Impact of intramural non-cavity-distorting leiomyoma on placental histopathology and perinatal outcome in singleton live births resulting from in vitro fertilization treatment

Abstract

Purpose

To evaluate the effect of non-cavity-distorting intramural leiomyomas on the placental histopathology pattern and perinatal outcome in singleton live births resulting from in vitro fertilization treatment.

Methods

The study population included all singleton live births following in vitro fertilization treatment with autologous oocytes during the period from 2009 to 2017. Primary outcomes included anatomical, inflammation, vascular malperfusion, and villous maturation placental features. Secondary outcomes included fetal, maternal, delivery, and perinatal complications.

Results

A total of 1119 live births were included in the final analysis and were allocated to the group of pregnancies with non-cavity-distorting intramural myomas (n = 101) and without myomas (n = 1018). After the adjustment for confounding factors, the non-cavity-distorting intramural myomas were found to be significantly associated with assisted placental delivery (OR 2.4; 95% CI 1.5–3.9), furcate cord insertion (OR 3.6; 95% CI 1.4–9.3), circumvallate membranes insertion (OR 5.2; 95% CI 1.4–19.3), chronic deciduitis (OR 8.2; 95% CI 1.6–42.2), focal intramural fibrin deposition (OR 25.1; 95% CI 2.1–306.2), subchorionic thrombi (OR 3.6; 95% CI 1.7–7.6), maternal vasculopathy (OR 2.5; 95% CI 1.2–5.5), and chorangioma (OR 5.9; 95% CI 1.4–25.2) as well as with the failure of labor progress (OR 2.4; 95% CI 1.3–4.4) and induction (OR 3.2; 95% CI 1.2–9.0).

Conclusion

Intramural non-cavity-distorting myomas have a significant impact on the placental histopathology with a higher incidence of dysfunctional labor.

Introduction

Uterine leiomyomas (myomas) represent benign monoclonal tumors of smooth muscle cells and their prevalence reaches 60% among women of reproductive age [1]. The International Federation of Gynecology and Obstetrics (FIGO) classified myomas according to their location in the uterine wall as submucous, intramural, and subserosal leiomyomas. Additional subclassification categorizes the leiomyomas as types from 0 to 8 relative to the uterine cavity and myometrium depth [2].

Myomas are identified in over 10% of early pregnancies [3]. The impacts of a uterine leiomyoma on the obstetric and perinatal outcomes differ according to the myoma location. Large submucosal myomas distorting the uterine cavity (FIGO types 0–2) have been associated with pregnancy loss, preterm birth (PTB), placenta previa, and breech presentation [4, 5]. Abnormal myometrial blood flow circulation has also been demonstrated in the presence of intramural myomas. The adverse effect of intramural myomas on implantation could occur even when the uterine cavity was not distorted [6, 7]. It was speculated that intramural myomas may interfere with normal implantation and placentation through the alterations in implantation factors’ secretion, uterine junctional zones’ function, myoma pseudocapsule effects, and abnormal uterine peristalsis [8]. Disruption of the trophoblast invasion and abnormal placentation in the presence of uterine myomas may lead to spontaneous pregnancy loss, intrauterine fetal growth restriction (IUGR), and PTB [7, 9].

The effects of an intramural leiomyoma on placental histopathology characteristics involved in the development of perinatal complications remain unclear. The difficulty with such studies is the possibility of selection bias. In general, only placentas of high-risk pregnancies are sent for histopathological examination [10, 11]. The exclusion of low-risk pregnancies from the analysis, which encompass most live births, is an important confounding factor in the evaluation of the effect of uterine leiomyomas on placental histopathology pattern. At our institution, all placentas from pregnancies resulted after in vitro fertilization (IVF) treatments undergo pathological examination irrelevant of complication status or women’s age. This allows us to perform a comprehensive analysis of placental histopathology features in pregnancies complicated with uterine myomas.

The purpose of our study was to evaluate the effect of non-cavity-distorting intramural myomas on the placental histopathology pattern and perinatal outcome in singleton live births resulting from IVF treatments.

Material and methods

Population

We evaluated data of all live births resulting from IVF treatment at the Royal Victoria Hospital (the primary teaching hospital of McGill University) during the period from 2009 to 2017. The data were retrospectively collected from medical records and included female age, body mass index (calculated at 10 to 12 weeks of gestation), smoking status, chronic comorbidities, gynecological and obstetric history, infertility assessment results, characteristics of IVF treatment, maternal and fetal complications, delivery mode and complications, perinatal outcome, and placental histopathology results.

All live births resulting from autologous oocytes were included in our cohort study. We excluded cases with abnormal uterine cavity on the baseline preconception ultrasound examination (endometrial polyps, submucous myomas, intrauterine adhesions), intramural myomas extruding into the endometrial cavity (FIGO type 2), single intramural myomas < 1 cm in diameter, subserosal myomas (FIGO types 7), cervical myomas not affecting the myometrium (FIGO type 8), previous uterine surgery including cesarean sections, gestational carrier cycles, oocyte recipient cycles, in vitro maturation and preimplantation genetic diagnosis cycles, and multiple pregnancies. Placental pathology results, obstetrical and perinatal outcomes from pregnancies complicated by intramural myomas, were compared with those without uterine leiomyoma. McGill University Health Centre Research Ethics Board approved the study (MUHC 2019-5026).

