Reappraisal of adverse obstetric outcomes independently associated with contemporary fertility treatment practices: a US prospective cohort study.

The DESCRT study is the largest U.S. prospective cohort designed to evaluate how underlying infertility and fertility treatment may impact obstetric/perinatal outcomes. The current paradigm on ART-associated complications may be confounded by parental factors. Large population-based studies often lack accurate verification of these complications, with some requiring adequate clinical training in obstetrics and familiarity with how complications are documented. Understanding whether, and how, ART independently affects obstetric risks is crucial for developing evidence-based guidelines for ART-conceived pregnancies and counseling for patients considering this technology for elective reasons. We found that ART was an independent risk factor for abnormal placentation. Fresh embryo transfer was the predominant treatment parameter associated with abnormal placentation and low PAPP-A. When underlying infertility and baseline characteristics were adjusted for, there was no significantly increased risk of hypertensive disorders of pregnancy, spontaneous preterm birth, or gestational diabetes associated with ART. Our study substantiates that ART independently contributes to abnormal placentation. However, other traditionally associated complications were not observed, suggesting these may be primarily attributed to underlying infertility diagnoses, other baseline risk factors, and/or higher rates of multiple gestation. Our observation also adds to prior clinical/basic science evidence that demonstrated an association of placentation abnormalities with ART 11 , 17 , 34 – 40 . Importantly, this association was independent of infertility diagnosis, prior uterine instrumentation, and history of recurrent miscarriages – factors that could affect placentation but not systematically accounted for in previous investigations. While the proportion of individual placental abnormalities ranged from 0.9% (vasa previa) to 3.3% (abnormal cord insertion/placental morphology), the cumulative incidence of abnormal placentation was 8.7% collectively in the ART group, which is significantly higher than 1.4% in non-ART conceptions. Our estimates are similar to a population-based study from Massachusetts by Stern et al. , which used a similar definition for abnormal placentation and reported the incidence of “placental problems” to be 2.5–3.7% in non-ART and 4.0–9.3% in ART conceptions 17 . Therefore, our observation likely represents a true effect secondary to ART, and not due to bias related to a smaller sample size. Our results echo the current guidelines of the Society for Maternal-Fetal Medicine to include careful ultrasound examination of the placenta and cord insertion site for ART pregnancies 41 . The suggested inherent risk of abnormal placentation with ART has significant public health implications given its increasing utilization. ART is also commonly used for elective fertility preservation since the experimental label for egg freezing was lifted in 2012 42 . For many individuals who need ART treatment to build a family, the benefit of gaining a child most likely outweighs the increased risk of abnormal placentation. However, what would the risk-benefit ratio of “elective” ART look like for families and the healthcare system? For individuals considering elective fertility preservation, the risks of abnormal placentation with ART should not be minimized for valid informed consent. ART also should not be the default conception route for those with stored gametes/embryos if unassisted conception is still a viable option. Interestingly, among ART pregnancies, fresh ET was significantly associated with abnormal placentation. Other major treatment parameters did not appear to influence the risk of placentation abnormalities. The literature has conflicting results on whether fresh ET is superior/inferior to FET in regards to abnormal placentation 43 – 46 . It is difficult to draw conclusions given variations in study populations, adjusted covariates, ART protocols, and definition of outcomes. A recent study of over 200 singleton placentas, limiting biases from parental factors, found that placental DNA methylation patterns are particularly altered in fresh ET-conceived pregnancies (but not FET) 47 . To investigate this further, we provided biochemical correlation using PAPP-A, a well-studied placental analyte in which lower levels have been associated with abnormal placental histology and clinical placental dysfunction 23 – 27 , 48 – 50 . Concordant with our clinical observations, PAPP-A levels were lower in fresh ET conceptions compared to FET and non-ART conceptions; the latter two not significantly different from each other. An exploratory analysis also demonstrated similar trends of