Pregnancy and perinatal complications in untreated subfertile couples following singleton spontaneous conception: a narrative review

This narrative non-systematic review was conducted in compliance with the Scale for the Assessment of Narrative Review Articles – SANRA guidelines [ 25 ]. The six items of this scale were implemented as follows: (1) the importance of the article is explicitly justified; (2) one or more concrete aims or questions are formulated; (3) the literature search is described in detail, including search terms and inclusion criteria; (4) key statements are supported by references; (5) appropriate evidence is generally present; and (6) relevant outcome data are generally presented appropriately. The literature search was focused on English-language scientific publications, indexed in PubMed database from inception up to August 2025, on singletons spontaneously conceived by non-hormonal-treated subfertile couples. Studies that did not adhere to these criteria were excluded. No sample size thresholds were used as inclusion/exclusion criteria. Studies were identified using the following search terms: “(spontaneous OR natural) conceptions” AND “(non-treated OR untreated OR expectant management) women” AND “(pregnancy OR perinatal OR infants OR children OR offspring OR sons OR daughters) (complications OR outcome)”. All these search terms were combined with several reproductive disorders terms such as “polycystic ovary syndrome”, “endometriosis”, “adenomyosis”, “(premature ovarian failure OR primary ovarian insufficiency)”, “(diminished ovarian reserve OR premature menopause)”, “(unexplained OR unknown OR idiopathic) infertility”, “(semen quality OR male infertility OR semen parameters OR sperm aneuploidy OR sperm chromosomal abnormalities OR sperm DNA fragmentation OR unexplained recurrent abortion”. Special attention was paid to including studies on subfertile couples that used a control group of fertile couples. Nonetheless, the inherent nature of literature reviews prevented from following this strategy in some cases. A total of 1,380 original publications and literature reviews were identified using the search strategy. After assessment of the titles, abstracts, and text by the three coauthors, 20 potentially relevant publications were analyzed in detail. Finally, 6 publications met the stringent inclusion criteria laid down in the study (Fig. 1 ). These studies will be included in Table 2 . Fig. 1 The flow chart of study selection The flow chart of study selection Table 2 Pregnancy and perinatal complications associated with female and male reproductive disorders exhibited by untreated subfertile couples following Singleton spontaneous conception Reproductive disorders Study’s design Control group Hormonal treatment Pregnancy and perinatal complications Associated outcomes Level of certainty PCOS A registry linkage study of 3,552 deliveries of non-treated, non-infertile PCOS women [ 34 ] Non-treated, non-infertile, non-PCOS women ( n  = 88,273) Untreated Gestational diabetes aRR (95% CI): 1.37 (1.17-1.61) Low to moderate Pregnancy-induced hypertension/eclampsia/preeclampsia aRR (95% CI): 1.27 (1.10-1.47) Low to moderate Low birthweight (< 2,500 g) aRR (95% CI): 1.28 (1.01-1.61) Low to moderate Endometriosis A systematic review and meta-analysis of studies that evaluated the association between endometriosis and risk of preeclampsia [ 35 ] Fertile and subfertile women without endometriosis Not specified a Preeclampsia RR (95% CI): 1.44 (1.11-1.87); I 2  = 0%; Chi 2 P ≤ 0.36; n  = 2 studies Low DOR A prospective study of women in the first trimester of a spontaneous intrauterine pregnancy (< 12.6 weeks) with an embryo/fetus without cardiac activity by ultrasound examination (miscarraige group; n  = 30) [ 36 ] Women in the first trimester of a spontaneous intrauterine pregnancy (< 12.6 weeks) with a normal embryo/fetus ( n  = 33) Untreated Miscarriage (< 12.6 weeks of gestation) in women with serum AMH levels ≤ 1.1 ng/mL RR (95% CI): (95% CI): 3.66 (2.1-6.4) Low Low semen quality A systematic review and meta-analysis of couples with a history of idiopathic recurrent pregnancy loss who underwent sperm DNA fragmentation testing [ 37 ] Male partners of fertile couples Not specified b Higher levels of sperm DNA fragmentation EAMD (95% CI): 11.98 (6.64-17.32), P ≤ 0.001; I 2 = 97.3%; Cochran’s Q test P ≤ 0.0001; n = 13 studies Low to moderate A systematic review and meta-analysis of couples with a history of idiopathic recurrent pregnancy loss who underwent sperm DNA fragmentation testing and traditional semen parameters analyses [ 38 ] Male partners of fertile couples  Not specified b Higher levels of sperm DNA fragmentation WMDs (95% CI): 8.45 (1.48-15.42), P ≤ 0.018; I 2 = 99.4%; n = 8 studies Low to moderate Lower levels of total motility WMDs (95% CI): -10.30 (-15.03 - -5.57), P ≤ 0.05; I 2 = 82.3%; n = 7 studies Low Lower levels of progressive motility WMDs (95% CI): -4.75 (-8.35 - -1.15), P ≤ 0.05; I 2 = 99.4%; n = 12 studies Low A retrospective study of men, which were partners of women with at least three prior idiopathic recurrent pregnancy losses before 20 weeks of gestation ( n = 22) [ 39 ] Men of proven fertility ( n = 25) Not specified b Higher percentage of sperm apoptosis Mean ± SD: 5.95 ± 3.03 vs. 4.06 ± 2.05; P ≤ 0.01 Low Higher percentage of sperm 1818YY diploidy Mean ± SD: 0.114 ± 0.06 vs. 0.075 ± 0.043; P ≤ 0.05 Low Higher percentage of sperm 18YY disomy Mean ± SD: 0.09 ± 0.05 vs. 0.048 ± 0.032; P ≤ 0.01 Low a Authors did not specify whether endometriotic women received any hormonal treatment. However, we can infer that it is unlikely women were hormonally treated because hormonal therapies for endometriosis suppress ovarian activity and are contraindicated in women seeking a spontaneous/natural conception (for reviews, see [ 41 , 42 ]) b Authors did not specify whether men with low semen quality received any hormonal treatment [ 37 – 39 ]. We should note that the own definition of unknown/unexplained/idiopathic recurrent pregnancy loss presents a difficulty to treat these men. Nevertheless, there is evidence that links lifestyle to sperm DNA fragmentation. Consequently, these men are usually recommended to quit smoking, limit alcohol consumption, control normalization of body weight, and uptake of a normal exercise program (for review, see [ 64 ]). Furthermore, it is important to remark that the term “idiopathic recurrent pregnancy loss” includes both singleton and multiple gestations. Our literature search has not found studies providing the frequency of multiple gestations in women experiencing recurrent pregnancy loss. However, literature shows that the estimated current global twinning rate is relatively small: 12.0 twin deliveries per 1000 deliveries [ 69 ]. Moreover, the definition of “recurrent pregnancy loss” implies a complete loss of pregnancy, irrespective of whether it is singleton or multiple. Consequently, plurality of pregnancy does not affect the outcome of the studies analyzed in Table 2 [ 37 – 39 ] Abbreviations: AMH anti-Müllerian