Abstract
Purpose
To assess obstetric outcomes and placental histology following intracytoplasmic sperm injection (ICSI), for non-male infertility.
Methods
This was a retrospective cohort of live born singleton deliveries after in vitro fertilization (IVF) at a single university affiliated medical center between 2009 and 2017. Excluded were IVF cycles with male infertility and oocyte recipients. We compared obstetric outcomes and placental histology in cases ICSI was performed (ICSI group) and cases with no ICSI (IVF group).
Results
A total of 400 deliveries following ICSI were compared to 218 in the IVF group. Maternal age was similar between the groups, while diminished ovarian reserve was more common among ICSI patients and tubal disease less common (p < 0.001). The rate of blastocyte transfer was also significantly lower in the ICSI group—67.5% vs. 77%, p = 0.01. Pregnancies following ICSI were characterized by similar rates of preeclampsia, preterm birth, and small for gestational age neonates. Although cesarean delivery rate was significantly higher in the group, this did no attain significance after adjustment for confounders. Placentas in the ICSI group were notable for a lower rate of villitis of unknown etiology (1% vs. 4.5%, p = 0.007) and a higher rate of maternal surface calcifications (33% vs. 23.8%, p = 0.01) after adjustment for confounders.
Conclusion
The employment of ICSI with no male indication is associated with similar obstetric outcomes. Despite isolated placental differences among many investigated, placental histology seems overall comparable as well. These results are reassuring to clinicians and patients.
Keywords: Intracytoplasmic sperm injection (ICSI), In vitro fertilization (IVF), Placenta, Villitis of unknown etiology, Placental calcification
Introduction
The development of intracytoplasmic sperm injection (ICSI) remains one of the major milestones in the history of in vitro fertilization (IVF) treatments. First described in 1988 [1], this technique was developed and implemented successfully by Palmero and colleagues in 1992, as a solution for male factor infertility [2]. Since its introduction, additional indications have been explored for its use. Indeed, an increase in ICSI use has been occurring, so that between 1996 and 2012 the use rose from 36.4 to 76.2% of IVF cycles in the USA, with a marked increase in cycles with no male indication, 15.4 to 66.9% [3], both mirroring similar global trends [4].
The increased use of ICSI for non-male factor infertility has not been advocated by all, as it generally does not seem to increase pregnancy and live birth rates [5, 6]. However, several studies have focused on unique patient populations for which ICSI may be beneficial, even without the presence of male factor infertility. ICSI for unexplained infertility was assessed in a past study [7], and a meta-analysis of randomized controlled trials [8], which demonstrated an increase in fertilization rates and decrease in failed fertilization. For patients with a low oocyte yield or advanced maternal age, a clear clinical advantage with ICSI was not established in some studies [9, 10], while others did not improved results with ICSI [11]. For cases of prior failed fertilization with conventional insemination, the literature does seem to support ICSI to optimize fertilization rates [12], as is the case for in vitro maturation [13], frozen-thawed oocytes, and pregenetic testing to increase testing accuracy [14]. These studies lead the American Society for Reproductive Medicine and the Society for Assisted Reproductive Technology to publish a 2020 committee opinion, supporting the use of ICSI for non-male indications in select patients only [15], while avoiding it in other groups.
The recommendations to limit ICSI use were related to risks concerning an increase in birth defects, as demonstrated for both male factor and non-male factor infertility in recent literature [16]. Yet, ICSI for non-male infertility continues to be in wide use in many of centers worldwide. Few studies have focused on the effect of ICSI for non-male infertility on obstetric outcomes [17, 18]. Moreover, the few existing studies to date have not incorporated an evaluation of placental histology, which may prove valuable to our understanding of the placentation process and point to potential intrauterine insults which affect prognosis. IVF has been associated with an increased risk of adverse obstetric outcomes [19], possibly related to altered placentation and epigenetic changes [20]. Thus, current studies face the objective of differentiating the contribution of infertility to these outcomes, as compared to the different procedures employed, and their individual contribution. The objective of our review was to assess obstetric outcomes and placental histology in pregnancies following ICSI for non-male infertility.