lower maternal serum alpha-fetoprotein and estriol levels in fresh ET conceptions ( Supplemental Table S5 ). It has been postulated that the supraphysiologic hormonal milieu following ovarian stimulation creates an aberrant endometrial microenvironment during embryo implantation, potentially leading to defective trophoblastic invasion and placentation 51 – 55 . This drastically altered uterine environment during the peri-conception window may be obviated when using cryopreserved embryos. It is important to note that the higher rate of abnormal placentation in fresh ET conceptions may reflect underlying patient factors that influenced treatment choice. To assess this, we compared baseline characteristics between fresh ET and FET groups ( Supplemental Table S6 ). A higher proportion of FET patients had a history of prior cesarean delivery and other uterine surgery (p=0.02 and p<0.01, respectively), which are risk factors for abnormal placentation. This difference would theoretically bias our findings towards the null, further supporting a potential independent contribution from fresh ET. Nonetheless, there could be residual confounding from patient-related factors not captured in this study. The association between fresh ET and abnormal placentation warrants further confirmation. These investigations may help identify risk-reducing strategies at a public health level to enhance maternal/neonatal health outcomes following ART. This study has several key strengths to augment the field’s understanding of ART-related obstetric complications. It is the largest U.S. prospective clinical cohort with estimates of adverse outcomes similar to prior population studies. The cohort included patients diagnosed with infertility who subsequently conceived without assistance –a unique and key reference group to provide baseline risks of various complications among patients with infertility. Obstetric outcomes and key covariates were assessed by OB/GYN physicians, enhancing the reliability of the results. Fertility treatment protocols were overall uniform as a single center study, and were tracked rigorously to reflect accurate exposure. Prior studies from retrospectives databases may lack granularity and accuracy of assessed covariates and outcomes, which then affect the conclusions being drawn. Many outcomes in women’s health, such as HDP, severe maternal morbidity, and even birth defects, were not reliably identified in registry databases or through International Classification of Diseases codes 56 – 58 . Lastly, we captured factors such as nulliparity, prior miscarriages, and uterine instrumentation, which could all be effect modifiers for obstetric complications in an infertility patient population. We recognize our study’s limitations. “Abnormal placentation” was a composite outcome due to the rarity of these conditions, and included pathologies that have poorly understood (and likely divergent) etiologies. Therefore, we cannot hypothesize which placentation pathway is specifically affected by ART. Due to the relatively low number of abnormal placentation events, the confidence interval for relative risk associated with ART is wide. While we included numerous biologically plausible confounders related to abnormal placentation, residual confounding may exist. It is possible that patients who eventually conceived with ART may have more “severe” infertility. However, it is difficult to biologically categorize and adjust for extent of infertility within diagnoses. Many patients with infertility and unassisted pregnancies conceive while preparing for ART treatment, not solely because they continued to try conceiving longer. Given the cohort size and the low baseline prevalence of many outcomes, this study may have limited power to detect small or subtle differences, raising the potential for Type II error. We had a low participation rate (33.5%), which may introduce selection bias. The lower participation rate could be secondary to the COVID-19 pandemic and/or desire to not have additional contact or visits for research purposes given the sensitive and potentially traumatizing nature of needing infertility treatment. Our cohort is primarily composed of White and Asian patients, limiting the generalizability and understanding of ART-related risks in other racial/ethnic groups. In our prospectively collected data among patients with infertility, ART contributes to abnormal placentation, significantly more than in unassisted or NIFT pregnancies. This risk should be emphasized during patient counseling, particularly for those who are considering ART for elective reasons. Fresh embryo transfer was notably associated with aberrant placental development by clinical and biochemical assessments, while frozen embryo transfer was not, suggesting pathways for future research and practice implementation to reduce risks associated with ART.