Uterine myoma and placenta evaluation

Uterine myomas were identified on a transvaginal (4–9 MHz) and transabdominal (2–8 MHz) preconception ultrasound. The Voluson E8 ultrasound machine (GE Healthcare, Wauwatosa, WI, USA) was used for all examinations. We collected the data of the number, location, and size of the myomas. Those parameters, in addition to fetal and placental evaluation, were re-confirmed by the transabdominal ultrasound performed at 34 to 36 weeks of gestation. We also identified the cases where the placentation was adjacent to an overlying leiomyoma at 34 to 36 gestational weeks. All the ultrasound examinations were performed by experienced technicians using transverse, frontal, and sagittal planes; the mean diameter of each uterine myoma was calculated. All ultrasound images were additionally reviewed by a maternal-fetal medicine specialist who generated the report.

Placental histopathology analysis

Macroscopic and histopathology assessment of all placentas irrelevant of complication status or delivery mode was performed at the Royal Victoria Hospital (RVH) in the period from 2009 to 2017. All placentas were examined in one pathology department. The results were reviewed by one perinatal gynecology pathologist (T.N.T.N.) who was unaware of the clinical characteristics of the patients except for the gestational week. The pathologic findings were categorized according to the Amsterdam Placental Workshop Group Consensus into anatomic, inflammation, villous maturation, and vascular malperfusion features [12].

Outcomes and definitions

The primary outcomes of the study included anatomical, inflammation, vascular malperfusion, and villous maturation placental disorders. The secondary outcomes included fetal, maternal, perinatal, and delivery complications.

Statistical analysis

We evaluated data distribution using the Shapiro-Wilk test. Normally distributed data were compared using Student’s t test and presented as mean ± standard deviation. Skewed data were presented as median (with interquartile range); the Mann-Whitney U test was used for comparison in such cases. Categorical data were compared using the Chi-square test and presented as a number of exposed cases and percentage of total number of cases. A p value < 0.05 was considered statistically significant for all comparisons.

A multivariate logistic model was used to adjust the results for confounding factors potentially associated with significant placental and perinatal characteristics. Backward stepwise regression analysis was conducted; unadjusted and adjusted odds ratios (OR) with 95% confidence intervals (95% CI) were calculated. Data were analyzed using the JMP Pro 14.1.0 software (SAS Institute Inc., USA).

Results

During the period between 2009 and 2017, we encountered a total of 1364 live births following IVF treatment. After applying inclusion and exclusion criteria, 1119 live births were included in the final analysis (Fig. 1). Intramural myomas not distorting the uterine cavity were identified preconceptionally in 101 pregnancies (myoma group). The mean diameter of myomas was 3.5 cm (range 1.8 to 7.5 cm). Forty-eight women (47.5%) had multiple myomas. In 46 (45.5%) women, the placenta was found to be adjacent to an overlying myoma.

Fig. 1.

Flow diagram of patients’ selection process

Demography, smoking profile, obstetric history, and distribution of chronic comorbidities were similar between the myoma and non-myoma groups (Table 1). The results of infertility investigation including ovarian reserve, infertility factor, and partner’s semen parameters were also similar (Table 2). There was no difference in IVF treatment characteristics between the two groups including the distribution of treatment protocol, peak estradiol and endometrial thickness before the transfer, number of transferred embryos per cycle, number of cycles with top-quality embryos, embryo stage at transfer, and number of intracytoplasmic sperm injection (ICSI) cycles, as well as the initial serum levels of beta-human chorionic gonadotropin (beta-HCG).

Table 1.

Demography and clinical characteristics

Characteristic	Myoma group	Non-myoma group	p value
Female age at oocyte retrieval (years)	36.8 ± 4.2	36.1 ± 4.1	0.11
Female age at embryo transfer (years)	37.9 ± 4.2	37.0 ± 4.8	0.08
Body mass index (kg/m2)	25.4 ± 2.2	25.1 ± 2.3	0.16
Smoking (n (%))	4 (4.0)	34 (3.3)	0.74
Number of previous pregnancies (n)	2 (1–3)	2 (1–2)	0.08
Number of previous deliveries (n)	0 (0–1)	0 (0–1)	0.47
Number of previous miscarriages (n)	0 (0–2)	0 (0–1)	0.13
Chronic comorbidities (n (%)):
- Hypothyroidism   - Diabetes mellitus   - Chronic hypertension   - Seizure disorder   - Depression   - Autoimmune disorders   - Polycystic ovary syndrome	11 (10.9) 1 (1.0) 3 (3.0) 0 (0) 3 (3.0) 2 (2.0) 3 (3.0)	97 (9.5) 15 (1.5) 14 (1.4) 15 (1.5) 23 (2.3) 9 (0.9) 45 (4.4)	0.66 0.69 0.21 0.22 0.65 0.29 0.49

Data are median (quartiles) or mean ± standard deviation unless stated otherwise

Table 2.