Methods
Study population
This was a retrospective cohort of deliveries at the Royal Victoria Hospital, the main obstetrical teaching Health Center affiliated with McGill University, from 2009 to 2017. During this period, the center employed a protocol which required histopathological assessment for placentas from all deliveries, regardless if complicated or uncomplicated. Included were live singleton deliveries at a minimal gestational age of 24 weeks, of pregnancies attained by IVF with autologous oocytes. Excluded were IVF cycles with documented male infertility and in vitro maturation cycles. Male infertility was determined in the presence of one of the following, as diagnosed by two separate samples [21]: concentration < 15 million per ml, progressive motility < 32% and morphologically normal forms < 4%. Computerized files of suitable cases were reviewed, and data was collected, including patient background characteristics, infertility workup, infertility etiology, cycle characteristics, obstetric outcomes, and placental histopathological examination. We compared obstetric outcomes and placental histology of pregnancies in which ICSI was performed (ICSI group) to those in which ICSI was not performed (IVF group).
Intracytoplasmic sperm injection
ICSI was performed on a personalized basis, as dependent on patient characteristics, cycle outcomes, and treatment history. Indications included past failed fertilization, diminished oocyte yield, decreased ovarian reserve, and unexplained infertility. Following oocyte retrieval, oocytes were placed in a fertilization media (LifeGlobal, Guilford, CT). One hour later, oocytes were denuded with hyaluronidase, so that the corona-cumulus complex was removed. Semen samples were those obtained by ejaculation. Samples were processed by density gradient centrifugation, subsequent washing, and room temperature incubation. ICSI was performed on mature oocytes 1 h after denuded, under guidance of the PolScope spindle view system (LC-PolScope™). Following insemination, oocytes were separately placed into 10 µl culture media (LifeGlobal, Guilford, CT). The ICSI procedure used at our institution is described more in depth in our previous publication [22].
Embryo transfer and luteal replacement
Single blastocyte transfers are principally performed at our institution, with rare exceptions of cases for which transfer of cleavage state embryos in women at least 37 years of age or transfer of more than one embryo is recommended, as based on number of embryos achieved (few), embryo quality (low), number of failed past transfers, and patient age (advanced). Blastocytes chosen for transfer are high-quality embryos, with Gardner trophectoderm grading of A/B.
Following fresh transfer, luteal support consisted of progesterone supplementation, either in vaginal form or intramuscular administration. For programmed frozen-thawed transfers, estradiol and progesterone were continued following transfer, and for natural frozen-thawed transfer, luteal support is not given except for rec-hCG trigger (Merck Serono, Canada) 250mcg.
Placental examination
A single pathology department performed all placental examinations, and pathologists were blinded to patient-assisted reproductive history and treatments employed. Initially, macroscopic examination of the placenta was performed and included measurement of placental weight and size and description of the umbilical cord, free membrane, fetal surface, maternal surface, placental parenchyma, and any additional abnormality identified. Following macroscopic examination, sections from the umbilical cord, membrane, and random placental parenchymal were fixated in formalin and examined. Placental histological lesions were categorized according to the Amsterdam Placental Workshop Group Consensus [23, 24], into four main pathophysiological categories—anatomic, inflammatory, villous maturation, and vascular malperfusion lesions.
Statistical analysis
Data were analyzed 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)) as appropriate and compared using the Student’s t-test or the non-parametric Mann–Whitney test as appropriate. Categorical variables were calculated as number (percentage) and compared with chi-squared or Fisher’s exact test as appropriate. All tests were two tailed, and the threshold for statistical significance was defined as p-value < 0.05.
Following initial inspection of our data, the ratio between the ICSI and control groups was found to be approximately 1:2. The baseline rate of any main obstetric complication, as reported previously with regard to the effect of ICSI on obstetric outcomes [18], was demonstrated to be approximately 20%. The sample size of our cohort thus proved sufficient to demonstrate a 10% increase in complication rate with ICSI (25% vs. 15%), with 80% power and an alpha of 0.05.
The study was approved by the Research Ethics Board of the McGill University Health Center, approval number MUHC-2019–5026.
Results
A total of 618 live singleton deliveries following IVF were identified as eligible for inclusion in the study—400 following the application of ICSI as part of infertility treatment (ICSI group) and 218 following regular insemination (IVF group).