A total of 5,170 patients had a confirmed pregnancy during the recruitment period and were invited to participate in DESCRT. Of these, 2,228 did not respond, 178 declined, and 432 were diagnosed with a non-viable early pregnancy. Among the 2,332 patients who were approached for recruitment, 782 patients (33.5%) enrolled in the study. After excluding 126 patients – primarily due to subsequent miscarriage or a non-singleton gestation – 656 patients with singleton live births were analyzed: 92 unassisted, 116 NIFT, and 448 from ART ( Supplemental Figure S2 ). Baseline characteristics and the treatments received are presented in Table 1 . The distributions of female age at time of conception significantly differed among the three groups. The median (interquartile range; IQR) ages of female patients were 37 (35–39) in unassisted, 36 (34–38) in NIFT, and 38 (35–41) in the ART group (p<0.01). Similarly, distributions of age of male partners were significantly different: 36 (34–40) in unassisted, 36 (34–40) in NIFT, and 39 (36–43) in the ART group (p<0.01). The distribution of primary infertility diagnosis was significantly different among the three groups (p<0.01). Among unassisted conceptions, unexplained infertility (50.0%) was the predominant diagnosis, followed by recurrent pregnancy loss (22.8%). In the NIFT group, many patients were affected by PCOS (26.7%) or other ovulatory disorders (14.7%), in addition to unexplained infertility (28.4%). Unexplained infertility (42.4%) and male factor infertility (18.5%) were the prevailing diagnoses in ART pregnancies. Most participants were of White or Asian race/ethnicity ( Table 1 ). The proportion of nulliparous patients was 66.3% in unassisted, 75.0% in NIFT, and 62.5% in the ART conception group (p=0.04). The percentages of patients with pre-pregnancy chronic hypertension, pre-pregnancy diabetes, and history of cesarean delivery were similar across groups (all p>0.05). A larger proportion of patients in the unassisted group had prior uterine surgery other than cesarean delivery (p=0.01) and carried a history of 2+ miscarriages (p<0.01). Cumulative incidences of adverse obstetric outcomes by mode of conception are shown in Table 2 . We first compared cumulative incidences in unassisted vs. NIFT vs. ART conceptions. The cumulative incidence of abnormal placentation was higher in ART conceptions (8.7%[95%CI, 6.3%-11.7%]) compared to unassisted (1.1%[95%CI,0.03%-5.9%]) and NIFT conceptions (1.7% [95%CI,0.2%-6.1%]) (p<0.01). The proportion of patients who developed HDP, FGR, PTB, and GDM did not significantly differ by primary mode of conception. We also compared the cumulative incidences of adverse outcomes in non-ART versus ART pregnancies. The cumulative incidence of abnormal placentation remained higher in ART versus non-ART conceptions (1.4%[95%CI, 0.3%-4.1%]) (p<0.01). To augment the clinical relevance of this finding, we also examined a subset of highly clinically significant abnormal placentation – by excluding isolated abnormal cord insertion or abnormal placental morphology events – in ART and non-ART pregnancies. The cumulative incidence of highly clinically significant abnormal placentation remained significantly higher among ART (6.0%[95%CI,4.0%-8.7%]) compared to non-ART conceptions (1.4%[95%CI, 0.3%-4.1%]) (p=0.009). There was a trend towards ART pregnancies having a higher cumulative incidence of spontaneous PTB (5.1% [95%CI, 3.3%-7.6%]) compared to non-ART pregnancies (1.9% [95%CI, 0.5%-4.9%]) (p=0.054). Log-binomial regression did not show statistically significantly increased crude or adjusted RRs of PTB with ART ( Supplemental Table S3 ). No significant differences in cumulative incidences of HDP, FGR, and GDM were observed between ART and non-ART pregnancies (all p>0.05). Table 3 shows the results of univariable log-binomial regression to assess for potential associations between covariates and abnormal placentation. Among the baseline covariates, mode of conception was the only significant predictor associated with abnormal placentation (crude RR, 6.04[95%CI,1.89–19.31]; p<0.01). Multivariable log-binomial regression, adjusted for maternal age, BMI, infertility diagnosis, prior uterine instrumentation, prior cesarean delivery, and miscarriage history, demonstrated a persistently higher relative risk of abnormal placentation with ART compared to non-ART pregnancies (adjusted RR, 6.19 [95%CI,1.84–20.82]; p<0.01). We also used propensity score analysis with inverse probability of treatment weighting to adjust for potential confounding, and ART pregnancies remained at significantly higher risk of abnormal placentation (adjusted RR, 6.99 [95%CI, 1.33–36.7]; p=0.02). With ART identified as a risk factor, we assessed for potential associations between major ART treatment parameters and abnormal placentation ( Table 4 ). Within ART pregnancies, fresh embryo transfer was associated with abnormal placentation on univariable analysis (crude RR, 1.97 [95%CI,1.07–3.61]; p=0.03). Adjusted for maternal age, BMI, infertility diagnosis, history of prior uterine instrumentation, prior cesarean delivery, and miscarriage history, fresh ET remained a significant predictor of abnormal placentation (adjusted RR, 2.07 [95%CI,1.10–3.92]; p=0.025). Insemination technique (conventional IVF versus intracytoplasmic sperm injection), trophectoderm biopsy for preimplantation genetic testing, and embryo culture length (3-day cleavage stage versus extended blastocyst stage culture) were not significantly associated with abnormal placentation. Sensitivity analyses limited to each patient’s first live birth after enrollment and excluding pregnancies where the obstetric complication information was derived primarily from the patient (n=615) continued to demonstrate higher crude and adjusted RR of abnormal placentation with ART, and fresh ET as a predominant risk factor among ART pregnancies ( Supplemental Table S4 ). The distribution of PAPP-A levels in non-ART, FET-conceived, and fresh ET-conceived pregnancies are illustrated ( Figure 1 ). The median MoM (IQR) PAPP-A values significantly differed by mode of conception: 1.09MoM (0.70–1.56MoM) in unassisted conceptions, compared to 0.89MoM (0.65–1.35MoM) in FET and 0.65MoM (0.42–1.02MoM) in fresh ET conceptions (p<0.001). Pairwise analysis with correction for multiple comparisons showed that the distribution of PAPP-A levels was not significantly different between non-ART and FET pregnancies. However, PAPP-A levels were significantly lower in fresh ET compared to FET (p=0.02) and non-ART pregnancies (p<0.001).