Infertility treatment characteristics

Characteristic	Myoma group	Non-myoma group	p value
AFC (n)	14 (6–23)	15 (9–25)	0.09
Baseline FSH (IU/L)	7 (6–8)	7 (6–8)	0.76
Primary IVF treatment factor (n (%)):
- Mechanical   - Ovulatory   - Endometriosis   - Male   - Unexplained	10 (10.0) 36 (35.6) 7 (6.9) 30 (29.7) 18 (17.8)	100 (9.8) 287 (28.2) 50 (4.9) 332 (32.6) 249 (24.5)	0.11
Embryo transfers (n (%)):
- Fresh   - Frozen	57 (56.4) 44 (43.6)	622 (61.1) 396 (38.9)	0.36
IVF protocol (n (%)):
- Antagonist   - Long agonist   - Microdose flare   - Natural frozen ET   - Artificial frozen ET	33 (32.7) 2 (2.0) 26 (25.7) 3 (3.0) 37 (36.6)	354 (34.8) 96 (9.4) 195 (19.2) 40 (3.9) 333 (32.7)	0.11
Stimulation in fresh ET cycles (n (%)):
- Recombinant FSH   - HMG	40 (70.2) 17 (30.9)	475 (76.4) 147 (23.6)	0.11
Total FSH dose in fresh IVF cycles (IU)	2325 (1350–4050)	2025 (1531–2700)	0.26
Peak estradiol (pmol/L)	4552 (3186–7225)	5748 (3534–8807)	0.09
Peak endometrial thickness (mm)	10.2 ± 2.4	10.2 ± 2.2	0.88
Number of retrieved oocytes (n)	11.1 ± 8.8	11.7 ± 7.9	0.49
Sperm volume (mL)	2 (1.1–3.0)	2.2 (1.5–3.0)	0.14
Sperm concentration (mln/mL)	28 (9–40)	20 (6–40)	0.97
Sperm motility (mean %)	30 (20–40)	25 (15–35)	0.08
ICSI cycles (n (%))	83 (82.2)	766 (75.2)	0.44
Cycles with top-quality transferred embryos (n (%))	79 (78.2)	816 (80.2)	0.64
Number of embryos per transfer (n)	1 (1–2)	1 (1–1)	0.12
Embryo stage at transfer (n (%)):
- Cleavage-stage   - Blastocyst	18 (17.8) 83 (82.2)	258 (25.3) 771 (74.7)	0.11
First beta-HCG value (mIU/mL)	369 (247–540)	382 (246–599)	0.65

Data are median (quartiles) or mean ± standard deviation unless stated otherwise

AFC, antral follicle count; FSH, follicle-stimulating hormone; IVF, in vitro fertilization; ET, embryo transfer; HMG, human menopausal gonadotropin; ICSI, intracytoplasmic sperm injection; HCG, human chorionic gonadotropin

The rate of maternal complications including gestational diabetes mellitus (GDM) and preeclampsia (PET), as well as the rate of congenital malformations, was similar (Table 3). Non-vertex fetal presentation diagnosed at delivery was more common in the myoma group (odds ratio (OR) 5.3; 95% confidence interval (CI) 2.8–9.9). The incidence of failed progress of labor (OR 2.3; 95% CI 1.2–4.1) and failed induction (OR 5.3; 95% CI 1.9–14.4) was also higher in the myoma group compared with the non-myoma group. Similarly, the cesarean section rate was significantly higher in the myoma group (OR 2.1; 95% CI 1.4–3.3). The prevalence of intrapartum fetal distress, delivery week, newborn gender distribution, preterm birth (PTB), Apgar scores, and birth weight were similar between the groups.

Table 3.

Pregnancy complications and perinatal outcome

Characteristic	Myoma group	Non-myoma group	p value
Maternal complications during pregnancy (n (%)):
- Gestational diabetes mellitus   - Preeclampsia   - Oligohydramnios   - Polyhydramnios	16 (15.8) 8 (7.9) 3 (3.0) 1 (1.0)	112 (11.0) 43 (4.2) 34 (3.3) 18 (1.8)	0.15 0.09 0.84 0.56
Congenital malformations (n (%)):
- Cardiovascular malformations   - Limb malformations   - Urinary tract malformations   - Brain malformations	0 (0) 1 (1.0) 0 (0) 1 (1.0)	7 (0.7) 4 (0.4) 10 (1.0) 4 (0.4)	0.41 0.39 0.32 0.39
Non-vertex fetal presentation (n (%))	16 (15.8)	35 (3.4)	0.0001
Delivery complications (n (%)):
- Fetal distress   - Failure to progress   - Failure of induction	12 (11.9) 15 (14.9) 6 (5.9)	111 (10.9) 73 (7.2) 12 (1.2)	0.76 0.006 0.0001
Delivery mode (n (%)):
- Normal vaginal delivery   - Vacuum/forceps   - Cesarean section	43 (42.6) 7 (6.9) 51 (50.5)	606 (59.5) 75 (7.4) 337 (33.1)	0.002
Delivery week	39 (38–39)	39 (38–40)	0.11
Preterm birth rate (n (%))	12 (11.9)	90 (8.8)	0.31
Gender (n (%)):
- Males   - Females	55 (54.5) 46 (45.5)	508 (49.9) 510 (50.1)	0.38
Apgar 1′ (mean score)	9 (7–9)	9 (8–9)	0.33
Apgar 5′ (mean score)	9 (9–9)	9 (9–9)	0.08
Birth weight (g)	3290 (2910–3588)	3330 (2980–3670)	0.24

Data are median (quartiles) unless stated otherwise

Placental characteristics including histopathology evaluation outcomes are shown in Table 4. Placental weight and cord length as well as the prevalence of small (< 10 percentile) and large (> 90 percentile) placentas were similar between the groups. Placentas from the myoma group were significantly thinner compared with those in the non-myoma group (p = 0.001). Manual extraction or curettage for placental delivery was more common in the myoma group (OR 5.2; 95% CI 3.4–8.0).