hormone, aOR adjusted odds ratio, CI confidence interval, DOR diminished ovarian reserve, EAMD estimated average mean difference, HR hazard ratio, OR odds ratio, PCOS polycystic ovary syndrome, RR relative risk, SD standard deviation, WMDs weighted mean differences Pregnancy and perinatal complications associated with female and male reproductive disorders exhibited by untreated subfertile couples following Singleton spontaneous conception a Authors did not specify whether endometriotic women received any hormonal treatment. However, we can infer that it is unlikely women were hormonally treated because hormonal therapies for endometriosis suppress ovarian activity and are contraindicated in women seeking a spontaneous/natural conception (for reviews, see [ 41 , 42 ]) b Authors did not specify whether men with low semen quality received any hormonal treatment [ 37 – 39 ]. We should note that the own definition of unknown/unexplained/idiopathic recurrent pregnancy loss presents a difficulty to treat these men. Nevertheless, there is evidence that links lifestyle to sperm DNA fragmentation. Consequently, these men are usually recommended to quit smoking, limit alcohol consumption, control normalization of body weight, and uptake of a normal exercise program (for review, see [ 64 ]). Furthermore, it is important to remark that the term “idiopathic recurrent pregnancy loss” includes both singleton and multiple gestations. Our literature search has not found studies providing the frequency of multiple gestations in women experiencing recurrent pregnancy loss. However, literature shows that the estimated current global twinning rate is relatively small: 12.0 twin deliveries per 1000 deliveries [ 69 ]. Moreover, the definition of “recurrent pregnancy loss” implies a complete loss of pregnancy, irrespective of whether it is singleton or multiple. Consequently, plurality of pregnancy does not affect the outcome of the studies analyzed in Table 2 [ 37 – 39 ] Abbreviations: AMH anti-Müllerian hormone, aOR adjusted odds ratio, CI confidence interval, DOR diminished ovarian reserve, EAMD estimated average mean difference, HR hazard ratio, OR odds ratio, PCOS polycystic ovary syndrome, RR relative risk, SD standard deviation, WMDs weighted mean differences A GRADE (Grading of Recommendations Assessment, Development, and Evaluation)-like heuristic approach suitable for narrative reviews [ 26 ] was used to assign a rating of high, moderate, low, or very low certainty to the estimates of the effect sizes provided in the original studies included in Table 2 . In contrast, the I 2 statistic was used to rate the inconsistency, heterogeneity, or degree of variation in effect sizes across the studies analyzed in the systematic reviews and meta-analyses included in Table 2 . As reported by the Cochrane Handbook for Systematic Reviews of Interventions [ 27 ], the significance of the observed I 2 value depends on the magnitude and direction of effects and the strength of evidence for heterogeneity, evaluated by the P value from the Chi 2 test or the confidence interval (CI) for I 2 . Accordingly, an I 2 value of 0% to 40% suggests that the heterogeneity may not be important, 30% to 60% may represent moderate heterogeneity, 50% to 90% suggests substantial heterogeneity, and 75% to 100% may denote considerable heterogeneity. Note that the thresholds for the interpretation of I 2 can be misleading if the number of studies analyzed is small [ 27 ]. The next section shows the pregnancy, perinatal, and childhood complications found in the general/non-stratified population of subfertile women. That is, studies that used time to pregnancy to define couples’ subfertility and considered subfertile couples as a single homogeneous group. Thereafter, we will analyze one-by-one the 20 potentially relevant publications focused on reproductive disorders in order to select the studies that satisfy the stringent inclusion criteria laid down in the present study. The study by Messerlian et al. [ 28 ] was the first published systematic review and meta-analysis reporting on the association between subfertility and adverse pregnancy outcomes. The study was focused on non-treated subfertile women who conceived after a time to pregnancy of ≥ 12 months versus fertile women from the general obstetric population who reached a pregnancy within 12 months of trying. The meta-analysis evidenced increased risk for preterm birth [adjusted odds ratio (aOR) (95% CI): 1.31 (1.21-1.42)], small-for-gestational-age [aOR (95% CI): 1.17 (1.03‐1.33)], and low birthweight [aOR (95% CI): 1.34 (1.21‐1.48)]. This outcome was mostly based on singleton pregnancies (11 out of 14 of the studies analyzed were limited to singleton pregnancies). Thereafter, Wise et al. [ 29 ] performed an internet-based prospective cohort study of pregnancy planners in Denmark. After adjusting for several covariates, including the use of fertility medication, evidenced a higher risk for preterm birth < 36 weeks [adjusted relative risk (aRR) (95% CI): 2.25 (1.09–4.65)], preterm birth < 35 weeks [aRR (95% CI): 4.20 (1.48–11.9)], low birthweight (< 2,500 g) [aRR (95% CI): 1.99 (1.08–3.65)], placental disorders [aRR (95% CI): 2.21 (1.07–4.56)], cesarean delivery [aRR (95% CI): 1.64 (1.27–2.12)], and postpartum hemorrhage [aRR (95% CI): 1.58 (1.14–2.19)] in women who conceived after a time to pregnancy ≥ 12 menstrual cycles compared with women who became pregnant in less than 3 menstrual cycles. More recently, Fine et al. [ 30 ] in a population-based cohort study of singletons that were spontaneously conceived by non-treated subfertile women, reported an increased risk for attention deficit/hyperactivity disorder in children aged 4–8 years compared with a control group of children from unassisted spontaneous conceptions [adjusted hazard ratio (aHR) (95% CI): 1.19 (1.16‐1.23)]. PCOS is defined as “a heterogeneous condition, which requires the presence of two of the following three criteria: (1) Oligoovulation or anovulation; (2) Hyperandrogenism (clinical evidence of hirsutism, acne, alopecia and/or biochemical hyperandrogenemia); (3) Polycystic ovaries, as assessed by ultrasound scan with more than 24 total antral follicles (2–9 mm in size) in both ovaries” [ 31 ]. PCOS accounts for ≈ 80% of women with anovulatory infertility (for review, see [ 32 ]), and 62% of PCOS infertile women use fertility hormone treatment to induce regular ovulation [ 33 ]. Oral anti-estrogen clomiphene citrate or the aromatase inhibitor letrozole is the first-line hormonal therapy used to induce ovulation. In anovulatory infertile women who have clomiphene citrate resistance and/or failure, parenteral gonadotropin therapy or laparoscopic ovarian drilling is recommended as a second-line pharmacological therapy. The insulin sensitizer metformin, alone or combined with clomiphene citrate, may be also used when there are not facilities available for monitoring follicular development induced by clomiphene citrate or letrozole treatment, or in PCOS women who are clomiphene citrate resistant, respectively (for review, see [ 32 ]). Thus, the number of studies focusing on PCOS women who conceive a singleton spontaneously without ovulation induction treatment is quite limited. A registry linkage study of 3,552 deliveries to non-treated, non-infertile PCOS women versus 88,273 deliveries to non-treated, non-infertile, non-PCOS women from Massachusetts [ 34 ] (Table 2 ) reported higher risk for gestational diabetes [aRR (95% CI): 1.37 (1.17–1.61)], pregnancy-induced hypertension/eclampsia/preeclampsia [aRR (95% CI): 1.27 (1.10–1.47)], and low birthweight (< 2,500 g) [aRR (95% CI): 1.28 (1.01–1.61)]. Upgrading evidence of level of certainty in the estimate of the effect sizes includes: (1) a large sample size; and (2) aRRs estimates and their corresponding 95% CI boundaries higher than 1.00. In contrast, downgrading evidence of level of certainty includes (1) possibility of misdiagnosis of women defined as having PCOS because varying criteria necessary for diagnosis; and (2) a statistical analysis adjusted for many covariates, including plurality of pregnancy (singleton versus multiple births), but not for other important covariates such as gestational weight gain. Consequently, the level of certainty in the estimates of the effect sizes is rated low to moderate. Fauque et al. [ 8 ], in a longitudinal national French study, adjusted for many maternal covariates and newborn sex, reported an overall significant increase in the risk for congenital abnormalities in singletons born to PCOS women following natural conception compared with spontaneously conceived singletons born to control women from the general French population. Note that Fauque et al. [ 8 ] did not show these data in their publication. Moreover, the statistical analysis performed did not adjust for hormonal treatment. Therefore, this study in not included in Table 2 . Finally, a covariate-controlled district-wide Chinese population-based questionnaire study by Zhang et al. [ 40 ], after excluding twin pregnancies, showed that children aged 3–6 years born to non-medically treated PCOS women ( n = 518) versus children born to control non-PCOS women ( n = 61,723) had higher risks for attention-deficit/hyperactivity disorder [aOR (95% CI): 1.41 (1.08–1.83)] and borderline symptoms, including at least mild symptoms of inattention [aOR (95% CI): 1.67 (1.20–2.25)], hyperactivity/impulsivity [aOR (95% CI): 1.51 (1.11–2.01)], or opposition/defiance [aOR (95% CI): 1.65 (1.37–1.98)]. Upgrading evidence of level of certainty in the effect size estimates includes: (1) a large sample size; and (2) aOR estimates and their corresponding 95% CIs boundaries higher than 1.00. In contrast, downgrading evidence of level of certainty includes (1) possible risk of sampling, design, and/or response bias associated with questionnaire studies; (2) use of a control group of non-PCOS women that may include women suffering from other reproductive disorders; and (3) a statistical analysis adjusted for many covariates related to socio-demographics and environmental exposures, but not for parental history of psychiatric disorders or child characteristics, including conception with infertility treatment, mode of delivery, gestational weeks, and birth weight. As the statistical analysis did not adjust for conception with infertility treatment, this study is not included in Table 2 . In symptomatic premenopasal women who do not desire pregnancy, endometriosis is usually treated with hormonal medications that suppress ovarian activity and generate a hypoestrogenic environment. However, if hormonal therapies are ineffective, contraindicated (e.g., women seeking a natural or spontaneous conception ), or have undesirable adverse effects, surgical removal of lesions is recommended (for reviews, see [ 41 , 42 ]). Notably, hormonal treatments and/or surgical removal of lesions do not cure endometriosis (for review, see [ 41 ]). As a matter of fact, endometriosis is a chronic, multifactorial disorder associated with many pathophysiological changes, including genetic and epigenetic variations in genes involved in inflammatory responses, hormone receptors, and oxidative stress (for review, see [ 43 ]). Thus, in this section, we will focus our attention on untreated endometriotic women who conceive spontaneously, regardless of whether they underwent surgical removal of endometriosis lesions before trying to conceive spontaneously. Nowadays, there is general consensus that endometriosis and adenomyosis are different gynecological conditions with specific pathways and clinical presentation (for review, see [ 44 ]). In particular, endometriosis is defined as “a disease characterized by the presence of endometrium-like epithelium and/or stroma outside the endometrium and myometrium, usually with an associated inflammatory process” [ 45 ]. On the other hand, adenomyosis is defined as “a benign uterine disorder in which endometrial glands and stroma are pathologically demonstrated in the myometrium” (for review, see [ 44 ]). However, the majority of previous studies dealing with endometriosis did not discriminate between endometriosis and adenomyosis. Several factors may explain this circumstance. For instance, these conditions may coexist in the same woman, with a prevalence of adenomyosis of 6% (95% CI: 3–11%) in subfertile women with concurrent endometriosis (for systematic review and meta-analysis, see [ 46 ]). Diffuse adenomyosis is present in one-third of women < 42 years of age regardless of whether or not women suffer from endometriosis [ 47 ]. Moreover, many previous studies recruited endometriotic women following the criteria laid down by the World Health Organization (WHO) International Classification of Diseases (ICD) editions prior to the 11th. These editions considered adenomyosis as a subtype of endometriosis and, consequently, adenomyotic women were included in the endometriosis group. In contrast, the current ICD-11 edition considers the two conditions as different entities. Taking into account these remarks, the systematic review and meta-analysis by Huang et al. [ 48 ] evidenced an increased risk for miscarriage (< 28 weeks) [OR (95% CI): 1.81 (1.44–2.28); I 2 = 96%; Chi 2 P ≤ 0.00001; n = 7 studies] in women with endometriosis who conceived spontaneously compared with fertile or subfertile women without endometriosis. Note that whereas adenomyosis was excluded from the meta-analysis and the effect size (OR) estimate and its corresponding 95% CI boundary were higher than 1.00, I 2 statistic was 96%, and Chi 2 test was highly significant ( P ≤ 0.00001). These values indicate the presence of a considerable heterogeneity across the seven studies analyzed. Furthermore, the control group included both fertile and subfertile women without endometriosis, and the statistical analysis did not adjust for plurality of pregnancy. Thus, this study is not incorporated into Table 2 . Later on, Breintoft et al. [ 49 ], in another systematic review and meta-analysis, found that women with endometriosis who conceived spontaneously (adenomyosis was excluded from this