This prospectively collected sample was drawn from the Developmental Epidemiological Study of Children born through Reproductive Technologies (DESCRT) at the University of California, San Francisco (UCSF). DESCRT was established with three aims: i) to establish an epidemiological cohort of children born from parents with infertility, ii) to examine the effects of ART on the intrauterine environment, focusing on obstetric/perinatal outcomes, and iii) determine how parental factors and/or ART influence subsequent cardiometabolic risk of the conceived children 28 . DESCRT study protocol details were previously published 28 . This study was approved by the UCSF Institutional Review Board (IRB#16–20474) and registered on ClinicalTrials.gov ( NCT03799107 ). All participants signed informed consent. Patients were evaluated and treated for infertility at the UCSF Center for Reproductive Health (CRH), a high-volume practice that provides over 2000 retrieval cycles annually. Patients were recruited from 09/2017–12/2021. This prospective cohort enrolled 782 patients: 103 unassisted (13.2%), 145 NIFT (18.5%), and 534 ART (68.3%). Multiple gestations (n=31, 4.0%) were excluded from analysis due to their higher baseline risk for pregnancy complications. Gestational carriers (n=5, 0.6%) were also excluded. Prenatal records and obstetric data were reviewed by OB/GYN physicians. Twenty-two patients (2.8%) had two live births during the study period. In addition to clinical data collection, participants have the option to attend four in-person study visits during pregnancy (primarily for biobanking) occurring at approximately 6–7, 8–10, 11–13, and 18–20 weeks of gestation. Parental factors were obtained from the UCSF CRH electronic medical record (EMR) (IDEAS; Mellowood Medical Inc.) and the overarching UCSF Health EMR (APeX; Epic Systems Corporation), which also contains external records via Care Everywhere. A standardized protocol to review baseline covariates was implemented by three co-authors (DH, YS, JQ). For potentially subjective or unclear classifications (e.g., primary infertility diagnosis), the first author (DH) reviewed and made the final determination. Maternal and paternal age, race/ethnicity, body mass index at the time of conception, infertility diagnosis, prior parity (before enrollment in the study), pre-pregnancy diagnoses of chronic hypertension and diabetes, prior uterine instrumentation, cesarean delivery, and miscarriage history were also systematically reviewed using this protocol. The primary mode of conception was recorded. Unassisted conceptions are pregnancies from no medical interventions after the infertility diagnosis. NIFT conceptions result after oral (letrozole, clomiphene citrate) or injectable gonadotropin medications alone, IUI alone, or a combination of medications with IUI. ART conceptions use oocytes (autologous or donor) and/or embryos that derived from ovarian stimulation medications, oocyte retrieval, and in vitro culture/manipulation. Our center’s typical ART process is illustrated in Supplemental Figure S1 . Major ART treatment parameters were tracked, including method of insemination, length of embryo culture, use of preimplantation genetic testing (PGT), and fresh embryo transfer (fresh ET) versus frozen embryo transfer (FET). Ovarian stimulation was achieved with recombinant follicle-stimulating hormone and human menopausal gonadotropin, using various protocols as described previously 29 , 30 . Laboratory culture primarily used the EmbryoScope ™ + time-lapse incubators (Vitrolife, Sweden) with single-step medium (LifeGlobal ™ ; CooperSurgical, Connecticut USA). Gas concentrations were maintained at 6.0–6.5% CO 2 and 5.0% O 2 . Periodic quality control was performed by the laboratory director, ensuring consistent laboratory outcomes over time. For fresh ET, patients received hCG trigger and vaginal progesterone for luteal support. For FET, endometrial preparation was primarily via modified natural cycle (mNC) or programmed cycle (PC) protocols. In mNC-FET, ovulation was triggered with choriogonadotropin alfa (EMD Serono, Rockland, MA) when the lead follicle was ≥18mm and endometrium ≥7mm, followed by vaginal progesterone. In PC-FET, patients received exogenous estradiol for ≥12 days before starting intramuscular progesterone-in-oil. Progesterone support continued until at least 9w6d gestation. Treatment choice was determined collaboratively between patient and physician, considering female age, infertility diagnosis, logistical flexibility, and whether treatment plan entailed PGT. The primary outcome was adverse obstetric outcomes following