Patient baseline characteristics and infertility workup are presented in Table 1. No differences were demonstrated between the groups regarding maternal age, body mass index, and parity. The main indication for infertility treatment was significantly different between the groups (p < 0.001), as a higher rate of patients in the ICSI group underwent treatment for diminished ovarian reserve and a higher rate of patients in the IVF group underwent treatment for tubal factor.
Table 1.
Demographic characteristics of the ICSI and IVF groups
| ICSI n = 400 |
IVF n = 218 |
p | |
|---|---|---|---|
| Age, (years), mean ± SD | 35.8 ± 4.3 | 35.2 ± 4.2 | 0.10 |
| BMI (kg/m2), mean ± SD | 25.0 ± 2.2 | 25.1 ± 2.2 | 0.80 |
| Gravidity, median (range) | 2 (1–16) | 2 (1–9) | 0.45 |
| Parity, median (range) | 0 (0–4) | 0 (0–3) | 0.20 |
| Smoking, n (%) | 14 (3.5%) | 6 (2.7%) | 0.61 |
| Antral follicle count, median (range) | 14 (1–80) | 16 (1–65) | 0.28 |
| Uterine fibroids, n (%) | 34 (8.5%) | 20 (9.1%) | 0.77 |
| Infertility etiology (main): | < 0.001 | ||
| Unexplained infertility, n (%) | 143 (35.7%) | 84 (38.5%) | |
| Ovulation disorder, n (%) | 81 (20.2%) | 47 (21.5%) | |
| Diminished ovarian reserve, n (%) | 91 (22.7%) | 18 (8.2%) | |
| Tubal factor, n (%) | 37 (9.2%) | 54 (24.7%) | |
| Endometriosis, n (%) | 36 (9.0%) | 13 (5.9%) | |
| Other, n (%) | 12 (3.0%) | 2 (0.9%) |
SD standard deviation, n number, BMI body mass index, pre-gestational
About two-thirds of deliveries in the cohort were following a fresh embryo transfers and one-third following frozen-thawed transfers, and this rate was similar between the study groups (Table 2). A lower rate of patients in the ICSI group had a single embryo transfer (67.5% vs. 76.6%, p = 0.01), and less commonly were transferred blastocytes (67.5% vs. 77%, p = 0.01). No differences were demonstrated between the groups for the majority of obstetric outcomes (Table 2), including preeclampsia, preterm delivery, and low birth weight, except for cesarean delivery, which occurred significantly more often in the ICSI group—44.2% vs. 35.7%, p = 0.04. Congenital malformations were found in 1.5% and 1.8% of the ICSI and control neonates, respectively, p = 0.74.
Table 2.
In vitro fertilization cycle, pregnancy, and obstetric outcomes of the assisted hatching and no assisted hatching groups
| ICSI n = 400 |
IVF n = 218 |
p | |
|---|---|---|---|
| Cycle course | |||
| Fresh embryo transfer, n (%) | 271 (67.7%) | 159 (72.9%) | 0.18 |
| Single embryo transfer, n (%) | 270 (67.5%) | 167 (76.6%) | 0.01 |
| Blastocyte transferred, n (%) | 270 (67.5%) | 168 (77.0%) | 0.01 |
| Pregnancy complications | |||
| Gestational diabetes mellitus, n (%) | 50 (12.5%) | 26 (11.9%) | 0.83 |
| Preeclampsia, n (%) | 13 (3.2%) | 10 (4.5%) | 0.40 |
| Low lying placenta, n (%) | 15 (3.7%) | 13 (5.9%) | 0.20 |
| Placenta Accreta, n (%) | 9 (2.2%) | 5 (2.2%) | 0.97 |
| Obstetric outcomes | |||
| Gestational age (weeks), mean ± SD | 38.6 ± 1.9 | 38.3 ± 2.6 | 0.37 |
| Preterm delivery, n (%) | 34 (8.5%) | 18 (8.2%) | 0.91 |
| Cesarean delivery, n (%) | 177 (44.2%) | 78 (35.7%) | 0.04 |
| Gender: male, n (%) | 211 (52.7%) | 100 (45.8%) | 0.10 |
| Birth weight | 3287 ± 593 | 3196 ± 664 | 0.08 |
| Low birth weight, n (%) | 48 (12.0%) | 22 (10.0%) | 0.47 |
| Congenital malformation, n (%) | 6 (1.5%) | 4 (1.8%) | 0.74 |
SD standard deviation, IQR interquartile range, n number. Congenital malformation—any cardiovascular, urinary tract, neurological, or limb malformation, as coded after birth
Placental findings are presented in Table 3. Placental weight was similar between the groups, as was the rate of anatomical disorders, including abnormal cord insertion and placental structural abnormalities. In regard to placental inflammatory lesions, a significantly lower rate of villitis of unknown etiology was found in the ICSI group (1.0% vs. 4.5%, p = 0.007), while among vascular lesions, a significantly higher rate of avascular villi was noted following ICSI (3% vs. 0.4%, p = 0.03). Finally, placentas in the ICSI group were notable for a higher rate of maternal surface calcifications—33% vs. 23.8%, p = 0.01.
