Abstract
PURPOSE
In vitro fertilization (IVF) is associated with abnormal trophoblast invasion and resultant decreased levels of circulating placental biomarkers such as placental growth factor (PlGF). Our objective was to evaluate maternal serum levels of second/third trimester PlGF, sonographic placental parameters, and clinical outcomes among IVF frozen embryo transfer (FET) pregnancies with and without embryo trophectoderm biopsy.
METHODS
This was a retrospective study of pregnant patients who conceived using a single frozen embryo transfer (FET) and gave birth between 30 January 2018 and 31 May 2021. We compared PlGF levels, sonographic placental parameters, and clinical outcomes between FET with biopsy and FET without biopsy groups.
RESULTS
The median PlGF level was 614.5 pg/mL (IQR 406–1020) for FET pregnancies with biopsy, and 717.0 pg/mL (IQR 552–1215) for FET pregnancies without biopsy. The adjusted mean difference was 190.9 pg/mL lower in the FET biopsy group (95% CI, –410.6, 28.8; p = 0.088). There were no statistically significant differences in placental parameters or clinical pregnancy outcomes.
CONCLUSION
This exploratory study demonstrated a possible trend toward lower maternal serum PlGF in the pregnancies conceived with FET using a biopsied embryo. Further investigation is warranted into the potential placental health effects of trophectoderm biopsy.
Keywords: Pregnancy, Preeclampsia, In vitro fertilization, Preimplantation diagnosis, Placenta growth factor
Introduction
Advances in preimplantation genetic testing (PGT) have led to improved implantation rates, lower early pregnancy loss rates, and overall higher live birth rates for patients undergoing in vitro fertilization (IVF) by selecting against aneuploidy and other genetic conditions [1–3]. However, the potential hazards of trophectoderm (TE) biopsy performed for PGT testing are not fully known, in particular the potential placental impacts of this technology. It has been hypothesized that TE biopsy may affect future placental development and function by downregulating Placental Growth Factor (PGF) gene expression in the placenta, thereby decreasing production and release of placental growth factor (PlGF) into the maternal circulation[4]. PlGF is a pro-angiogenic member of the vascular endothelial growth factor (VEGF) family. In normal pregnancies, maternal circulating PlGF concentrations gradually increase starting in the second trimester coinciding with non-branching angiogenesis of the feto-placental vessels and utero-placental circulation maturation [5]. In disordered placental development, deficient trophoblast invasion and uterine vascular remodelling during the earliest stages of embryonic development result in a maternal-vascular malperfusion (MVM) pattern of placental pathogenesis [6]. The ensuing placental disease results in suppressed pro-angiogenic PlGF levels, along with elevated levels of circulating anti-angiogenic soluble fms-like tyrosine kinase-1 (sFlt-1) [7, 8]. In patients with MVM pathology, PlGF continues to decline through the second and third trimesters [9]. Low PlGF is associated with increased risk of preeclampsia, preterm birth, fetal growth restriction, and stillbirth, making PlGF an important clinical predictor of these adverse outcomes [10, 11].
IVF is a risk factor for abnormal trophoblast invasion and resultant decreased circulating PlGF levels compared to spontaneously conceived pregnancies [12]. In trophoblast cells, PGF is upregulated by transcription factors glial cells missing 1 (GCM1) and Distal-less 3 (DLX3) [13]. IVF is associated with downregulation of the trophoblast transcription factor GCM1 that drives PlGF production, demonstrating a potential link between IVF technologies and future placental function [14]. This illustrates the importance of understanding the mechanisms that confer an increased risk of placenta-mediated adverse outcomes among IVF pregnancies [2, 6]. Studies have also shown an association between TE biopsy and higher risks of preeclampsia and preterm birth above those attributable to IVF alone [15–17]. Whether this indicates a truly independent adverse effect of TE biopsy remains inconclusive [2, 18]. Hypothetically, embryo TE biopsy may affect placental function through further downregulation of PGF gene expression, thus reducing subsequent placental production of PlGF throughout gestation and increasing the risk of preeclampsia and associated adverse outcomes [4]. TE biopsy necessarily reduces the cellular mass of the trophectoderm, and it is possible that this decreased tissue volume may also impact growth and development of the future placenta. PlGF and other placental angiogenic biomarkers are known to differ between spontaneously conceived pregnancies and those conceived with IVF; however, the specific effects of TE biopsy on circulating PlGF levels and clinical measures of placental function have not yet been explored [19, 20]. This can only be achieved by comparing outcomes of IVF pregnancies where the main difference is whether TE biopsy was performed for PGT.