conception, and was reported as cumulative incidence (proportion of cohort that developed a specific adverse outcome during the study period). We assessed hypertensive disorders of pregnancy (HDP; which included gestational hypertension, preeclampsia with/without severe features, and/or eclampsia using the diagnostic criteria as set forth by the American College of Obstetrics and Gynecologists guidelines 31 ), abnormal placentation, fetal growth restriction (FGR), spontaneous preterm birth (PTB), and gestational diabetes (GDM). Abnormal placentation was a composite outcome, which included one or more of the following: placenta previa, vasa previa, abnormal cord insertion, atypical placental morphology on ultrasound or surgical pathology, placenta accreta spectrum, and clinically significant placental abruption necessitating delivery and/or hospital admission. FGR was defined by an estimated fetal weight <10 th percentile for gestational age. PTB was defined as unplanned delivery before the 37 th week of pregnancy, excluding iatrogenic/medically indicated preterm deliveries. Our rationale for excluding clinician-initiated preterm deliveries is that, in these cases, the effect of ART on preterm birth is mediated by the underlying clinical condition (e.g., preeclampsia with severe features, placentation abnormalities) rather than being directly attributable to ART itself. GDM was assessed using a 1-hour 50-gram glucose loading screen, followed by 3-hour 100-gram glucose tolerance test when applicable 32 . Cases controlled by diet or hypoglycemic agents were documented. All outcomes were adjudicated by OB/GYN physicians. Prenatal/triage visits, ultrasound reports, delivery admission encounter, and postpartum visits were systematically reviewed. Of note, 19 patients (2.4%) were missing comprehensive records for physician review, and only had patient-derived obstetric complication data that were submitted to the Society for Assisted Reproductive Technology (SART) registry. Maternal serum analyte levels were offered as part of routine prenatal care by the California Department of Public Health (CDPH) and measured using a standardized platform, and data was collected as part of the study design. We specifically assessed PAPP-A levels to provide biochemical correlation of placental development in fresh ET-conceived pregnancies compared to other pregnancies given the significant outcome of abnormal placentation. Serum PAPP-A levels were measured between 10–14 weeks by the CDPH in patients who opt-in (N=349) for prenatal serum analyte screening with their prenatal provider. Three hundred and seven patients opted out. Median PAPP-A concentrations were determined by the California Prenatal Screening Program (CPSP) using the state’s pregnant population for each day in this gestational period. PAPP-A levels were reported as multiple of the median (MoM), adjusted for gestational age, race/ethnicity, weight, smoking, and diabetic status 33 . Baseline characteristics were compared by mode of conception using Kruskal-Wallis test, χ 2 test, or Fisher’s exact test as appropriate. Cumulative incidences of obstetric complications were compared using χ 2 test using two approaches: 1) unassisted vs. NIFT vs. ART, and 2) non-ART vs. ART. Due to the smaller cohort sizes and the relatively low incidences of most adverse outcomes in the unassisted and NIFT groups, which did not involve in vitro manipulation of oocytes/embryos, we combined them into a “non-ART” group for analysis. Univariable log-binomial regression generated crude risk ratios (RR) and their 95% confidence intervals (CIs) to assess for associations between putative risk factors (i.e., parental factors, primary mode of conception, and ART parameters) and abnormal placentation. Multivariable log-binomial regression was used to estimate adjusted RR and 95% CIs of ART and its treatment parameters for abnormal placentation, adjusting for covariates that may impact baseline uterine environment for placentation: maternal age, BMI, infertility diagnosis, history of uterine instrumentation, history of cesarean delivery, and miscarriage history. These variables were selected based on literature review and clinical knowledge of factors associated with abnormal placentation. Additionally, a directed acyclic graph (DAG) was constructed using DAGitty software to identify a minimally sufficient adjustment set that included the main exposure (mode of conception) and potential confounders that would block biasing (backdoor) paths. We assessed model fits using Akaike Information Criterion (AIC) and Bayesian Information Criterion (BIC) and the confounding