meta-analysis) displayed increased risk for preeclampsia [OR (95% CI): 1.29 (1.19–1.40); I 2 = 0%; Chi 2 P ≤ 0.63; n = 3 studies], placenta previa [OR (95% CI): 2.63 (2.41–12.87); I 2 = 0%; Chi 2 P ≤ 0.67; n = 3 studies], cesarean delivery [OR (95% CI): 1.88 (1.61–2.19); I 2 = 0%; Chi 2 P ≤ 0.87; n = 4 studies], small-for-gestational-age [OR (95% CI): 1.05 (1.02–1.08); I 2 = 0%; Chi 2 P ≤ 0.87; n = 5 studies], and preterm birth (birth before 37 completed weeks of gestation) [OR (95% CI): 1.81 (1.29–2.54); I 2 = 72%; Chi 2 P ≤ 0.006; n = 5 studies] compared with women without endometriosis. We should remark, that the effect sizes (ORs) estimates and their corresponding 95% CIs boundaries were higher than 1.00. In addition, I 2 statistic was 0% and Chi 2 test significance higher than 0.05 in practically all pregnancy and perinatal complications analyzed, indicating that heterogeneity across studies may not be important. The only exception was preterm birth with I 2 = 72% and a Chi 2 test significance ≤ 0.006, values that represent substantial heterogeneity. Other downgrading evidences of level of certainty include (1) a control group that likely contained both fertile and subfertile women without endometriosis; (2) the number of studies analyzed was small (3 to 5 studies), which may be associated with a large uncertainty in the estimates of I 2 ; and (3) the statistical analysis did not adjust for plurality of pregnancy. Consequently, this study is excluded from Table 2 . Interestingly, the adverse maternal and fetal/neonatal outcomes reported by Breintoft et al. [ 49 ] were confirmed (except the increased risk for cesarean delivery) and extended in a covariate-controlled longitudinal national French study by Epelboin et al. [ 50 ]. The reported additional risks were for venous thrombosis [OR (95% CI): 1.51 (1.18–1.94)] and placental abruption [OR (95% CI): 1.54 (1.34–1.77)]). However, the database did not discriminate between adenomyosis and endometriosis. Therefore, this study is not included in Table 2 . More recently, another systematic review and meta-analysis by Drummond et al. [ 35 ] (Table 2 ) involving singleton, spontaneously conceived pregnancies reported that endometriotic women have increased risk for preeclampsia compared with women without endometriosis. The increased risk for preeclampsia was observed both before [RR (95% CI): 1.47 (1.13–1.89); I 2 = 0%; Chi 2 P ≤ 0.49; n = 3 studies] and after excluding a study of women with adenomyosis [RR (95% CI): 1.44 (1.11–1.87); I 2 = 0%; Chi 2 P ≤ 0.36; n = 2 studies]. Upgrading evidence of level of certainty in the effect size estimate includes: (1) an RR estimate and its corresponding 95% CI boundary with values higher than 1.00; (2) I 2 = 0%; and (3) a non-significant Chi 2 test ( P ≤ 0.36). In contrast, downgrading evidence of level of certainty includes: (1) a control group likely composed by both fertile and subfertile women without endometriosis; and (2) a small sample size ( n = 2 studies), which is associated with uncertainty in the estimate of I 2 . Consequently, the level of certainty in the estimate of the effect size is rated low. As Drummond et al. [ 35 ] likely used a control group of fertile and subfertile women without endometriosis, the independent association of endometriosis with preeclampsia is likely underestimated. In other words, the effect size reported by Drummond et al. [ 35 ] is likely smaller than the effect size that may has been obtained if a control group of only fertile women had been selected. However, the fact that the effect size remained significant despite this potential underestimation would strengthen rather than weaken the validity of the significant association reported. Finally, a recent population-based, retrospective observational study of women with or without endometriosis, aged 20–49 years, with singleton, spontaneously conceived pregnancies [ 51 ] has reported increased risk for intrauterine growth restriction only in endometriotic women aged 20–29 years [aOR (95% CI): 1.41 (1.12–1.76)]. In contrast, the risk for pre-eclampsia and eclampsia [aOR (95% CI): 1.22 (1.05–1.41)] and preterm birth [aOR (95% CI): 1.36 (1.19–1.54)] was increased only in women aged 30–39 years. We should remark that the criteria followed by Chiu and Wang [ 51 ] to recruit endometriotic women were based on the diagnostic codes of the Ninth and Tenth ICD editions, which considered adenomyosis as a subtype of endometriosis. Thus, this study is not included in Table 2 . Likewise, another longitudinal national French study by Fauque et al. [ 8 ], adjusted for many maternal covariates and newborn sex, reported an overall significant increased risk for congenital abnormalities for singletons born to endometriotic women following natural conception compared with spontaneously conceived singletons born to control women from the general French population. Nonetheless, Fauque et al. [ 8 ] did not show these data in their publication and the statistical analysis did not adjust for the presence of adenomyosis. Therefore, this study is not included in Table 2 . Our literature search did not retrieve studies analyzing the potential association of endometriosis itself with postnatal health of spontaneously conceived singletons. Nevertheless, the larger study published so far on intergenerational inheritance of endometriosis [ 52 ] shows that daughters of endometriotic mothers have increased risk for endometriosis compared with control daughters of mothers without endometriosis [RR (95% CI): 2.12 (1.89–2.37)]. Regrettably, the study did not focus on spontaneous conceptions. In addition, the criteria followed to establish the group of daughters conceived by mothers with endometriosis were based on the diagnostic codes of the Eighth and Tenth ICD editions, which included adenomyosis as a subtype of endometriosis. Shin et al. [ 53 ] performed a retrospective study focused on singletons conceived spontaneously by 47 adenomyotic women and 8,087 women without adenomyosis using timed coitus without controlled ovulation stimulation. Non-significant associations between women withadenomyosis and women without adenomyosis of risk for preterm delivery (< 37 weeks) [4.3%(2/47) vs. 4.0% (324/8057); P ≤ 0.71] and low birthweight [6.4% (3/47) vs. 3.1% (246/8057);P ≤ 0.175] were evidenced. The sample size of adenomyotic women used by Shin et al. [ 53 ] was small ( n = 47) leading to low statistical power, which makes harder to detect real differences between groups if one existed. In addition, (1) the study was focused on singleton pregnant women with a diagnosis of adenomyosis only by ultrasounds in the first trimester of pregnancy, which may have led to a selection bias; and (2) the possible concomitant occurrence of adenomyosis with endometriosis and leiomyomas was not evaluated. Other studies have shown that adenomyosis may enhance or increase the risk for maternal/fetal complications associated with endometriosis when both conditions are manifested in the same woman. For instance, Berlanda et al. [ 54 ], in a questionnaire-based