Table 3.
Placental findings in the assisted hatching and no assisted hatching groups
| ICSI n = 400 |
IVF n = 218 |
p | |
|---|---|---|---|
| Placental weight (grams), mean ± SD | 638 ± 166 | 636 ± 176 | 0.87 |
| Weight < 10th percentile, n (%) | 105 (26.2%) | 54 (24.7%) | 0.68 |
| Placental thickness (cms), mean ± SD | 1.98 ± 0.61 | 1.90 ± 0.65 | 0.25 |
| Anatomic disorders | |||
| Single umbilical artery, n (%) | 4 (1.0%) | 1 (0.4%) | 0.66 |
| Umbilical cord marginal insertion, n (%) | 105 (26.2%) | 47 (21.5%) | 0.19 |
| Umbilical cord furcate insertion, n (%) | 10 (2.5%) | 6 (2.7%) | 0.85 |
| Umbilical cord velamentous insertion, n (%) | 37 (9.2%) | 22 (10.0%) | 0.73 |
| Circummarginate insertion, n (%) | 52 (13.0%) | 23 (10.5%) | 0.37 |
| Circumvallate insertion, n (%) | 1 (0.2%) | 3 (1.3%) | 0.12 |
| True knot, n (%) | 4 (1.0%) | 2 (0.9%) | > 0.99 |
| Hypercoiling of cord, n (%) | 2 (0.5%) | 1 (0.4%) | > 0.99 |
| Bilobated placenta, n (%) | 8 (2.0%) | 3 (1.3%) | 0.75 |
| Accessory lobe, n (%) | 5 (1.2%) | 3 (1.3%) | > 0.99 |
| Inflammatory disorders | |||
| Acute chorioamnionitis (any), n (%) | 4 (9.2%) | 21 (9.6%) | 0.87 |
| Acute chorioamnionitis with moderate to severe maternal inflammatory response, n (%) | 25 (6.2%) | 13 (5.9%) | 0.88 |
| Acute chorioamnionitis with moderate to severe fetal inflammatory response, n (%) | 10 (2.5%) | 5 (2.2%) | 0.87 |
| Chronic deciduitis, n (%) | 2 (0.5%) | 1 (0.4%) | > 0.99 |
| Villitis of unknown etiology, n (%) | 4 (1.0%) | 10 (4.5%) | 0.007 |
| Maturation disorders | |||
| Accelerated villous maturation, n (%) | 25 (6.2%) | 16 (7.3%) | 0.60 |
| Delayed villous maturation, n (%) | 8 (2.0%) | 8 (3.6%) | 0.21 |
| Distal villous hypoplasia, n (%) | 7 (1.7%) | 7 (3.2%) | 0.24 |
| Increased syncytial knotting, n (%) | 28 (7.0%) | 12 (5.5%) | 0.47 |
| Vascular disorders | |||
| Retroplacental hematoma, n (%) | 8 (2.0%) | 6 (2.7%) | 0.54 |
| Cord thrombosis, n (%) | 0 | 0 | |
| Intervillous thrombosis, n (%) | 54 (13.5%) | 25 (11.4%) | 0.46 |
| Intramural fibrin, n (%) | 1 (0.2%) | 0 | > 0.99 |
| Villous infarction, n (%) | 17 (4.2%) | 5 (2.2%) | 0.20 |
| Avascular villi, n (%) | 12 (3.0%) | 1 (0.4%) | 0.03 |
| Perivillous fibrin deposition, n (%) | 43 (10.7%) | 17 (7.8%) | 0.23 |
| Maternal vasculopathy, n (%) | 25 (6.2%) | 14 (6.4%) | 0.93 |
| Fetal vasculopathy, n (%) | 6 (1.5%) | 2 (0.9%) | 0.71 |
| Chorangiosis, n (%) | 42 (10.5%) | 16 (7.3%) | 0.19 |
| Fetal vascular malperfusion (one criteria) | 22 (5.5%) | 6 (2.7%) | 0.11 |
| Fetal vascular malperfusion (more than one criteria) | 7 (1.7%) | 3 (1.3%) | > 0.99 |
| Maternal vascular malperfusion (one criteria) | 166 (41.5%) | 89 (40.8%) | 0.87 |
| Maternal vascular malperfusion (more than one criteria) | 52 (13.0%) | 30 (13.7%) | 0.78 |
| Calcifications | |||
| Chorionic plate calcifications | 14 (3.5%) | 8 (3.6%) | 0.91 |
| Maternal surface calcifications, n (%) | 132 (33.0%) | 52 (23.8%) | 0.01 |
| Parenchymal calcifications, n (%) | 21 (5.2%) | 12 (5.5%) | 0.89 |
| Nucleated RBC, n (%) | 3 (0.7%) | 2 (0.9%) | > 0.99 |
| Chorangioma, n (%) | 5 (1.2%) | 0 | 0.16 |
SD standard deviation, n number