Table 4.

Placental histopathology characteristics

Characteristic	Myoma group	Non-myoma group	p value
Placental weight (g)	484.9 ± 123.8	478.5 ± 112.7	0.62
Small (< 10 percentile) placental weight (n (%))	23 (22.8)	232 (22.8)	0.99
Large (> 90 percentile) placental weight (n (%))	11 (10.9)	89 (8.7)	0.49
Placental thickness (cm)	1.4 (1.3–1.5)	2.0 (1.5–2.4)	0.001
Cord length (cm)	50 (41–57)	50 (42–60)	0.31
Assisted placental delivery (n (%)):	6 (5.9)	19 (1.9)	0.01
Placenta previa (n (%))	1 (1.0)	3 (0.3)	0.26
Placenta accreta (n (%))	1 (1.0)	1 (0.1)	0.04
Anatomic disorders (n (%)):
- Single umbilical artery   - Marginal insertion   - Furcate cord insertion   - Velamentous insertion   - Circummarginate membranes insertion   - Circumvallate membranes insertion   - True knot   - Hypercoiled umbilical cord   - Bilobed placenta   - Accessory lobe	0 (0) 17 (16.8) 2 (2.0) 8 (7.9) 9 (8.9) 4 (4.0) 0 (0) 3 (3.0) 0 (0) 2 (2.0)	10 (1.0) 244 (23.9) 3 (0.3) 94 (9.2) 138 (13.6) 7 (0.7) 10 (1.0) 5 (0.5) 18 (1.8) 13 (1.3)	0.32 0.11 0.01 0.66 0.19 0.001 0.32 0.005 0.18 0.56
Inflammatory disorders (n (%)):
- Acute chorioamnionitis with moderate to severe maternal inflammatory response   - Acute chorioamnionitis with moderate to severe fetal inflammatory response   - Chronic deciduitis   - Villitis of unknown etiology	5 (5.0) 2 (2.0) 3 (3.0) 4 (4.0)	66 (6.5) 26 (2.6) 5 (0.5) 36 (3.5)	0.55 0.72 0.005 0.83
Maturation disorders (n (%)):
- Accelerated villous maturation   - Delayed villous maturation   - Distal villous hypoplasia   - Increased syncytial knotting	12 (11.9) 1 (1.0) 3 (3.0) 7 (6.9)	65 (6.4) 23 (2.3) 15 (1.5) 72 (7.1)	0.03 0.39 0.25 0.96
Vascular disorders (n (%)):
- Retroplacental hematoma/hemorrhage   - Cord thrombosis   - Intervillous thrombosis   - Intervillous non-subchorionic fibrin   - Focal Intramural fibrin   - Villous infarction   - Villous agglutination   - Avascular villi   - Perivillous fibrin deposition   - Maternal vasculopathy   - Fetal vasculopathy   - Chorionic thrombosis   - Chorangiosis   - Subchorionic fibrin   - Subchorionic thrombi   - Fetal vascular malperfusion (one criteria)   - Fetal vascular malperfusion (> one criteria)   - Maternal vascular malperfusion (one criteria)   - Maternal vascular malperfusion (> one criteria)	2 (2.0) 0 (0) 8 (7.9) 0 (0) 2 (2.0) 3 (3.0) 0 (0) 1 (1.0) 13 (12.9) 11 (10.9) 0 (0) 1 (1.0) 10 (9.9) 4 (4.0) 11 (10.9) 4 (4.0) 1 (1.0) 39 (38.6) 15 (14.9)	52 (5.1) 2 (0.2) 57 (5.6) 3 (0.3) 1 (0.1) 32 (3.1) 9 (0.9) 18 (1.8) 100 (9.8) 49 (4.8) 3 (0.3) 9 (0.9) 103 (10.1) 23 (2.3) 42 (4.1) 40 (3.9) 15 (1.5) 409 (40.2) 127 (12.5)	0.39 0.66 0.34 0.59 0.0001 0.92 0.34 0.56 0.33 0.009 0.58 0.91 0.95 0.29 0.002 0.98 0.69 0.76 0.49
Nucleated red blood cells (n (%))	1 (1.0)	11 (1.1)	0.93
Chorangioma (n (%))	3 (3.0)	5 (0.5)	0.005

Data are median (quartiles) or mean ± standard deviation unless stated otherwise

A higher prevalence of placenta accreta was found in pregnancies complicated by myomas compared with those without myomas (OR 3.3; 95% CI 1.2–9.1). The incidence of placenta previa was similar between the two groups.

The myoma group was found to have a higher prevalence of hypercoiled umbilical cord (OR 6.2; 95% CI 1.5–26.3), furcate cord (OR 3.5; 95% CI 1.4–9.1), and circumvallate membranes insertion (OR 5.9; 95% CI 1.7–20.7) as opposed to the non-myoma group. Chronic deciduitis (OR 6.2; 95% CI 1.5–26.3) and accelerated villous maturation (OR 2.0; 95% CI 1.1–3.8) were also more common in the myoma group. Analysis of PTBs (n = 102) revealed that the incidence of accelerated villous maturation was similar between the myoma and non-myoma groups (5 (41.7%) vs. 32 (35.6%); OR 1.3; 95% CI 0.4–4.4; p = 0.68).