Our institute launched real-time clinical PlGF testing in March 2017 and was the first to offer this test in Canada and among the first in the world [10]. We have a specialized Placenta Clinic focused on the assessment of placental function with PlGF testing and sonography [21]. This positioned us to uniquely investigate placental parameters and clinical pregnancy outcomes specifically associated with embryo TE biopsy.
The objective of this exploratory study was to evaluate maternal serum PlGF levels of the second/third trimester among IVF pregnancies, comparing those with and without TE biopsy. We also evaluated sonographic features of abnormal placentation including impaired uteroplacental blood flow, placenta previa, velamentous cord insertion, and clinical pregnancy outcomes including gestational age at birth, birth weight, preeclampsia, and stillbirth.
Methods
This was a retrospective cohort study of patients seen consecutively for obstetrical care in a specialized clinic for IVF pregnancies at a tertiary maternity center in Toronto, Canada. The study included pregnant patients who conceived using a single frozen embryo transfer (FET) and gave birth between 30 January 2018 and 31 May 2021. The clinic lab used vitrification for embryo freezing. Pregnancies conceived with a donor oocyte and multiple gestation pregnancies were excluded. At this time in our center, PlGF testing was clinically available in outpatient clinics and inpatient units [10]. A pragmatic cutoff value of 100 pg/mL was used to define low PlGF [10, 11, 22]. In the setting of a low PlGF result, clinicians were advised to perform a comprehensive maternal–fetal evaluation; however, specific recommendations were not provided for clinical management based solely on low PlGF. For this study, maternal serum PlGF was quantified as part of routine antenatal bloodwork between 19 and 32 weeks’ gestational age (GA). Patients underwent a targeted placental ultrasound examination around 22 weeks’ gestation comprising assessment of placental anatomy and bilateral uterine artery Doppler waveforms, reported as the mean pulsatility index (UtAPI). We collected data on patient demographics, medical and obstetrical history, obstetrical ultrasounds, and pregnancy outcomes. Data were extracted from medical records into a secured database. We performed summary statistics showing patient characteristics among IVF-FET pregnancies with and without embryo TE biopsy. Two-sided Student’s T tests were used to evaluate serum PlGF and other continuous outcomes between the FET groups. Fisher’s exact Chi-square tests were used to compare categorical outcomes. We adjusted for gestational age at time of PlGF testing and for maternal age using linear regression. For birth weight, we further adjusted for gestational age at birth. We performed one prespecified sensitivity analysis to evaluate whether the type of FET protocol (natural cycle or programmed cycle) influenced the association between trophectoderm biopsy and PlGF. We performed two post hoc analyses: (1) limiting the sample to PlGF levels measured between 25 and 28 weeks’ gestational age and (2) evaluating the full sample with PlGF gestational age-adjusted centiles as a binary variable with cutoff at the 10th centile [23]. Statistical analyses were performed and figures created using STATA version 13.1 (StataCorp, College Station, TX).
Results
A total of 137 pregnancies conceived by FET were identified, of which 99 had information on maternal PlGF levels, placenta ultrasound parameters, and pregnancy outcomes. Of these, 61 (61.6%) were FET without embryo TE biopsy, and 38 (38.4%) were FET with TE biopsy. Maternal age and body mass index were similar between groups, and most were primiparous (Table 1). Infertility diagnoses are shown in Table 1 and are similar between groups, with a few exceptions. There was a higher rate of recurrent pregnancy loss in the FET biopsy group (28.9% vs 3.3%) consistent with the use of preimplantation genetic testing for this indication. In contrast, diminished ovarian reserve was less likely in the FET biopsy group (2.6% vs 21.3%). Four (10.5%) patients in the FET biopsy group underwent preimplantation genetic testing to select against monogenic diseases (PGT-M). Unexplained infertility was similar in both groups and was the largest diagnostic category overall.
