Does a history of recurrent pregnancy loss affect subsequent obstetric outcomes and placental findings in in vitro fertilization?

Purpose To assess perinatal outcomes and placental findings in in vitro fertilization (IVF) patients with previous recurrent pregnancy loss (RPL).

This was a retrospective cohort of live singleton births following IVF at a single university–affiliated center between 2009 and 2017. Outcomes were compared between patients with previous RPL, defined as two miscarriages (RPL group), and patients without RPL (control group). Placental examination was performed for all deliveries irrelevant of complications, and findings categorized according to the Amsterdam Placental Workshop Consensus.

One hundred seventy-two deliveries of women with previous RPL (RPL group) were compared to 885 controls. Maternal age, 36.2 ± 4.2 vs. 35.4 ± 4.2 years, p = 0.02, and rate of uterine fibroids, 12.7% vs. 7.3%, p = 0.01, were higher in the RPL group. The rate of nulliparity was lower in the RPL group, 63.3% vs. 74.1%, p = 0.003. Unexplained infertility and diminished ovarian reserve were more common in the RPL group and male factor infertility in controls. There was a lower rate of fresh embryo transfer in the RPL group, 50.5% vs. 64.7%, p < 0.001, and reduced endometrial thickness. Similar obstetric outcomes were noted in the groups after adjustment for confounders. Placental examinations were notable for lower placental thickness, β − 0.17 cm, 95%CI − 0.30–(− 0.0), a lower rate of velamentous cord insertion, aOR 0.44, 95%CI 0.20–0.95, and a higher rate of villous infarction, aOR 2.82, 95%CI 1.28–6.20 in the RPL group.

In IVF patients with a history of RPL, subsequent deliveries were associated with a limited number of placental lesions, yet with similar obstetric outcomes.

Recurrent pregnancy loss (RPL), In vitro fertilization (IVF), Placenta

Recurrent pregnancy loss (RPL) is typically determined in the presence of two or three pregnancy losses [1]. Different causes have been identified for RPL, and include structural uterine abnormalities, thyroid function disorders, thrombophilias, and genetic causes, which are assumed to explain most cases of early loss [2]. Indeed, in the absence of a formal genetic evaluation of products of conception, the assumption is of a sporadic genetic abnormality [3]. Unless higher order RPL has occurred, patients are often reassured in the context of younger maternal age, given lower risks for recurrence. The focus on the subfertility population is of interest, especially on in vitro fertilization (IVF) pregnancies, as this population has been demonstrated to exhibit a higher risk for adverse pregnancy outcomes [4]. This may stem from the inherent characteristics of this population and subfertility itself, or the effects of different technologies employed in assisted reproduction [5]. The incidence of RPL has been previously demonstrated to be higher than that for unassisted pregnancies [6, 7], most probably due to an increased incidence of clinical miscarriages and not biochemical pregnancy losses [8]. This raises the question of the effect on subsequent successful pregnancies, in this growing group of patients. Past studies in the general population have pointed to an increased rate of adverse pregnancy outcomes following RPL, including gestational diabetes, preeclampsia, preterm birth, fetal growth restriction, placental abruption, oligo/polyhydramnios, cesarean delivery, and perinatal death [6, 7, 9–11], although the risk may vary according to the cause for RPL [12]. Yet, none of the above-mentioned studies focused on IVF pregnancies, and none incorporated placental examination. Placental analysis could potentially shed light on clinical correlations previously observed, as most obstetric complications are associated with typical placental pathologies, which may even precede clinical presentation [13]. Thus, the objective of this study was to investigate obstetric outcomes and placental findings in IVF pregnancies, of patients with previous RPL.