Italian multicenter study, analyzed the first singleton natural pregnancy of endometriotic women with adenomyosis. After stratifying endometriotic women ( n = 296) according to whether they suffered from either severe ( n = 13) or absent/mild adenomyosis ( n = 283), endometriotic women with severe adenomyosis exhibited increased risk for placenta previa [OR (95% CI): 16.68 (3.49–79.71)], preterm delivery (< 34 weeks) [OR (95% CI): 5.52 (1.38–22.09)], and cesarean delivery [OR (95% CI): 8.03 (1.69–38.25)] compared with endometriotic women with absent or mild adenomyosis. Note that the aim of the present study is to ascertain the independent/isolated association of female and male reproductive disorders displayed by untreated subfertile couples with pregnancy, perinatal, and childhood complications following singleton spontaneous conception. The interaction between adenomyosis and endometriosis reported by Shin et al. [ 53 ] and Berlanda et al. [ 54 ] does not satisfy this independence condition. Consequently, these studies [ 53 , 54 ] are not included in Table 2 . No studies on the potential association of adenomyosis itself with postnatal complications of singletons conceived spontaneously have been reported to date. DOR is “a term generally used to indicate a reduced number and/or reduced quality of oocytes, such that the ability to reproduce is decreased” [ 31 ]. Among the proposed tests to assess ovarian reserve, serum anti-Müllerian hormone (AMH) level is today considered one of the most reliable biomarkers of ovarian reserve (for systematic review and meta-analysis, see [ 55 ]). The prospective cohort study on naturally conceived pregnancies by Lyttle Schumacher et al. [ 56 ] found that women with severely DOR (AMH ≤ 0.4 ng/mL; n = 26) displayed a 2.3-fold increased risk for miscarriage prior to 20 weeks of gestation compared with women with an AMH ≥ 1 ng/mL ( n = 388) [HR (95% CI): 2.3 (1.3–4.3)]. That is, serum AMH levels were inversely associated with risk for miscarriage in naturally conceived pregnancies. Women were 30–44 years of age, had been attempting to conceive naturally for ≤ 3 months and were not currently breastfeeding, with no known history of infertility, PCOS, or endometriosis, and a non-infertile partner. Furthermore, the statistical analysis applied adjusted for age, race, obesity and history of recurrent pregnancy loss. Whereas the effect size (HR) was relatively high, the main limitations of the study by Lyttle Schumacher et al. [ 56 ], lie in the following facts: (1) a small sample size of women with severely DOR; (2) miscarriage was categorized into three groups: biochemical pregnancy, early pregnancy loss, and clinical pregnancy loss before 20 weeks of gestation; (3) the etiology of the miscarriage was unknown; (4) the own patients were who interpreted the definition of miscarriage in a baseline questionnaire; and (5) the statistical analysis did not adjust for plurality of pregnancy. Accordingly, this study is excluded from Table 2 . In another prospective study, Kostrzewa et al. [ 36 ] (Table 2 ) analyzed AMH levels of women in the first trimester of a spontaneous intrauterine pregnancy (< 12.6 weeks). The study compared the AMH levels displayed by women with an embryo/fetus without cardiac activity by ultrasound examination (miscarriage group; n = 30) versus control women with a normal embryo/fetus ( n = 33). Women were aged 18–34 years and had no history of fertility treatment, endocrine disorders, PCOS, obesity, antiphospholipid syndrome, thrombophilia, uterine anomalies, acute infections, assisted conception, and multiple gestations. The statistical analysis showed a 3.7-fold higher risk for miscarriage in women with AMH levels ≤ 1.1 ng/mL (4/30 in the miscarriage group vs. 0/33 in the control group) [RR (95% CI): 3.66 (2.1–6.4)]. The relatively high effect size (RR) evidenced by Kostrzewa et al. [ 36 ] together with the inclusion of women younger than 35 years suggest a high level of certainty. However, this is counteracted by the small sample size analyzed. Thus, the level of certainty in the estimate of effect size is rated low. POI is “a condition characterized by hypergonadotropic hypogonadism in women younger than age 40 years (also known as premature or primary ovarian failure). It includes women with premature menopause” [ 31 ]. POI is a multifactorial condition including multiple causes such as idiopathic/unknown, X-chromosome alterations, autosomal genetic disorders, autoimmune, infections, and iatrogenic following treatment with immunosuppressant drugs, surgery for gynecological disorders, or chemotherapy/pelvic irradiation for malignancy (for review, see [ 57 ]). Among these factors, Turner Syndrome or monosomy of the X chromosome is the most well-known genetic cause of POI. The monosomy of the X chromosome may be due to partial or complete loss of one X chromosome in 46,XX fetuses or complete loss of the Y chromosome in 46,XY fetuses (for review, see [ 58 ]). An early review of the literature analyzed 160 pregnancies coming from 74 women with Turner syndrome who conceived spontaneously [ 59 ]. Only 38% of the 160 pregnancies resulted in healthy children. The remaining pregnancies ended in spontaneous abortions (29%), stillbirths (7%), and malformed babies (20%) with either multifactorial congenital anomalies (6.9%) or chromosomal defects associated with Turner syndrome or Down’s syndrome (13.1%). No information was available in 6% of pregnancies and no control group for comparisons was documented. More recently, a retrospective study by Bernard et al. [ 60 ] evidenced a significantly ( P < 0.01) higher percentage of spontaneous miscarriages in 27 adult women with Turner syndrome who conceived naturally to 52 fetuses/newborns compared with women from the general French population (30.8% vs. 15.0%). Women with Turner syndrome were followed up in seven French endocrine units and control women were recruited using a database from the Directorate General for Health belonging to the French Health Ministry. Only 30 out of the 52 pregnancies (57.7%) resulted in a full-term delivery. Cesarean delivery percentages were also significantly ( P < 0.001) higher than in the general population (46.7% vs. 21%). However, in two patients (7.4%, 2/27), their spontaneous pregnancies occurred whereas they were on hormonal replacement therapy, and one patient (3.7%, 1/27) became pregnant while she was on oral combined contraceptive pill. In addition, the study by Bernard et al. [ 60 ] did not provide any information on the selection criteria and number of control women analyzed. Thus, the study is not included in Table 2 . Classic galactosemia is an autosomal recessive disease associated with POI. It affects 80% of infertile POI women, but the percentage increases up to 85% in women over 35 years of age (for review, see Derks et al. [ 61 ]). In a large international multicenter cohort study of 85 women suffering from both classic galactosemia and POI, van Erven et al. [ 62 ] found that five out of 20 (25%) spontaneous pregnancies from nine women ended in