Although the rate of fetal vasculopathy was similar, the incidence of maternal vasculopathy was higher in the myoma group (OR 2.4; 95% CI 1.2–4.8). The myoma group was found to have a higher incidence of focal intramural fibrin (OR 20.5; 95% CI 1.8–228.6), subchorionic thrombi (OR 2.8; 95% CI 1.4–5.7), and chorangioma (OR 6.2; 95% CI 1.5–26.3) compared with pregnancies without leiomyomas.

Factors potentially associated with placental pathology and dysfunctional labor including female age at embryo transfer, body mass index, number of previous pregnancies, hypothyroidism, chronic hypertension, pre-gestational diabetes mellitus, endometriosis, antral follicle count, peak endometrial thickness before embryo transfer, ICSI cycles, embryo stage at transfer, frozen embryo transfer cycles, number of transferred embryos, PET, GDM, newborn gender, PTB, and birth weight as well as the presence of intramural myoma were tested in the multivariate analysis (Table 5). After the adjustment for potential confounders, placental histopathology findings including, furcate cord insertion, circumvallate membranes insertion, chronic deciduitis, focal intramural fibrin deposition, subchorionic thrombi, maternal vasculopathy, and chorangioma were significantly associated with the presence of intramural myoma. Failed progress of labor and failed induction, as well as assisted placental delivery, was also significantly associated with pregnancies complicated by intramural myomas.

Table 5.

Unadjusted and adjusted odd ratios of significant placental pathology results and intrapartum complications in the myoma group

Characteristic	Unadjusted OR (95% CI)	Adjusted OR (95% CI)
Placenta accreta	3.3 (1.2–9.1)	3.5 (0.9–10.4)
Furcate cord insertion	3.5 (1.4–9.1)	3.6 (1.4–9.3)
Circumvallate membranes insertion	5.9 (1.7–20.7)	5.2 (1.4–19.3)
Hypercoiled umbilical cord	6.2 (1.5–26.3)	1.9 (0.2–19.8)
Chronic deciduitis	6.2 (1.5–26.3)	8.2 (1.6–42.2)
Accelerated villous maturation	2.0 (1.1–3.8)	1.8 (0.9–3.8)
Focal intramural fibrin	20.5 (1.8–228.6)	25.1 (2.1–306.2)
Maternal vasculopathy	2.4 (1.2–4.8)	2.5 (1.2–5.5)
Subchorionic thrombi	2.8 (1.4–5.7)	3.6 (1.7–7.6)
Chorangioma	6.2 (1.5–26.3)	5.9 (1.4–25.2)
Assisted placental delivery	5.2 (3.4–8.0)	2.4 (1.5–3.9)
Failure to progress	2.3 (1.2–4.1)	2.4 (1.3–4.4)
Failure of induction	5.3 (1.9–14.4)	3.2 (1.2–9.0)

OR, odd ratio; CI, confidence intervals

To evaluate the significance of adjacent placental and leiomyoma location, we conducted an additional analysis comparing pregnancies with congruent uterine myoma and placenta location (n = 46) and those where the myoma and placenta were identified in the different uterine walls (n = 55). Demography and IVF cycle characteristics, PET and GDM incidence, delivery complications, perinatal outcomes, and placental outcomes were similar between the groups (Table 6).

Table 6.

Baseline parameters, delivery complications, and placental histopathology characteristics according to the congruence of myoma and placental location

Characteristic	Congruent location	Non-congruent location	p value
Female age at embryo transfer (years)	37.8 ± 4.1	37.5 ± 4.4	0.73
Body mass index (kg/m2)	25.3 ± 2.5	25.1 ± 2.3	0.79
Smoking (n (%))	2 (4.3)	2 (3.6)	0.86
Myoma diameter (cm)	3.4 ± 1.6	3.7 ± 2.4	0.58
Cases with multiple myomas (n (%))	26 (56.5)	22 (40.0)	0.23
Number of previous pregnancies (n)	2 (1–3)	2 (1–2)	0.28
Number of previous deliveries (n)	0 (0–1)	0 (0–1)	0.27
Number of previous miscarriages (n)	0 (0–1)	0 (0–2)	0.67
Major chronic comorbidities (n (%)):
- Hypothyroidism   - Diabetes mellitus   - Chronic hypertension   - Autoimmune disorders   - Endometriosis   - Polycystic ovary syndrome	4 (8.7) 1 (2.2) 2 (4.3) 1 (2.2) 3 (6.5) 1 (2.2)	7 (12.7) 0 (0) 1 (1.8) 1 (1.8) 4 (7.2) 2 (3.6)	0.54 0.27 0.46 0.89 0.89 0.67
Peak endometrial thickness (mm)	10.4 ± 2.3	10.7 ± 2.5	0.57
Number of retrieved oocytes (n)	9.8 ± 6.4	9.1 ± 6.0	0.57
ICSI cycles (n (%))	40 (86.9)	43 (78.2)	0.63
Cycles with top-quality transferred embryos (n (%))	37 (80.4)	42 (76.4)	0.82
Number of embryos per transfer (n)	1 (1–1)	1 (1–2)	0.88
Embryo transfers (n (%)):
- Fresh   - Frozen	26 (56.5) 20 (43.5)	31 (56.4) 24 (43.6)	0.78
Major maternal complications during pregnancy (n (%)):
- Gestational diabetes mellitus   - Preeclampsia	10 (21.7) 4 (8.7)	6 (10.9) 4 (7.3)	0.17 0.67
Delivery complications (n (%)):
- Fetal distress   - Failure to progress   - Failure of induction	6 (13.0) 8 (17.4) 3 (6.5)	6 (10.9) 7 (12.7) 3 (5.5)	0.76 0.54 0.83
Delivery mode (n (%)):
- Normal vaginal delivery   - Vacuum/forceps   - Cesarean section	17 (37.0) 4 (8.7) 25 (54.3)	26 (47.3) 3 (5.4) 26 (47.3)	0.12
Delivery week	39 (37–39)	39 (38–40)	0.49
Birth weight (gr)	3195 (2760–3580)	3335 (2825–3570)	0.71
Placental weight (g)	488.7 ± 109.9	465.1 ± 158.5	0.52
Placental thickness (cm)	1.5 (1.4–1.5)	1.4 (1.2–1.4)	0.09
Assisted placental delivery (n (%))	4 (8.7)	2 (3.6)	0.29
Placental histopathology features (n (%)):
- Placenta accreta   - Placenta previa   - Furcate cord insertion   - Circumvallate membranes insertion   - Hypercoiled umbilical cord   - Chronic deciduitis   - Accelerated villous maturation   - Focal intramural fibrin   - Maternal vasculopathy   - Subchorionic thrombi   - Chorangioma	0 (0) 1 (2.2) 4 (8.7) 1 (2.2) 0 (0) 2 (4.3) 6 (13.0) 2 (4.3) 7 (15.2) 3 (6.5) 1 (2.2)	1 (1.8) 0 (0) 2 (3.6) 3 (5.5) 3 (5.5) 1 (1.8) 6 (10.9) 0 (0) 4 (7.3) 8 (14.6) 2 (3.6)	0.36 0.27 0.30 0.41 0.11 0.46 0.76 0.12 0.23 0.22 0.67