Study population This is a retrospective cohort study of live-born singleton deliveries at the Royal Victoria Hospital, affiliated with McGill University from 2009 to 2017. During the study period, an institutional policy was implemented, according to which pathological examination of placentas was performed for all deliveries, of both complicated and uncomplicated pregnancies. Included in the study were live singleton deliveries at 24-week gestation or greater, of pregnancies attained by IVF with autologous oocytes. Excluded were cycles with oocyte donation, in vitro maturation, preimplantation genetic testing, and pregnancies that started with two gestational sacs. None of the subjects in the study had uterine anomalies. Computerized files eligible for inclusion were reviewed and data were collected, regarding patient demographics, infertility history, and IVF cycle characteristics, obstetric outcomes, and placental histopathological findings. We defined RPL as two or more previous miscarriages, which included documented biochemical or clinical pregnancies. We compared obstetric outcomes and placental histology of IVF pregnancies with previous RPL (RPL group) and controls with no history of RPL (control group). Notably, previous pregnancy losses were either following IVF treatments or from past spontaneous conceptions, as documented in patients’ files by clinic physicians. Treatment protocols Ovarian stimulation was achieved with Follicle Stimulating Hormone (FSH) with or without Luteinizing Hormone (LH), and the dose was adjusted according to patient age, ovarian reserve markers, body mass index, and treatment history. Ovulation suppression was achieved by GnRH antagonists (Antagonist protocol), given on the sixth day of gonadotropin treatment, or GnRH agonists (Agonist protocol), initiated in the luteal phase, after which stimulation was started following sonographic evaluation. Patients were evaluated throughout stimulation by sonographic monitoring of follicular growth and endometrial thickness and assessment of serum estradiol levels. Triggering with hCG and/or GnRH agonists was undertaken when a minimum of two follicles reached 18 mm in mean diameter measured in two perpendicular planes, and the choice of triggering was according to stimulation protocol and ovarian hyperstimulation risk assessment. Single blastocyte transfer was preferred, although the transfer of more than one embryo and cleavage stage embryos was considered in accordance with patient age, the number of past failed transfers, and treatment outcomes. All remaining adequate quality embryos following fresh transfer were cryopreserved, while in cases at risk for ovarian hyperstimulation syndrome, no fresh transfer was performed and all embryos were frozen. Following a fresh transfer, vaginal or intramuscular progesterone supplementation was prescribed for luteal support. For programmed frozen-thawed transfers, estradiol was administered until adequate endometrial thickness was achieved, and estradiol and progesterone were continued following embryo transfer. For natural frozen-thawed transfer, luteal support was not routinely given. All β-HCG level measurements were performed on day 16 of embryo age following transfer. For losses which occurred while treated at our center, a positive β-HCG value (> 10 mUI/mL) which remained below 1000 mUI/mL and did not progress to a clinical or ectopic pregnancy was considered a biochemical pregnancy. RPL investigation and treatment Our institution initiated the investigation of RPL in the presence of two miscarriages [14]. The investigation included a diagnostic hysteroscopy with endometrial biopsy, and treatment of intracavitary pathologies as needed (polyps/adhesions/submucosal fibroids). In addition, sonographic evaluation was performed to exclude new hydrosalpinx, and serum assessment of inherent or acquired thrombophilia and thyroid function was undertaken and repeated as needed[1]. Treatment with low molecular weight Heparin and/or Micropirin was administered in accordance with findings and the attending physician’s discretion [1]. Placental examination By the Royal Victoria institutional protocol, placental evaluation was performed for all deliveries during the study period, regardless of pregnancy complication status. All examinations were performed by the institutional pathology department, with examiners blinded to reproductive history. The examination was initiated with macroscopic placental evaluation, which included evaluation and documentation of placental weight and size, examination of the umbilical cord, free membrane, fetal and maternal surface, placental parenchyma, and any additional abnormality identified. Following gross examination, chosen sections from the umbilical cord, membrane, and random placental parenchymal were fixated in formalin for histological inspection. Placental histological lesions were categorized into four main pathophysiological groups according to the Amsterdam Placental Workshop Group Consensus [15, 16]—anatomic, inflammatory, villous maturation, and vascular malperfusion lesions. Statistical analysis Statistical analysis was performed with Epi Info, version 7.0 (Centers for Disease Control and Prevention, Atlanta, GA). Continuous variables were calculated as mean ± standard deviation (SD) or median (range/interquartile range (IQR)) and compared with Student’s t-test or the non-parametric Mann–Whitney test as appropriate. Categorical variables were calculated as numbers (percentage) and compared with chi-square or Fisher’s exact test as appropriate. All tests were two-tailed, and statistical significance was determined as a p-value < 0.05. Regression analyses were employed for all outcomes found significant, in which patient baseline and IVF cycle characteristics found significant in univariable analysis served as independent variables. This included, among others, controlling for the confounding effect of fresh vs. frozen-thawed embryo transfer, previously correlated with different placental lesions [17, 18]. Ethical approval of the study was obtained from the Research Ethics Board of the McGill University Health Center, approval number MUHC-2019–5026.