Table 1.
Baseline characteristics of the study sample
| Maternal and pregnancy characteristics | FET no biopsy (n = 61) |
FET with biopsy (n = 38) |
|---|---|---|
| Maternal age, median (IQR) | 37 (35, 40) | 37 (34, 40) |
| Body mass index, median (IQR) | 23.6 (21.6, 28.9) | 23.8 (21.3, 27.4) |
| Primiparous, n (%) | 50 (82.0%) | 29 (76.3%) |
| Male fetal sex, n (%) | 30 (51.7%) | 18 (47.4%) |
| ASA prophylaxis in pregnancy, n (%) | 54 (88.5%) | 32 (84.2%) |
| Infertility diagnosisa | ||
| History of recurrent pregnancy loss, n (%) | 2 (3.3%) | 11 (28.9%)* |
| Polycystic ovarian syndrome, n (%) | 4 (6.6%) | 2 (5.3%) |
| Ovulatory dysfunction, n (%) | 3 (4.9%) | 1 (2.6%) |
| Diminished ovarian reserve, n (%) | 13 (21.3%) | 1 (2.6%)* |
| Endometriosis, n (%) | 1 (1.6%) | 1 (2.6%) |
| Tubal factor, n (%) | 5 (8.2%) | 1 (2.6%) |
| Male factor, n (%) | 9 (14.7%) | 5 (13.2%) |
| Single parent/LGBTQ + family building, n (%) | 1 (1.6%) | 1 (2.6%) |
| PGT-M embryo selection, n (%) | – | 4 (10.5%) |
| Other diagnosis, n (%) | 8 (13.1%) | 2 (5.3%) |
| Unexplained, n (%) | 24 (39.3%) | 14 (36.8%) |
aDiagnostic categories are not mutually exclusive, with the exception of “unexplained”
*p < 0.05
PlGF levels were measured between 19 and 32 weeks’ GA, with the majority of tests performed between 25 and 28 weeks (Fig. 1). PlGF levels were lower in the FET biopsy group compared with the FET no biopsy group. The median maternal PlGF level was 614.5 pg/mL (interquartile range, IQR 406–1,020) for FET pregnancies with biopsy and 717.0 pg/mL (IQR 552–1,215) for FET pregnancies without biopsy (Fig. 2). The adjusted mean difference was 190.9 pg/mL lower in the FET biopsy group (95% confidence interval (CI), − 410.6, 28.8; p = 0.088); however, this was not statistically significant (Table 2). Adjusted mean differences for UtAPI, gestational age at birth, and birth weight were also not statistically different between groups. In the FET biopsy group, the unadjusted rates of preeclampsia (2.63% vs 1.64%) and velamentous cord insertion (5.26% vs 1.64%) were higher, and the rate of placenta previa was lower (0% vs 1.64%) compared to the FET no biopsy group; however, these differences were not statistically significant. We did not perform adjusted analyses for these outcomes due to the low numbers in both groups. There was one termination of pregnancy > 20 weeks’ GA in the FET biopsy group, and no spontaneous stillbirths in either group.
Fig. 1.
PlGF levels for FET groups by gestational age at time of testing
Fig. 2.
PlGF levels with boxplots of median and interquartile range by FET group
Table 2.