Data are median (quartiles) or mean ± standard deviation unless stated otherwise

ICSI, intracytoplasmic sperm injection

Discussion

The results of our study revealed a significant impact of intramural myoma not distorting the uterine cavity on the placental histopathological features. Multivariate regression model demonstrated that the presence of intramural myoma was associated with furcate cord insertion, circumvallate membranes insertion, chronic deciduitis, focal intramural fibrin deposition, subchorionic thrombi, maternal vasculopathy, and chorangioma as well as with dysfunctional labor.

Uterine myomas contribute to a variety of clinical problems including infertility, recurrent pregnancy loss, and pregnancy-related complications. There is a consensus of a negative effect on clinical pregnancy and live birth rates for leiomyomas distorting the uterine cavity (FIGO types 0–2) [13, 14]. However, it appears that non-cavity-distorting intramural myoma also has a negative effect on implantation, clinical pregnancy, and live birth rates [6, 7, 15]. In fact, live birth rates were found to be significantly reduced in patients with intramural myomas of > 1.5 cm, and the presence of one intramural non-cavity-distorting myoma may reduce the clinical pregnancy and live birth rates [6, 15]. Our results demonstrated that even if successful implantation occurs, there is a negative impact of intramural leiomyomas on the placentation process detected in placental histopathology analysis.

Increased prevalence of intrauterine growth retardation and PTB was previously shown in association with submucosal myomas [4, 5]. Our study demonstrated similar birth weight and PTB rate in the group of intramural non-cavity-distorting myomas and the control group. However, the study group was found to be significantly associated with placental histopathology abnormalities that might cause adverse perinatal outcomes including PET, placental abruption, or stillbirth.

In our analysis, we excluded cases with previous uterine surgery including cesarean deliveries, which is one of the risk factors for placenta accreta [16]. An increased rate of placenta accreta, which represents a low grade of abnormal placental adherence spectrum [17], may contribute to a higher incidence of manual removal of placenta and curettage in the myoma group. Although an increased incidence of placenta accreta has been demonstrated in pregnancies complicated by intramural myomas, this result should be reviewed with caution due to a low incidence of placenta accreta in our study population (n = 2). Placenta accreta was not one of the findings significantly associated with intramural myomas in the multivariate analysis.

Placental thickness linearly increases with gestational age throughout normal pregnancy. Our analysis demonstrated that placentas from live births complicated by intramural myomas were thinner. Moreover, the median placental thickness in the myoma group (1.4 cm) was less than an average thickness of a normal placenta (range 2.0–4.0 cm) [18]. A thin placenta was found to be associated with vascular malperfusion and villous maturation placental abnormalities that might be associated with the development of PET and IUGR [19].

In terms of other anatomic placental disorders, increased rates of hypercoiled umbilical cord, furcate cord, and circumvallate membranes insertion were shown in pregnancies with intramural leiomyoma. Furcate cord and circumvallate membranes insertion were also significantly associated with uterine myomas after the adjustment for other confounding variables. Furcate cord insertion is a rare abnormality characterized by the separation of umbilical vessels prior to their attachment into the placenta [20]. Circumvallate membranes’ insertion is a form of extrachorial placenta, with a raised placental margin in an annular shape. Both entities are serious obstetric conditions associated with an increased rate of IUFD, PTB, placental abruption, and emergency cesarean section [21, 22].