We examined the main outcomes found significantly different between the groups—cesarean deliveries, placental villitis of unknown etiology, placental avascular villi, and maternal surface calcifications—to further adjust for differences in baseline characteristics between the groups (analysis hereby described and not presented as table). The main baseline variables found significant between the groups were diminished ovarian reserve, number of embryos transferred, and blastocyte transfer, and after assessing the correlation between the three, diminished ovarian reserve was found correlated to both number of embryos transferred and blastocyte transfer. Therefore, we adjusted the differences found in outcomes to diminished ovarian reserve only. The difference in cesarean delivery and avascular villi rates were not attained, while villitis of unknown etiology was still significantly lower in the ICSI group (OR 0.18, 95% CI 0.05–0.61, p = 0.006) and the rate of maternal surface calcifications significantly higher (OR 1.50, 95% CI 1.02–2.20, p = 0.03). We similarly composed a linear regression analysis for birth weight, to also account for the effect of fresh/frozen-thawed transfer, in addition to the previously mentioned confounders. ICSI was not found correlated to birth weight after adjustment.
Discussion
The objective of our manuscript was to assess obstetric outcomes and placental findings in pregnancies obtained following ICSI. We excluded cycles with a diagnosis of male factor, to better focus on the effect on the procedure itself and minimize the contribution of male infertility. After adjusting for confounders, we observed similar obstetric outcomes between the ICSI and conventional IVF groups. Placental analyses were overall similar between the groups, except for a lower rate of villitis of unknown etiology and higher rate of maternal surface calcifications following ICSI.
ICSI for non-male infertility is increasingly performed worldwide, despite debatable efficacy and the alternative availability of conventional IVF. Thus, establishing the safety of this technology seems especially important. Past studies have demonstrated an increase in birth defects with ICSI for non-male infertility [16], hence the Society of Maternal Fetal Medicine’s recommendation for a detailed obstetric ultrasound and fetal echography following ICSI [25]. Yet, data regarding obstetric outcomes following ICSI for non-male infertility is scarce. In a report by Liu and colleagues excluding couples with severe oligoasthenozoospermia [17], live singleton births following a first fresh embryo transfer with ICSI and IVF were assessed for obstetric outcomes. No differences were noted in the rates of hypertensive disorders of pregnancy, cesarean deliveries and small for gestational age neonates overall, and when analyzed according to infertility indication. In an additional report [18], the correlation between different aspects of fresh embryo transfer and perinatal outcomes was evaluated. ICSI was found to have been performed in a significantly higher rate in patients with obstetrics complications, including hypertensive disorders of pregnancy, small for gestational age, and placenta accreta. This correlation attained significance after adjustment for male infertility. Our findings are in line with the former, although the number of cases in our cohort is probably not adequately powered for this sole purpose. The different conclusions from the latter report most probably lie in the heterogenicity of populations and underpowered samples to assess obstetric outcomes individually.