clinical miscarriages and another pregnancy resulted in fetal death at 36 weeks because of placental abnormalities. Note that most of the 85 women analyzed (78.7%) were using some form of hormone replacement therapy, mostly the birth control pill (42.7%). As in PCOS and endometriotic women, a longitudinal national French study by Fauque et al. [ 8 ], adjusted for many maternal covariates and newborn sex, reported an overall significant increase in the risk for congenital abnormalities for singletons born to POI women following natural conception compared with spontaneously conceived singletons born to control women from the general French population. Nevertheless, Fauque et al. [ 8 ] did not show these data in their publication, and the statistical analysis did not adjust for hormonal treatment. Note that the POI studies analyzed in this section did not meet the stringent inclusion criteria laid down in the present review. Consequently, none of them is included in Table 2 . In addition to conventional analyses, such as assessment of sperm vitality, motility, concentration, and morphology, complementary extended analyses, such as sperm DNA fragmentation and chromosomal anomalies, may be applied in certain situations, e.g. idiopathic recurrent pregnancy loss [ 63 ]. The idiopathic condition, accounts for 50–75% of couples experiencing recurrent pregnancy loss (for review, see Suker et al. [ 64 ]. We should mention that the definition of recurrent pregnancy loss varies widely in the literature. For instance, this term was defined, in 2017, as “The spontaneous loss of two or more clinical pregnancies prior to 22 completed weeks of gestational age” by the International Glossary on Infertility and Fertility Care [ 31 ]; in 2020, as “the spontaneous loss of two or more pregnancies” by the American Society for Reproductive Medicine (ASRM) [ 65 ]; in 2023, as ”the loss of two or more pregnancies. It excludes ectopic pregnancy and molar pregnancy” by the European Society for Human Reproduction and Embryology (ESHRE) [ 66 ]; and, in 2023, as “three or more first trimester miscarriages” by the Royal College of Obstetricians and Gynaecologists (RCOG) [ 67 ]. In this context, the systematic review and meta-analysis by Tan et al. [ 37 ] (Table 2 ) reported higher levels of sperm DNA fragmentation in male partners of women with a history of ≥ 2 or ≥ 3 idiopathic recurrent pregnancy losses following natural conception compared with male partners of fertile control couples [estimated average mean difference (EAMD) (95% CI): 11.98 (6.64–17.32), P ≤ 0.001; I 2 = 97.3%; n = 13 studies]. The high significance of the effect size (EAMD) estimate ( P ≤ 0.001) provides upgrading evidence of level of certainty. Nonetheless, this evidence is counteracted by the considerable heterogeneity across studies in the effect size estimate indicated by I 2 = 97.3%. Thus, the level of certainty in the effect size estimate is rated low to moderate. Thereafter, another systematic review and meta-analysis by Dai et al. [ 38 ] (Table 2 ), also focused on spontaneous conceptions with a control group of male partners of fertile couples, evidenced a significant association of ≥ 2 or ≥ 3 idiopathic recurrent pregnancy losses, not only with sperm DNA fragmentation [weighted mean differences (WMDs) (95% CI): 8.45 (1.48–15.42), P ≤ 0.018; I 2 = 99.4%, P ≤ 0.001; n = 8 studies], but also with lower levels of total motility [WMDs (95% CI): -10.30 (-15.03 - -5.57), P ≤ 0.05; I 2 = 82.3%, P ≤ 0.001; n = 7 studies] and progressive motility [WMDs (95% CI): -4.75 (-8.35 - -1.15), P ≤ 0.05; I 2 = 99.4%, P ≤ 0.001; n = 12 studies]. Upgrading evidence of level of certainty includes the presence of significant effect sizes (WMDs). However, the level of significance of the effect size for sperm DNA fragmentation ( P ≤ 0.018) was not as high as the value previously reported by Tan et al. [ 37 ] ( P ≤ 0.001), likely due to the lower number of studies analyzed (8 vs. 13). The levels of significance of effect sizes for total motility and progressive motility were even in the limits of statistical significance ( P ≤ 0.05). Furthermore, the estimated levels of heterogeneity across studies provided by I 2 statistic were considerable (99.4%, 82.3%, and 99.4%, respectively). Thus, the level of certainty in the estimated effect size for sperm DNA fragmentation is rated low to moderate, and for total motility and progressive motility is rated low. Recently, a cross-sectional study [ 68 ] has reported that male partners of women with ≥ 2 idiopathic recurrent pregnancy losses at < 24 weeks of gestation following natural conception display a significantly higher percentage of mean DNA fragmentation index ≥ 30% than control men with at least one previous live birth (54.2% vs. 25.7%; n = 35) [aOR (95% CI): 4.32 (1.39–13.48)]. However, women from control men conceived either spontaneously or following fertility treatments for female factor infertility such as ovulation induction or intrauterine insemination. Therefore, this study [ 68 ] is not included in Table 2 . Literature reporting an association between sperm chromosomal anomalies and idiopathic recurrent pregnancy loss following natural conception is much scarcer. Nevertheless, Collodel et al. [ 39 ] (Table 2 ) performed a retrospective study of 22 Italian male partners (aged 28–46 years) of women with ≥ 3 idiopathic recurrent pregnancy losses before 20 weeks of gestation following natural conception. Men were non-azoospermic with a normal 46, XY karyotype and normal hormonal profile, no history of radiotherapy, chemotherapy, chronic illness or medication, and absence of sperm defects of possible genetic origin. A cohort of 25 men (aged 22–40 years) of proven fertility was chosen as a control group. The study reported a significant higher percentage of sperm apoptosis [mean ± standard deviation (SD): 5.95 ± 3.03 vs. 4.06 ± 2.05; P ≤ 0.01], 1818YY diploidy [mean ± SD: 0.114 ± 0.06 vs. 0.075 ± 0.043; P ≤ 0.05], and 18YY disomy [mean ± SD: 0.09 ± 0.05 vs. 0.048 ± 0.032; P ≤ 0.01] in the idiopathic recurrent miscarriage group compared with the control group of men of proven fertility. Although differences between groups were significant, the retrospective design of the study together with the small sample size and associated low statistical power prevent from drawing strong conclusions on the reported effect sizes. Consequently, the level of certainty in the estimate of the effect sizes is rated low. The main limitation of this study lies in the scarce number of publications analyzing the adverse pregnancy and perinatal outcomes in singletons spontaneously conceived by non-hormonal-treated subfertile women. Even more striking is the fact that, as far as we are aware, no studies analyzing the potential health complications that may exhibit the resultant naturally-conceived singletons during childhood (and later long-term health) have been evidenced following the strict inclusion criteria laid down in the present study. Thus, a research priority for future studies is warranted to fill this knowledge