PlGF, placental parameters, and clinical outcomes for IVF-FET pregnancies with and without embryo trophectoderm biopsy
| Variable | FET no biopsy (n = 61) |
FET with biopsy (n = 38) |
Difference (95% CI) | P | Adjusteda difference (95% CI) | P |
|---|---|---|---|---|---|---|
| PlGF, mean (sd) | 931.6 (589.7) | 743.0 (466.9) | − 188.6 (− 412.6, 35.4) | 0.098 | − 190.9 (− 410.6, 28.8) | 0.088 |
| UtAPI, mean (sd) | 0.86 (0.20) | 0.86 (0.18) | − 0.009 (− 0.09, 0.09) | 0.98 | − 0.0008 (− 0.09, 0.09) | 0.97 |
| GA at birth, mean (sd) | 39.0 (1.41) | 38.7 (2.97) | − 0.28 (− 1.17, 0.62) | 0.54 | − 0.28 (− 1.18, 0.61) | 0.53 |
| Birth weight, mean (sd) | 3368 (545.2) | 3306 (683.0) | − 62.5 (− 312.5, 187.4) | 0.62 | 6.4 (− 178.2, 191.0) | 0.95 |
| Preeclampsia, n (%) | 1 (1.64%) | 1 (2.63%) | 0.99% (− 4.8, 6.8) | 0.74 | – | – |
| Velamentous cord, n (%) | 1 (1.64%) | 2 (5.26%) | 3.62% (− 3.53, 10.7) | 0.32 | – | – |
| Placenta previa, n (%) | 1 (1.64%) | 0 (0%) | − 1.64% (− 5.77, 2.49) | 0.43 | – | – |
aPlGF was adjusted for GA at PlGF test and maternal age. GA at birth was adjusted for maternal age. Birth weight was adjusted for GA at birth and maternal age.
Most embryo transfers were performed with programmed cycles, although 3 (7.9%) were with natural cycles in the FET biopsy group and 2 (3.3%) in the FET no biopsy group. A sensitivity analysis adjusting for FET protocol did not materially affect the difference in PlGF between these groups or the level of significance (adjusted mean difference − 190.6; 95% CI, − 412.5, 31.3; p = 0.091). The post hoc analysis restricted to pregnancies with PlGF levels measured between 25 and 28 weeks’ gestational age showed no significant difference between FET groups (adjusted mean difference − 151.7; 95% CI, − 376.3, 73.0; p = 0.18). We also evaluated PlGF levels below the 10th centile for gestational age between biopsy (5.3%) and no biopsy (4.9%) groups and found no significant difference (p = 0.94).
Discussion
This study evaluated second/third trimester maternal serum PlGF levels, placental parameters, and pregnancy outcomes among pregnancies conceived by frozen embryo transfer, comparing those with and without embryo trophectoderm biopsy. Maternal PlGF levels were lower among the FET biopsy group, and this difference trended toward but did not reach statistical significance in this small study. This is the first study to evaluate second/third trimester maternal PlGF levels among pregnancies conceived with a biopsied embryo. Using pregnancies conceived with FET without biopsy as a comparison group ensured that other patient and IVF technological factors were similar between the groups, allowing for the assessment of TE biopsy effects on PlGF and placental outcomes. These findings suggest a potentially important link between TE biopsy and differences in subsequent placental function worthy of further investigation with larger sample sizes. Understanding how TE biopsy could influence placental development is particularly important since PGT offers significant benefits in embryo selection to avoid aneuploidy and other genetic conditions [1–3]. As PGT technology is increasingly used, it is paramount to understand how to optimize the safety of this intervention. In addition, the advent of non-invasive PGT (niPGT) could potentially reduce or eliminate issues with TE biopsy and the applications of this technology should continue to be developed [24]. Our study did not demonstrate differences in other placental parameters (UtAPI, placenta previa, velamentous cord insertion), or clinical pregnancy outcomes (gestational age at birth, birth weight, preeclampsia, stillbirth). Overall, the current literature is limited and shows mixed results with respect to outcomes associated with TE biopsy, with some evidence for higher risks of preeclampsia, preterm birth, and male fetal sex [15–17]. However, the results of other studies, including a recent meta-analysis, do not reflect these differences [2, 18].
Our study fits into the body of literature investigating the effects of IVF technologies on placental biomarkers. For example, another study evaluating serum ß-human chorionic gonadotropin (ßhCG) at day 12 post transfer found significantly lower ßhCG levels in pregnancies with a TE biopsied embryo compared to those without biopsy [18]. Placental biomarkers could theoretically assist clinicians in guiding pregnancy management for this population.