A total of 1057 live singleton deliveries following IVF were eligible for inclusion in the study, 172 in the RPL group and 885 controls. Patient demographics and infertility workup are listed in Table 1. Maternal age was higher in the RPL group, 36.2 ± 4.2 vs. 35.4 ± 4.2 years, p = 0.02. As per study design, higher gravidity was noted in the RPL group, and a lower rate of nulliparity, 63.3% vs. 74.1%, p = 0.003. Antral follicle counts were similar between the groups, and a higher rate of uterine fibroids was noted in the RPL group, 12.7% vs. 7.3%, p = 0.01. Infertility etiology differed for some indications between the groups so that a higher rate of patients in the RPL group had a diagnosis of unexplained infertility and diminished ovarian reserve and a lower rate of patients in that group had a diagnosis of male factor infertility. Table 1. | Variable | RPL group n = 172 | Controls n = 885 | p | |---|---|---|---| | Age (years), mean ± SD | 36.2 ± 4.2 | 35.4 ± 4.2 | 0.02 | | BMI (kg/m2), mean ± SD | 25.1 ± 2.1 | 25.0 ± 2.2 | 0.80 | | Gravidity, median (IQR) | 4 (3–5) | 1 (1–2) | < 0.001 | | Nulliparous, n (%) | 109 (63.3%) | 656 (74.1%) | 0.003 | | Smoking, n (%) | 6 (3.4%) | 29 (3.2%) | 0.88 | | Antral follicle count, median (IQR) | 16 (9–25) | 15 (9–25) | 0.96 | | Uterine fibroids, n (%) | 22 (12.7%) | 65 (7.3%) | 0.01 | | Paternal age, n (%) | 40.2 ± 5.8 | 39.0 ± 5.9 | 0.01 | | Infertility etiology (main): | ||| | Male factor, n (%) | 40 (23.2%) | 312 (35.2%) | 0.002 | | Ovulation disorder, n (%) | 17 (9.8%) | 12 (14.0%) | 0.14 | | Unexplained infertility, n (%) | 53 (30.8%) | 202 (22.8%) | 0.02 | | Diminished ovarian reserve, n (%) | 28 (16.2%) | 96 (10.8%) | 0.04 | | Tubal factor, n (%) | 20 (11.6%) | 88 (9.9%) | 0.50 | | Endometriosis, n (%) | 9 (5.2%) | 48 (5.4%) | 0.91 | | Other, n (%) | 5 (2.9%) | 15 (1.6%) | 0.28 | SD standard deviation, n number, BMI body mass index, pre-gestational A lower rate of patients in the RPL group underwent fresh embryo transfer, 50.5% vs. 64.7%, p < 0.001, and average endometrial thickness before transfer was noted to be lower in the RPL group, 9.9 ± 2.1 vs 10.3 ± 2.2 mm, p = 0.03 (Table 2). A higher rate of patients in the RPL group were treated with aspirin and/or low molecular weight heparin, 16.8% vs. 4.6%, p < 0.001 and 12.7% vs. 2.3%, p < 0.001, respectively. Obstetric outcomes and birthweight were similar between the groups, except for placenta accreta, which was more common in the RPL group, 4.0% vs. 1.4%, p = 0.02. Table 2. | RPL group n = 172 | Controls n = 885 | p | | |---|---|---|---| | Cycle course: | ||| | Fresh cycle, n (%) | 87 (50.5%) | 573 (64.7%) | < 0.001 | | Intracytoplasmic sperm injection, n (%) | 106 (68.8%) | 583 (75.9%) | 0.06 | | Single embryo transfer, n (%) | 125 (72.6%) | 646 (72.9%) | 0.93 | | Blastocyte transferred, n (%) | 136 (79.0%) | 653 (73.7%) | 0.14 | | Endometrial thickness (millimeters), mean ± SD | 9.9 ± 2.1 | 10.3 ± 2.2 | 0.03 | | Aspirin treatment, n (%) | 29 (16.8%) | 41 (4.6%) | < 0.001 | | Low molecular weight heparin treatment, n (%) | 22 (12.7%) | 21 (2.3%) | < 0.001 | | Pregnancy complications: | ||| | Gestational diabetes mellitus, n (%) | 26 (15.1%) | 96 (10.8%) | 0.10 | | Preeclampsia, n (%) | 10 (5.8%) | 33 (3.7%) | 0.20 | | Low lying placenta, n (%) | 9 (5.2%) | 34 (3.8%) | 0.39 | | Placenta accreta, n (%) | 7 (4.0%) | 13 (1.4%) | 0.02 | | Obstetric outcomes: | ||| | Gestational age (weeks), mean ± SD | 38.4 ± 2.1 | 38.5 ± 2.0 | 0.49 | | Preterm delivery, n (%) | 13 (7.5%) | 81 (9.1%) | 0.50 | | Placental abruption, n (%) | 7 (4.0%) | 24 (2.7%) | 0.33 | | Cesarean delivery, n (%) | 69 (40.1%) | 290 (32.7%) | 0.06 | | Gender—male, n (%) | 95 (55.2%) | 435 (49.1%) | 0.14 | | Birthweight | 3284 ± 568 | 3293 ± 608 | 0.86 | | Low birth weight, n (%) | 11 (6.5%) | 66 (7.6%) | 0.59 | SD standard deviation, IQR interquartile range, n number Placental findings of the study groups are presented in Table 3 and Fig. 1. On gross placental examination, placental thickness was noted to be lower in the RPL group, 1.74 ± 0.72 vs. 1.98 ± 0.59 cm, p < 0.001. Velamentous insertion of the cord was significantly more common in the placentas of controls, 9.7% vs. 4.6%, p = 0.03, while an accessory placental lobe was significantly more common in the RPL group, 3.4% vs. 0.7%, p = 0.003. Inflammatory and maturation disorder lesions were similar between the groups. Among vascular lesions, a significantly higher rate of villous infarction was demonstrated in the RPL group, 6.4% vs. 2.4%, p = 0.004, as was a higher rate of parenchymal calcifications, 8.1% vs. 4.2%, p = 0.03. Table 3. | RPL group n = 172 | Controls n = 885 | p | | |---|---|---|---| | Placental weight (grams), mean ± SD | 636 ± 152 | 638 ± 171 | 0.86 | | Placental thickness (cms), mean ± SD | 1.74 ± 0.72 | 1.98 ± 0.59 | 0.99 | | Umbilical marginal insertion, n (%) | 35 (20.3%) | 212 (23.9%) | 0.30 | | Umbilical furcate insertion, n (%) | 3 (1.7%) | 21 (2.3%) | 0.78 | | Umbilical velamentous insertion, n (%) | 8 (4.6%) | 86 (9.7%) | 0.03 | | Circummarginate insertion, n (%) | 21 (12.2%) | 120 (13.5%) | 0.63 | | Circumvallate insertion, n (%) | 0 | 10 (1.1%) | 0.38 | | True knot, n (%) | 2 (1.1%) | 8 (0.9%) | 0.67 | | Hypercoiling of cord, n (%) | 2 (1.1%) | 6 (0.6%) | 0.62 | | Bilobated placenta, n (%) | 5 (2.9%) | 12 (1.3%) | 0.13 | | Accessory lobe, n (%) | 6 (3.4%) | 7 (0.7%) | 0.003 | | Inflammatory disorders | ||| | Acute chorioamnionitis (any), n (%) | 16 (9.3%) | 88 (9.9%) | 0.79 | | Acute chorioamnionitis with moderate to severe maternal inflammatory response, n (%) | 12 (6.9%) | 57 (6.4%) | 0.79 | | Acute chorioamnionitis with moderate to severe fetal inflammatory response, n (%) | 7 (4.0%) | 20 (2.2%) | 0.16 | | Chronic deciduitis, n (%) | 1 (0.5%) | 6 (0.6%) | > 0.99 | | Villitis of unknown etiology, n (%) | 5 (2.9%) | 31 (3.5%) | 0.69 | | Maturation disorders | ||| | Accelerated villous maturation, n (%) | 10 (5.8%) | 70 (7.9%) | 0.34 | | Delayed villous maturation, n (%) | 5 (2.9%) | 17 (1.9%) | 0.40 | | Distal villous hypoplasia, n (%) | 3 (1.7%) | 14 (1.5%) | 0.74 | | Increased syncytial knotting, n (%) | 11 (6.4%) | 64 (7.2%) | 0.69 | | Vascular disorders | ||| | Retroplacental hematoma, n (%) | 1 (0.5%) | 22 (2.4%) | 0.15 | | Cord thrombosis, n (%) | 1 (0.5%) | 1 (0.1%) | 0.29 | | Intervillous thrombosis, n (%) | 26 (15.1%) | 96 (10.8%) | 0.10 | | Intramural fibrin, n (%) | 0 | 2 (0.2%) | > 0.99 | | Villous infarction, n (%) | 11 (6.4%) | 21 (2.3%) | 0.004 | | Avascular villi, n (%) | 2 (1.1%) | 17 (1.9%) | 0.75 | | Perivillous fibrin deposition, n (%) | 19 (11.0%) | 84 (9.4%) | 0.52 | | Maternal vasculopathy, n (%) | 12 (6.9%) | 44 (4.9%) | 0.28 | | Fetal vasculopathy, n (%) | 0 | 11 (1.2%) | 0.22 | | Chorangiosis, n (%) | 11 (6.4%) | 94 (10.6%) | 0.08 | | Fetal vascular malperfusion (one criterion or more) | 7 (4.0%) | 37 (4.1%) | 0.94 | | Maternal vascular malperfusion (one criterion or more) | 68 (39.5%) | 354 (40.0%) | 0.90 | | Calcifications | ||| | Chorionic plate calcifications | 7 (4.0%) | 32 (3.6%) | 0.77 | | Maternal surface calcifications, n (%) | 44 (25.5%) | 265 (29.9%) | 0.24 | | Parenchymal calcifications, n (%) | 14 (8.1%) | 38 (4.2%) | 0.03 | | Nucleated RBC, n (%) | 3 (1.7%) | 8 (0.9%) | 0.40 | | Chorangioma, n (%) | 2 (1.1%) | 5 (0.5%) | 0.31 | Multivariate logistic regression analyses were composed, in which outcomes with a trend for significance/significance on univariable analysis served as dependent variables (placenta accrete, cesarean delivery, velamentous cord insertion, accessory lobe, villous infarction, and parenchymal calcifications). Baseline variables and cycle characteristics significant between the groups served as independent variables and included maternal age, nulliparity, uterine fibroids, diminished ovarian reserve, male factor, unexplained infertility, fresh transfer, endometrial thickness, aspirin, and low molecular weight heparin treatment, as well as RPL. After adjustment for confounders, RPL attained significance for velamentous insertions (aOR 0.44, 95%CI 0.20–0.95) and villous infarctions (aOR 2.82, 95%CI 1.28–6.20), and a trend for significance for accessory placental lobes (aOR 3.20, 95%CI 0.99–10.33). In a linear regression analysis for placental thickness with similar confounders, RPL was also found independently associated with reduced placental thickness, β − 0.17 cm (95%CI − 0.30–(− 0.03) (Table 4). Table 4. | OR | 95% C.I | p | || |---|---|---|---|---| | Lower | Upper | ||| | Model I – Velamentous cord insertion | 0.44 | 0.20 | 0.95 | 0.03 | | Model II – Accessory lobe | 3.20 | 0.99 | 10.33 | 0.05 | | Model III – Villous infarction | 2.82 | 1.28 | 6.20 | 0.009 | | Linear analysis β | |||| | Model IV – Placental thickness, centimeters | − 0.17 | − 0.30 | − 0.03 | 0.01 | OR odds ratio, C.I confidence interval Adjusted for maternal age, nulliparity, uterine fibroids, diminished ovarian reserve, male factor, unexplained infertility, fresh transfer, and endometrial thickness A separate analysis was performed for patients with three or more miscarriages (n = 83) and patients with no such history (n = 974), hereby described and not presented as a table. Patient demographics were notable for a higher maternal age, lower rate of nulliparity, and a lower rate of treatment for male factor infertility, and cycle course was notable for a higher rate of intracytoplasmic injection, a lower rate of fresh embryo transfers, and higher rate of treatment with aspirin and/or low molecular weight heparin. After similar adjustment for confounders, RPL found associated only with significantly lower placental thickness, β − 0.22 cm (95%CI − 0.40–(− 0.04).

The objective of our study was to evaluate obstetric outcomes and placental findings in IVF pregnancies of patients with previous RPL. After adjustment for confounders, we noted similar obstetric outcomes in the RPL group. Placental examination was notable for reduced placental thickness, a lower rate of velamentous cord insertion, and a higher rate of villous infarction. Previous studies have addressed the effect of RPL on subsequent pregnancy outcomes in the general population. In a large cohort of over 60,000 deliveries, RPL was found independently associated with preeclampsia, stillbirth, small for gestational age neonates, preterm birth, and placental abruption in subsequent deliveries [7]. Field et al. investigated 2030 deliveries of women with three or more miscarriages and 28,023 deliveries with no such history [6]. The authors noted a higher rate of preterm birth and perinatal death among RPL patients. These findings were reaffirmed in additional studies [9–12], which also demonstrated a higher rate of intrauterine growth restriction, preeclampsia, gestational diabetes, and cesarean delivery. Thus, it seems that women who experience RPL are at risk for placental complications of pregnancy, questioning the association between the two. Yet, although some of the studies did account for the effect of assisted reproduction by statistical means, none focused uniquely on this group and accounted for cycle variables that are known to affect obstetric outcomes (infertility etiology, fresh/frozen-thawed embryo transfer, endometrial thickness). Placental examination was performed for all deliveries in the study cohort irrespective of pregnancy complication status. The analysis of placentas enabled us to examine in utero processes that would not necessarily fully manifest as clinical complications and to assess whether any adverse signs of placentation exist in RPL pregnancies. Upon gross examination, placentas from the RPL group were found associated with decreased placental thickness and accessory lobes. Decreased thickness remained significant after adjustment for all potential confounders, including thin endometrium, recently noted by our group to entail adverse obstetric outcomes and placental findings [19]. While this may be regarded as a marker of suboptimal placentation [20], we must also take into account that we did not have information about previous curettage (as discussed in the limitations below), so that thinner placentas may also be a result of previous endometrial injury after miscarriages, and not an inherent characteristic of the RPL group. This is likely the cause of the increased rate of placenta accreta seen in the RPL group. We additionally noted a decreased risk of velamentous cord insertion with RPL. This may relate to the lower rate of fresh embryo transfer in this group, and probable lower estradiol levels, as velamentous cord insertion has been linked to supraphysiological estradiol levels in IVF [21]. Yet, we did adjust for fresh transfer in logistic regression, so an alternative pathogenesis should be additionally considered. Finally, we noted a significantly higher rate of villous infarction in the RPL group. This lesion is considered a maternal malperfusion lesion and has been associated in past studies with intrauterine fetal growth restriction [22], hypertensive disorders of pregnancy [23], and fetal death [24]. Although we did not demonstrate these clinical associations in our cohort, it is possible our sample size was not adequate for that purpose, and thus findings from previous studies should be considered in the interpretation of our results. Overall, it seems that the placental differences demonstrated between the groups in our study are few of many variables examined, and that placental examination was nonsignificant between the groups for the vast majority of outcomes investigated. Our study is not without limitations. The study was retrospective, and as such not all outcomes of interest were available for analysis. This included mode of treatment for previous pregnancy loss, which may affect subsequent pregnancies in cases of surgical evacuation of pregnancy