gap. Another important limitation of the present study stems from the fact that, due to the inherent nature of literature reviews, it has not always been possible to find studies that used a control group of only fertile couples for comparisons. These studies may lead to underestimate the resulting effect sizes. We should note that the data reported in the present study cannot be used to make causal inferences between reproductive disorders and pregnancy and perinatal complications. As mentioned in the Introduction section, subfertility/infertility is a multifactorial disease that may be affected by many clinical, biological, behavioral, lifestyle, and environmental risk factors (for reviews, see [ 21 – 24 ]). Most of these factors have not been controlled for in the studies included in Table 2 . Likewise, most of the studies analyzed in the present study, focused on female reproductive disorders, did not adjust for male-factor-co-pathology. We cannot forget either the potential diagnostic misclassifications reported in some of the studies analyzed. For instance, we have excluded several relevant publications on endometriosis because the studies did not discriminate between adenomyosis and endometriosis. However, even after excluding adenomyotic women from the endometriosis group, it is not possible to rule out the occurrence of residual confounding due to the high percentage of women (33%) < 42 years of age displaying diffuse adenomyosis, irrespective of whether or not women suffer from endometriosis [ 47 ]. Likewise, the systematic reviews and meta-analyses on endometriosis analyzed in the present study [ 35 , 48 , 49 ] may have included studies that recruited endometriotic women following the criteria laid down by the ICD editions prior to the 11th (these editions considered adenomyosis as a subtype of endometriosis. Lastly, we should remark that we have defined subfertility as a less severe fertility status than infertility , i.e., subfertile women may conceive spontaneously, but infertile women would need to undergo IUI and/or ART to reach a clinical pregnancy. Therefore, the pregnancy and perinatal complications linked to couples’ subfertility reported in the present study may be less severe than those likely associated with couples’ infertility. Table 3. shows that several reproductive disorders either share the same pregnancy complications or are exclusively associated with specific pregnancy and perinatal complications. In particular, both endometriosis and PCOS are associated with pregnancy-induced hypertension/eclampsia/preeclampsia, and both DOR and low semen quality are linked to miscarriage. In contrast, PCOS is exclusively associated with gestational diabetes mellitus and low birthweight. Table 3 Shared and exclusive pregnancy and perinatal complications associated with female and male reproductive disorders exhibited by untreated subfertile couples following singleton spontaneous conception Reproductive disorders sharing the same complications Pregnancy and perinatal complications Endometriosis and PCOS Pregnancy-induced hypertension/eclampsia/preeclampsia DOR and low semen quality Miscarriage Reproductive disorders with exclusive complications PCOS Gestational diabetes mellitus and low birthweight Abbreviations: DOR diminished ovarian reserve, PCOS polycystic ovary syndrome Shared and exclusive pregnancy and perinatal complications associated with female and male reproductive disorders exhibited by untreated subfertile couples following singleton spontaneous conception Abbreviations: DOR diminished ovarian reserve, PCOS polycystic ovary syndrome Notably, the level of certainty in the estimate of the effect sizes reported in the six studies included in Table 2 was rated either low (n = 7) or low to moderate (n = 5). The main downgrading evidence used to rate the level of certainty in the estimate of effect sizes includes: (1) small sample size (n = 3 studies) [ 35 , 36 , 39 ]; (2) levels of significance of effect sizes in the limits of statistical significance (n = 2 studies) [ 38 , 39 ]; (3) possibility of misdiagnosis (n = 2) [ 34 , 35 ]; (4) presence of considerable heterogeneity across the studies analyzed in systematic reviews and meta-analyses (n = 2 studies) [ 37 , 38 ]; (5) use of a control group composed of fertile and subfertile women (n = 1 study) [ 35 ]; (6) statistical analysis without adjusting for important covariates (n = 1 study) [ 34 ]; and (7) retrospective study’s design (n = 1) [ 39 ]. Therefore, future studies should improve or correct these deficiencies. Moreover, the associations between reproductive disorders and pregnancy and perinatal, complications disclosed in this study may be isolated more precisely by breaking down each reproductive disorder into each one of their respec­tive subtypes/phenotypes. Further large prospective, multicenter cohort studies adjusted for important con­founding variables, with strict definitions of subtypes/ phenotypes within each reproductive disorder, well-defined control group consisting of only fertile women/ men, and experimental groups of women/men displaying particular reproductive disorders without male/female factor-co-pathologies are warranted.

Literature shows that fertility treatments, including ovulation induction (OI), intrauterine insemination (IUI), and assisted reproductive technology (ART) are independently associated with increased risk for pregnancy, perinatal, and childhood health complications (Table 1 ). However, the independent association of couples’ subfertility/infertility with pregnancy, perinatal, and childhood health complications has not been yet discriminated or isolated precisely. For instance, Table 1 includes the most recent study carried out to date aimed to isolate the association of couples’ infertility from fertility treatments [ 7 ]. The study analyzed a large statewide longitudinally data-linked population-based cohort of singleton infants conceived by women following either ART or OI/IUI treatment. The study was planned to determine the isolated association of either ART or OI/IUI with perinatal complications while controlling for couples’ infertility, i.e., the study design did not allow ascertaining the independent association of couples’ infertility with perinatal complications. In addition, the study was not designed to ascertain the isolated association of hormonal treatment, nor the individual association of female and male reproductive disorders with perinatal complications. Note that hormonal treatment itself contributes to adverse pregnancy, perinatal and childhood outcomes (Table 1 ). Moreover, there are many different female and male mechanisms/pathologies that may lead to couples’ subfertility/infertility. These mechanisms/pathologies include reproductive disorders, duration of infertility, the couples’ genetic load, as well as socio-demographic (e.g., advanced maternal and paternal age), biological, physiological, medical, behavioral, lifestyle, and environmental risk factors (for reviews, see [ 21 – 24 ]). Therefore, to consider subfertility/infertility as