The introduction of placental biomarker testing to guide antenatal care has received increased attention clinically because of its potential to improve delivery timing and clinical outcomes for pregnancies at higher risk of preeclampsia and other placental diseases. PlGF testing improves the performance of multimodal preeclampsia screening prior to disease onset [25, 26]. As a diagnostic test after 20 weeks’ GA, PlGF reduces the time to diagnosis in patients presenting with suspected preeclampsia [11]. Our group previously demonstrated that the time to preterm birth was significantly shorter for hypertensive pregnancies with low PlGF compared to those with normal PlGF levels [10]. This placental biomarker is promising both as a screening and diagnostic tool in the evaluation and management of preeclampsia in IVF patients. A better understanding of placental risk factors, including those presented by IVF technologies, may alert clinicians to targeted PlGF testing and heightened clinical surveillance.
This was an exploratory study and had some limitations, including a small sample size. Although the majority of PlGF tests were performed in the narrow timeframe of 25–28 weeks’ GA, testing at a pre-determined GA may have allowed for better comparison between groups. However, post hoc analyses restricted to PlGF levels measured between 25 and 28 weeks’ GA and evaluating the full sample using a PlGF GA-adjusted 10th centile cutoff did not show any differences in this study. While the groups were similar with respect to baseline maternal characteristics, there were some differences in underlying infertility diagnoses reflective of the clinical indications for PGT, for example, among patients with a history of recurrent pregnancy loss. Most transfers in this sample were with programmed FET cycles. A sensitivity analysis did not demonstrate significant differences in the association between trophectoderm biopsy and PlGF when controlling for FET protocol; however, the study was underpowered to investigate this further. We were not able to measure placental PGF gene expression as this is not tested clinically, and we do not have placental pathology reports for all cases to allow meaningful comparison between groups. One strength of this study is the use of FET pregnancies without TE biopsy as the comparison group rather than spontaneously conceived pregnancies, thereby limiting selection effects and those potentially related to the IVF technology itself. Importantly, the study sample was comprised of consecutive IVF patients receiving fertility and pregnancy care at a single tertiary center where, at that time, PlGF was performed as part of standard investigations rather than solely in cases of suspected preeclampsia. More substantial differences in PlGF and placental function measures may exist in higher risk cohorts. To our knowledge, this was the first study evaluating PlGF and placental parameters among IVF pregnancies conceived with a TE biopsied embryo.
Conclusion
In this exploratory study, we found no statistically significant difference in maternal Placental Growth Factor (PlGF) levels between IVF pregnancies with and without embryo trophectoderm biopsy. A trend toward lower PlGF in the biopsied embryo group was observed and warrants further investigation of this important placental biomarker.
Author contribution
All authors contributed to the study conception and design. Data collection was performed by Rachel Lee and Yaanu Jeyakumar and data analysis was performed by John Snelgrove. Funding was obtained by John Snelgrove and Rhonda Zwingerman. The first draft of the manuscript was written by John Snelgrove and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Funding
This study was funded by a Canadian Fertility & Andrology Society Seed Grant, and by a research grant from the Department of Obstetrics & Gynaecology, Mount Sinai Hospital/University Health Network, University of Toronto. The analyses, conclusions, opinions, and statements expressed are solely those of the authors and do not necessarily reflect those of the funding sources.
Data availability
The data used in this study are not publicly available due to privacy/ethical restrictions.
Declarations
Ethics approval
This study was approved by the Mount Sinai Hospital Research Ethics Board (REB 19–0150-E).
Competing interests
John Snelgrove, John Kingdom, and Kelsey McLaughlin have received research funding from the Roche Diagnostics Grant Program. Rhonda Zwingerman has received honoraria from Ferring Pharmaceuticals for participating in symposia unrelated to this project. The other authors have no competing interests to declare that are relevant to the content of this article.
Footnotes
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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
The data used in this study are not publicly available due to privacy/ethical restrictions.