Among inflammatory disorders, the incidence of chronic deciduitis was higher in the myoma group compared with the non-myoma group. Deciduitis was diagnosed by the presence of plasma cells and lymphocytes in the basal plate of the placenta. Chronic deciduitis is thought to result from chronic inflammation of the maternal genital tract or an abnormal immune response to the placenta [23]. It can be identified in placentas from uncomplicated pregnancies, but a higher proportion of this inflammatory disorder is found in PTBs and pregnancies with growth-restricted fetuses [24]. Although there is a marked inconsistency in the diagnostic criteria of chronic deciduitis used in different studies [23–26], a single protocol was applied in our institution for all included cases [12, 25]. The extension and severity of the inflammatory infiltrate were also analyzed to confirm the diagnosis.

The prevalence of acute chorioamnionitis with moderate to severe maternal (acute or necrotizing chorioamnionitis with confluent polymorphonuclear leukocytes or with subchorionic microabscesses) and fetal (involvement of the umbilical vein and at least one umbilical artery or necrotizing funisitis with near-confluent intramural polymorphonuclear leukocytes) response [12] was separately analyzed and was found to be similar between the groups.

Accelerated villous maturation (AVM) is defined as the presence of small or short hypermature villi as a function of gestational age and is associated with placental insufficiency [27]. After the adjustment for the potential confounders, AVM was not found to be independently associated with intramural myomas. The incidence of increased syncytial knotting, which usually accompanies AVM [27], occurred at similar rates in the myoma and non-myoma groups.

Although the overall prevalence of fetal vascular malperfusion (FVM) was similar between the groups, the incidence of placental intramural fibrin deposition as one of FVM manifestations [28] was associated with the presence of intramural myomas. Among multiple FVM etiologies, abnormal maternal circulation could lead to increased intramural fibrin deposition and fetoplacental unit hypoperfusion [29].

Maternal vasculopathy is one of the placental vascular malperfusion disorders which was found to be associated with uterine myomas in our multivariate analysis. Previous studies reported ischemic changes as a mechanism of maternal vasculopathy development. Maternal vasculopathy is associated with preterm rupture of membranes and preterm labor and was demonstrated to be an important contributor to the development of the adverse outcome in the term pregnancies (stillbirth, PET, and placental abruption) [29, 30].

Subchorionic thrombi, which were more common in the myoma group, are the sign of bleeding on the maternal side or in the maternal-placental unit and are associated with an increased risk of fetal and maternal adverse events [31]. Subchorionic/retroplacental hemorrhage might be a result of abnormal development of the placental membranes in the first trimester due to the aberrant process of implantation and invasion [32].

Chorangioma is a nontrophoblastic placental tumor characterized by abnormal vascular development within the placental parenchyma and microscopically composed of numerous proliferative blood vessels in various stages of differentiation [33]. Multiple factors have been implicated in the pathogenesis of chorangioma including decreased oxygen tensions, vascular endothelial growth factor (VEGF), placental growth factor levels, and cytokines [34]. Chorangiomatosis has been associated with negative perinatal outcomes such as IUGR, PET, and PTB [35]. Despite a low incidence of chorangioma in our population (n = 8, 0.7%), this finding was more prevalent and significantly associated with intramural leiomyomas.

The mechanism explaining a higher incidence of the aforementioned placental histopathological features in pregnancies complicated by non-cavity-distorting intramural myomas is unclear. Several theories have been proposed to explain the effect of an intramural leiomyoma on reproduction, perinatal outcomes, and related placental patterns. Defective decidualization and abnormal maternal vascular remodeling may cause the development of thin placenta and excessive trophoblastic invasion [36, 37]. Increased uterine contractility may apply a negative effect on the dynamic of placental migration causing intrauterine hematoma and subchorionic thrombi formation [8]. Impairment of the myometrial and endometrial blood supply can also provoke the development of maternal vasculopathy and intramural fibrin deposition [38]. A decreased oxygen tension, suboptimal uterine perfusion in combination with paracrine growth factors (VEGF) exerting molecular effects, may contribute to an abnormal vascularization within the placental parenchyma and the chorangioma development [39]. In addition, increased secretion of local inflammatory substances (interleukin-1, interleukin-33, tumor necrosis factor-alpha), causing an abnormal immune response to the placenta [40, 41], may be capable of inducing a higher rate of chorionic deciduitis.

The limitations of our study include a low incidence of certain histopathology characteristics (chronic deciduitis, focal intramural fibrin deposition, chorangioma). However, the prevalence of placental features in our study was similar to that reported in the medical literature [12, 23, 33]. We used a multivariate analysis to calculate the adjusted odd ratios and demonstrated the significance of each parameter. Due to the large 95% confidence intervals of the adjusted odds for the chronic deciduitis, focal intramural fibrin deposition, and chorangioma, the significance of comparisons of those histopathology features should be viewed with caution.

We acknowledge the diagnostic limitation of the ultrasound in the investigation of myoma location. However, IVF patients’ monitoring includes repetitive ultrasound examinations evaluating the uterine cavity status. If there is any suspicion of intrauterine pathology, hysteroscopic evaluation of the uterine cavity is performed. These measures allowed to minimize the risk of missing the cases of intramural myomas with submucosal components.

Comparing the reports of preconceptional and obstetrical ultrasound examinations (at 34 weeks gestational age), no significant changes in the myoma diameter (< 1 cm) and location were observed in the myoma group. This is in agreement with the previous studies demonstrating that most myomas do not exhibit a significant change in volume during pregnancy [42]. In cases where the delivery occurred before 34 weeks of gestation, we compared the results of the last obstetrical ultrasound, which was not earlier than 2 weeks prior to the delivery in all cases of PTB. This allowed us to confirm the size, location of the myoma, and its position relative to the placenta.

