when investigating ovarian reserve to account for and limit the heterogeneity effects of existing empirical data.

However, until the effects of gene mutations and infertility are better understood, the narrative review presented here should raise awareness about the potential impact of parental consanguinity on offspring reproductive health and encourage individuals to actively seek counselling and assessment of their fertility status. Potentially, this review also urges the need for further investigation in understanding the scope of this topic globally. By systematically synthesizing disparate findings, this review provides a consolidated evidence base that highlights inconsistencies, identifies critical gaps, and sets a clearer research agenda than has previously been available, helping to better inform future research in this area. In case of a diagnosis of “reduced ovarian reserve”, existing fertility preservation techniques in form of oocyte and/or embryo cryopreservation after ovarian stimulation and/or ovarian tissue cryopreservation can be explored and performed, thereby forestalling the irredeemable loss of oocytes (39, 40).