and endometrial injury. Indeed, the RPL group was notable for thinner endometrial lining and a higher rate of placenta accreta, possibly supporting this notion. We did account for endometrial lining in multivariate regression, although it is possible that previous curettage exerts an independent effect on obstetric outcomes and subsequent placentation. We were also missing a distinction between explained versus unexplained cases of RPL, between biochemical pregnancies and miscarriages of clinical pregnancies, and between repeat losses of IVF-obtained pregnancies versus unassisted ones, which could prove to have different implications for future pregnancies. In a prospective study, we could better account for treatment variables (including stimulation protocol, triggering, and luteal support), and for a uniform definition of biochemical pregnancies (based in the current study on physician coding, for pregnancy losses prior to IVF treatment). In addition, numbers available for analysis remain limited, especially in the context of the sub-analysis of RPL cases with three or more previous losses. Finally, cases of preimplantation genetic testing were excluded from analysis due to the uncertain effects of the procedure on placental outcomes, and minimal cases available for inclusion. Yet, it is possible some patients with more pronounced RPL opted for preimplantation testing, and thus analysis would not include these cases. In practice, the number of cases performed at our center is low, so the actual effect of this exclusion is probably negligible. The study is notable for several unique aspects. The study adds to the limited literature to date on RPL in the IVF population and is also unique in its inclusion of placental analysis. We also addressed all potential confounders in regression analyses, so we could present independent correlations. Finally, placental examinations were performed by a single specialized perinatal pathologist, who was unaware of the patients’ previous reproductive history. Importantly, the risk of selection bias was minimized, as during the study period the institutional policy was for the assessment of placentas from all deliveries, and not only complicated ones. In conclusion, we found IVF pregnancies after RPL to entail similar obstetric outcomes to pregnancies in women without RPL. Despite several isolated differences in placental findings discussed above, the overall placental analysis was also similar for RPL patients. Our findings remain to be validated in studies with a larger number of cases, and an analysis of primary versus secondary RPL. Yet, these findings do offer reassurance to IVF patients who experienced past RPL, as future obstetric outcomes and placentation seem comparable. Our findings possibly support the notion of RPL as a sporadic event in most cases, as placental analysis did not point to an altered uterine-placental interface, for most characteristics analyzed. Author contribution All authors contributed to conception and design, acquisition of data, analysis and interpretation of the data, drafting of the article, and final approval of the version to be published. Data availability As per request from corresponding author. Code availability Not applicable. Declarations Conflict of interest The authors declare no competing interests. Footnotes Publisher's note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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