It is possible that our cohort was too small to demonstrate the expected differences in the rates of PET, IUGR, PTB, and adverse neonatal outcomes between the study groups. However, our analysis demonstrated an increased incidence of failed progress of labor and failed induction, as well as, a higher rate of cesarean deliveries, in the myoma group, which could be due to the differences in placental characteristics of the study and control group. A higher rate of dysfunctional labor was previously reported in patients with uterine myomas. It was postulated that it is related to an adverse effect on the force and coordination of uterine contractile waves [43, 44]. However, the type of uterine myoma was not specified in those studies [43, 44].

We analyzed the placentas from all singleton live births in the study period irrelevant to complication status, delivery mode, and women’s age. This allowed us to avoid a possible selection bias seen in the previous studies and thoroughly evaluate the placental histopathology pattern as a primary outcome. Since the revealed placental histopathology disorder will not necessarily develop to an obstetric or perinatal complication, the rates of adverse obstetrical outcomes (PET, PTB, IUGR) may be similar between the groups.

It is possible that the higher incidence of cesarean delivery could be related to the providers being aware of which patients have intramural myomas. However, all the cases with the uterine cavity distorting myomas, cervical myomas, and tumor previa were excluded from the study. A review of the cesarean section reports from our study revealed a higher rate of fetal malpresentation and dysfunctional labor in the study group, which represents an indication for cesarean delivery. The sole presence of the uterine myoma was not among the primary or secondary indications for cesarean delivery in any of the included patients. Therefore, it is unlikely that the finding of an increased cesarean section in the myoma group was due to provider bias.

The results of our study evoke some clinically important questions. First, the clinical significance of the relation between myoma and placenta location, which was tested in previous studies with conflicting results [45]. When pregnancies with congruent uterine leiomyoma and placenta location were compared with those with non-congruent location, we found similar baseline characteristics, IVF parameters, perinatal, and placental outcomes. Although the number of cases included in the study groups of this subanalysis was limited, the result contributes to the concept of the complementary direct and remote effect of intramural myomas on the placentation generating an altered secretion pattern of implantation factors, abnormal blood flow circulation, and uterine contractility. Second, the role of preconception myomectomy in the improvement of obstetric and perinatal outcomes in women with intramural uterine myomas. Although there is evidence of the negative effect of intramural myomas on fertility and perinatal outcomes [4, 6, 9], myomectomy carries risks including intraoperative bleeding, uterine adhesions formation, and fallopian tubes damage as well as the risk of placenta previa and placenta accreta due to a uterine scar formation [46, 47]. Those issues, as well as the effects of size, number, genetic pattern, and secretory activity of non-cavity-distorting intramural myomas, should be evaluated in large clinical trials.

Since the purpose of our study was to evaluate the effect of intramural myomas on the placental histopathology in singleton live births resulting from IVF treatment, we excluded spontaneous pregnancies from the analysis. Including a group that did not undergo IVF would have been inappropriate, preventing us from understanding if changes in placental pathology were due to the myomas or the IVF itself. The group of spontaneous pregnancies as a control group is relevant for the evaluation of the IVF impact on placental pathology in further studies and was not the aim of our analysis.

The strength of our study was the placental histopathology analysis policy applied to all deliveries including both low- and high-risk live births. This universal screening of all placentas makes our database an ideal mechanism to study the role of different situations on placental development without bias caused by the inclusion of only complicated pregnancies or deliveries.

Patients’ medical history was thoroughly evaluated, and the results were adjusted for chronic comorbidities, obstetric history and complications, IVF treatment results, and perinatal outcomes. Meticulous evaluation of women before IVF treatment allowed us to evaluate uterine abnormalities in the optimal conditions preconceptionally. The latter could be a diagnostic limitation in cases of spontaneous pregnancies and if the primary evaluation is performed during the pregnancy [3]. A rigorous patient assessment during infertility treatment also allowed us to evaluate other factors including peak estradiol level and endometrial thickness that could affect the implantation and placentation process. All IVF treatment cycles, deliveries, and placental histopathology analyses were performed in a single academic tertiary hospital.

To the best of our knowledge, this analysis was the first clinical study evaluating the placental features of live births complicated by intramural leiomyomas using Amsterdam Placental Workshop criteria for comprehensive placental histopathology assessment.

In conclusion, intramural non-cavity-distorting myomas have an impact on the placental histopathology including anatomic, villous maturation, and vascular placental features with a higher incidence of dysfunctional labor. The similar prevalence of obstetrical adverse outcomes (PET, PTB, IUGR) between the groups should be acknowledged and may be explained by a limited translation of placental abnormalities into clinical complications. The effect of specific placental changes on obstetric and neonatal outcomes remains to be evaluated further studies.

Authors’ contributions

All authors contributed to the study conception and design. Material preparation was performed by Tuyet Nhung Ton Nu, William Buckett, Yaron Gil, Alexander Volodarsky-Perel, and Michael H. Dahan. Data collection was performed by Alexandre Machado-Gedeon, Yiming Cui, Jonathan Shaul, and Alexander Volodarsky-Perel. Data analysis was performed by Togas Tulandi, Alexander Volodarsky-Perel, and Michael H. Dahan. The first draft of the manuscript was written by Alexander Volodarsky-Perel, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethics approval

McGill University Health Centre Research Ethics Board approved the study (MUHC 2019-5026).