impact of each covariate, removing non-confounders (e.g., race/ethnicity, paternal age) from the final model. We also supplemented our analysis with a statistical approach using calculated propensity scores based on the variables listed above, applying inverse probability of treatment weighting to adjust for baseline confounding. Sensitivity analysis was performed, which excluded pregnancy episodes lacking complete obstetric records for physician adjudication (n=19, 2.4%) and only analyzed each patient’s first live birth during the study period to limit potential bias from clustering of multiple births within the same patient. The distribution and frequency of PAPP-A values (MoM) were illustrated using a Violin Plot (GraphPad Prism v10). Median, 25 th percentile, and 75 th percentile PAPP-A values were reported. Kruskal-Wallis test was used to compare the distribution of PAPP-A levels. Dunn’s test was performed following Kruskal-Wallis test to correct for multiple pairwise comparisons. All tests were two-sided and conducted at the 0.05 level of significance in Stata v17.0.

The use of assisted reproductive technology (ART) has increased considerably in recent years, both for infertility treatment and elective fertility preservation. As defined by the Centers for Disease Control and Prevention, ART refers to fertility-related treatments where oocytes or embryos are manipulated. Non-IVF fertility treatments (NIFT) only entail sperm handling (such as intrauterine insemination (IUI)) or ovarian stimulation without oocyte retrieval 1 . In 2021, close to 240,000 patients underwent 413,776 ART cycles across the U.S., resulting in over 97,000 newborns, approximately 2–3% of U.S. live births 1 . Pregnancies from NIFT are not systematically tracked nationally, but were estimated to contribute to 2.8–7.1% of U.S.-born infants 2 . While ART is beneficial and necessary for some individuals, it has been traditionally reported with significant obstetric/perinatal risks. In its early stages, ART-related risks were attributed to an increased prevalence of multiple gestations 3 – 6 . This led to concerted efforts to limit the number of embryos transferred and cancel treatment at risk of higher-order births 7 , 8 . Despite a reduction in multiple pregnancy rates, population-based studies continue to demonstrate a higher incidence of obstetric complications in singleton pregnancies conceived by ART, signaling potential fundamental risks from this technology 9 – 13 . Adverse outcomes commonly reported with ART include preterm delivery, lower birth weight, placentation abnormalities, congenital malformation, gestational diabetes, and hypertensive disorders of pregnancy 10 , 11 , 13 – 15 . However, these associations were largely derived from retrospective comparisons of ART pregnancies in patients with infertility compared with unassisted pregnancies in fertile patients. Obstetric outcomes were often extracted from databases not designed to study pregnancy complications. Furthermore, subsequent investigations demonstrated that underlying parental factors independently contribute to these adverse outcomes, with many associations attenuated or statistically insignificant after adjusting for infertility diagnoses or fertility status 4 , 16 – 20 . Therefore, to pinpoint the specific risks associated with ART, it is important to utilize the appropriate control group – patients diagnosed with infertility who did not eventually conceive with ART (i.e., unassisted or NIFT conceptions). Fertility treatment practices have evolved over the years, including ovarian stimulation strategies, embryo culture conditions, and in vitro oocyte/embryo manipulation 21 . With the projected exponential use of ART, a reappraisal of how contemporary fertility practices affects obstetric risk is critical for informed patient consent and public health. Herein, we compared the cumulative incidences of various adverse obstetric outcomes in a large U.S. prospective cohort of 782 patients who were diagnosed with infertility and subsequently conceived by three modes of conception: unassisted, NIFT, or ART. To provide biochemical-clinical correlation, we also assessed levels of a maternal serum placental analyte – pregnancy-associated plasma protein A (PAPP-A). While not widely used in the clinical setting, low levels of PAPP-A have been extensively correlated to aberrant placental histology, placental dysfunction, and maternal/neonatal morbidity 22 – 27 . By utilizing an appropriate comparator group with rigorous physician adjudication of obstetric complications, we aimed to isolate the specific risks attributed to ART.