Placental examination offers potential insight to pathophysiological intrauterine processes. Indeed, typical histological features have been associated with common obstetrics complications, such as maternal malperfusion lesions in cases of pregnancy-induced hypertension and fetal growth restriction, or villitis of unknown etiology in cases of fetal growth restriction [26]. Yet, even in uncomplicated pregnancies, the presence of certain placental lesions has been correlated to an increased risk of obstetric complications in subsequent pregnancies [27]. In our cohort, after adjustment for diminished ovarian reserve, we observed a lower rate of villitis of unknown etiology and higher rate of maternal surface calcifications. Villitis of unknown etiology refers to non-infectious inflammation of the villi, typically involving maternal T cells and fetal macrophages and located in the terminal villi [28]. This inflammation is thought to exert a negative effect through local cytokines released and has been viewed by many as an immunological disruption to the fetal-maternal interface [29]. Thus, the reduced incidence following ICSI points perhaps to improved immunological facilitation following ICSI, although the overall low number of cases in the study precludes us from affirming this conclusion. In regard to placental calcifications, although research tying sonographic presence of calcifications to neonatal outcomes exists, the correlation to calcifications demonstrated on histological examination is less established. As it is unclear when such calcifications developed throughout pregnancy, one cannot differentiate between early onset calcifications and those appearing near term, a distinction demonstrated to affect prognosis [30]. Thus, we cannot comment on anticipated clinical associations, although such an association merits investigation. Overall, as the vast majority of placental findings were similar between the groups, the authors’ conclusion, based on the data in this article, is of similar placental histology following ICSI, as in non-ICSI IVF cases.
The study was limited by its retrospective design, and as such patients were not randomized to ICSI or conventional IVF, but treatment was decided by their physician as based on clinical considerations. As a result, the rate of diminished ovarian reserve in the ICSI group was higher, and the rate of single embryo and blastocyte transfer was lower. While we did adjust for confounders, it is possible that inherent characteristics associated with these differences may contribute to our results. Nevertheless, our results are in line with previous reports related to pregnancy complications. Due the study’s retrospective design, certain data of interest were also missing for analysis, such as data regarding sperm DNA fragmentation and genetic tests, which according to current literature may influence our interpretation of involvement of male factor [31]. An additional limitation of our study refers to sample size, which was not powered to detect differences in outcomes of lower occurrence. Sample size also did not allow us to separately analyze patients according to infertility indication, which may prove interesting.
Study strengths include its unique focus on placental histology, in addition to clinical aspects. This adds to our understanding of in utero processes and is important in light of an emerging body of literature, which supports the association between placental lesions and neonatal adverse outcomes and development [32]. The study is also one of few to specifically address ICSI in couples without male infertility. While some studies have not associated male infertility with adverse obstetric outcomes [18], others have noted a more favorable outcome in the absence of female factors [33, 34], so that by excluding male factor infertility, we aimed to avoid any bias in the interpretation of our results. Finally, all placentas during the study period were sent for evaluation as per departmental protocol and not just for complicated deliveries, so that despite the study’s retrospective design, a selection bias is less likely. Examination was also performed by pathologists blinded to infertility treatment history.
In conclusion, our study points to similar obstetric findings following ICSI for non-male infertility and overall similar placental histology. These findings are reassuring for clinicians and patients but need to be weighed against potential efficacy and data regarding an increase in congenital malformations, as conventional IVF can be offered alternatively. As IVF success rates increase with improved technology, the responsibility of safe practice and child well-being are priorities for fertility caregivers. Thus, our findings remain to be validated in a larger cohort, in a preferable prospective setting which enables sub analyses of different ICSI indications.
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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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
As per request from corresponding author.
Not applicable.