a single homogenous category may lead to drawing biased, imprecise, and unrealistic conclusions. A better approximation to ascertain the isolated association of couples’ subfertility/infertility would require the stratification of subfertile/infertile couples according to female and male reproductive disorders. Table 1 Risks for obstetric and perinatal adverse outcomes and childhood health complications associated with fertility treatments, including OI, IUI and ART Pregnancy/offspring complications Increased risks References OI  Obstetric and perinatal outcomes Placenta previa, pre-term delivery (< 37 weeks and < 34 weeks of gestation), non-spontaneous cephalic delivery, low birthweight (< 2,500 g, < 1,500 g, and < 1,000 g), small for gestational age, and neonatal resuscitation compared with naturally conceived singletons pregnancies [ 1 ] a  Childhood health complications Poorer cardiometabolic profiles in childhood compared with children born to fertile couples [ 2 ] IUI  Obstetric and perinatal outcomes Placenta previa, pre-term delivery (< 37 weeks and < 34 weeks of gestation), low birthweight (< 2,500 g and < 1,000 g), and small for gestational age compared with naturally conceived singletons pregnancies [ 1 ] b ART  Obstetric and perinatal outcomes Compared with spontaneously conceived pregnancies, higher risk for hypertensive disorders of pregnancy, including gestational hypertension and preeclampsia, cesarean delivery, preterm birth, very preterm birth, low Apgar score, composite neonatal adverse outcome indicator, admission to neonatal intensive care unit, prolonged birth admission (≥ 3 days), and rates of urgent and inpatient health services use during their first year, even in term singletons. Fresh embryo transfer is associated with PCOS-independent gestational diabetes mellitus, small for gestational age babies, low birthweight, and preterm birth; frozen embryo transfer is associated with large-for-gestational age babies and hypertensive disorders of pregnancy; IVF, but not ICSI, is associated with PCOS-independent gestational diabetes mellitus; ICSI may be associated with birth defects and poor semen quality in male progeny; and oocyte donation is associated with small for gestational age babies, and hypertensive disorders of pregnancy [ 3 ]; for review, see [ 4 ]; for systematic reviews and meta-analyses, see [ 5 , 6 ] Compared with spontaneously conceived singletons born to infertile parents, increased risk of preterm birth, large-for-gestational age, and hospital admission < 2 years of life. Fresh embryo transfer is associated with preterm birth, very preterm birth, small-for-gestational age, and hospital admission < 2 years of life. It has a protective effect for large-for-gestational age babies; frozen embryo transfer is associated with large-for-gestational age babies. It has a protective effect for small-for-gestational babies; IVF is associated with preterm birth, very preterm birth, and low Apgar score; ICSI is associated with preterm birth and hospital admission < 2 years of life [ 7 ] c Total, major, and most specific congenital malformations compared with infants conceived naturally [ 8 , 9 ]; for systematic reviews and meta-analyses, see [ 10 , 11 ] Childhood health complications Genetic and epigenetic alterations compared with naturally conceived offspring For reviews, see [ 4 , 12 , 13 ] Higher overall cancer risk in children (because increased risk of hematological malignancies, neural tumors, other solid tumors, leukemia, CNS tumors, retinoblastoma, hepatic tumors, bone tumors and extraosseous sarcomas, and epithelial tumors and melanoma) when compared with naturally conceived children, the general population, children not conceived via ART, and naturally conceived children of mothers with low fertility For systematic review and meta-analysis, see [ 14 ] ART conception is not significantly associated with increased risk of childhood overall cancer when compared with children conceived following non-ART treatments, such as fertility drugs or intrauterine insemination, in infertile populations For systematic review and meta-analysis, see [ 15 ] The presence of both chromosomal and non-chromosomal congenital malformations increases the childhood cancer risk for all cancers, for leukemia, and for embryonal tumors compared with children conceived naturally [ 9 ] Congenital anomalies, malignancies, pediatric hospitalization with any infectious morbidity, pediatric obstructive sleep apnea, asthma, obesity, metabolic syndrome, diabetes, cardiovascular diseases, and neurodevelopmental and psychiatric disorders compared with children from natural conceptions [ 16 , 17 ]; for review, see [ 4 ]; for systematic reviews and meta-analyses, see [ 18 – 20 ] a OI was defined as “the use of medication without any additional ART procedures to stimulate one or more mature follicles” b IUI was defined as “a fertilization procedure in which sperms are washed, concentrated, and injected directly into the uterus without ovulation stimulation medications” c A control group of spontaneously conceived singletons born to infertile parents was used to estimate the isolated effect of ART Abbreviations: ART assisted reproductive technology, CNS central nervous system, ICSI intracytoplasmic sperm injection, IUI intrauterine insemination, IVF in-vitro fertilization, OI ovulation induction, PCOS polycystic ovary syndrome Risks for obstetric and perinatal adverse outcomes and childhood health complications associated with fertility treatments, including OI, IUI and ART a OI was defined as “the use of medication without any additional ART procedures to stimulate one or more mature follicles” b IUI was defined as “a fertilization procedure in which sperms are washed, concentrated, and injected directly into the uterus without ovulation stimulation medications” c A control group of spontaneously conceived singletons born to infertile parents was used to estimate the isolated effect of ART Abbreviations: ART assisted reproductive technology, CNS central nervous system, ICSI intracytoplasmic sperm injection, IUI intrauterine insemination, IVF in-vitro fertilization, OI ovulation induction, PCOS polycystic ovary syndrome Being aware of the limited number of studies focused on discriminating the independent contribution of couples’ subfertility/infertility, as well as the difficulties in separating hormonal treatment from IUI and ART treatments, in the present study, we will focus our attention just on subfertile couples, not on infertile couples. Note that we define subfertile couples when women experience a spontaneous clinical pregnancy after a time to pregnancy of ≥ 12 months of regular, unprotected sexual intercourse. In contrast, we define infertile couples when women need to undergo OI/IUI and/or ART to reach a clinical pregnancy. Thus, the aim of this review is to ascertain the independent association of female and male reproductive disorders displayed by untreated subfertile couples with pregnancy, perinatal, and childhood complications following singleton spontaneous conception.