02/2021, Review , 074-084

Higher risk of hypertensive disorders of pregnancy and preeclampsia in pregnancies following frozen embryo transfer: a systematic review and meta-analysis


Background and purpose:

Does frozen-thawed embryo transfer (FET), compared with fresh embryo transfer (ET), increase the risk of hypertensive disorders of pregnancy (HDP) in women who become pregnant through in vitro fertilization?


Through a systematic review and meta-analysis the authors assessed the risk of HDP following FET versus fresh ET. An electronic literature search of the PubMed, Embase and Cochrane databases was performed. The primary outcome was HDP. Other aspects analyzed included preeclampsia and gestational hypertension.


Five studies were included. FET was found to be associated with a higher risk of HDP (RR 1.71; 95% CI 1.22, 2.39) and of preeclampsia (RR 1.92; 95% CI 1.28, 2.89). A subgroup analysis indicated that in PCOS/hyper-responder patients, FET increased the risk of HDP (RR 1.98; 95% CI 1.11–3.51) and preeclampsia (RR 2.86; 95% CI 1.54–5.32). However, non-PCOS/normo-responders showed no significant difference in HDP (RR 1.44; 95% CI 0.97–2.14). No statistical differences in the risk of gestational hypertension were noted.


Compared with fresh ET, FET resulted in a higher risk of HDP only in PCOS/hyper-responder patients, and a higher risk of preeclampsia both in non-PCOS/normo-responders and PCOS/hyper-responder patients. Unknown mechanisms related to altered hormonal concentrations and their influence on the placental development of pregnancies after artificial FET cycles could explain these differences.

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Nowadays, more than 3% of infants born in developed countries are conceived through assisted reproductive technology (ART) [1]. It has been suggested that ART pregnancies are related to poorer pregnancy outcomes compared with natural conceptions [2,3]. Recent studies have shown that singleton pregnancies after in vitro fertilization (IVF) treatment have an increased risk of adverse maternal outcomes, such as preeclampsia, placental abruption, placenta previa, placenta accreta and postpartum hemorrhage, and also adverse neonatal outcomes, such as preterm birth, low birth weight and small for gestational age [3-5]. Why IVF has been found to increase the risks of obstetric morbidity is still debated.

Most of these adverse outcomes are related to abnormal placentation [6,7]. It is hypothesized that different aspects related to ART could negatively influence the placentation process. There are increasing concerns over adverse effects of controlled ovarian stimulation (COS) on the endometrial and uterine environment, as well as its consequences on endometrial receptivity [8], particularly after fresh embryo transfer (ET). Elective frozen-thawed embryo transfer (FET) has emerged as an alternative to fresh ET for selected IVF treatments; FET avoids the deleterious effects of hyperstimulation, as the transfer can be performed in a more physiological uterine environment in a later cycle [9,10]. It has thus been suggested that performing FET may improve the maternal and perinatal outcomes of IVF treatment.

Early systematic reviews and meta-analyses reported better perinatal outcomes in children conceived following FET as opposed to fresh ET, with these children showing lower risks of preterm birth and low birthweight [11-14]. However, subsequent systematic reviews and meta-analyses of observational studies reported a higher rate of hypertensive disorders of pregnancy (HDP) following FET [15,16]. Moreover, a recently published meta-analysis of randomized controlled trials (RCTs) found the risk of preeclampsia to be increased after FET [17].

Hence, the association between FET and HDP warrants further investigation, and suggests the need for a conservative attitude towards the use of FET. In addition, since additional RCT data on obstetric outcomes are available [18-22], better-quality evidence from meta-analyses is now required.

HDP, which occur in 10% of pregnancies [23], are among the leading causes of prematurity, and of maternal and neonatal morbidity and mortality [24,25]. The prevalence of these disorders has increased over the last 30 years, consistent with increases in the risk factors of obesity, maternal age and ART [26]. Therefore, studies focused exclusively on this outcome are warranted.

The purpose of the present study was to evaluate the available literature (RCTs) and provide up-to-date and comprehensive evidence to address the question of whether FET increases the risk of HDP compared with fresh ET. We also examined the effects of cryopreservation and subsequent FET on preeclampsia and gestational hypertension separately.

Material and methods

Protocol and registration

We adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [27]. The study protocol is accessible at https://inplasy.com/ (registration number INPLASY202050113). This study did not require institutional review board approval, as it was a meta-analysis.

Search strategy

An electronic search strategy was developed and approved by all authors. The PubMed, Embase and Cochrane databases were searched for RCTs, specifically studies that assessed HDP and adverse perinatal outcomes after FET, published in English from 1978 to December 2019. The following combined search terms were used: (Fresh Embryos) OR (Frozen Embryos OR Cryopreserved Embryos OR Cryopreservation of Embryos OR Frozen Thawed Embryos OR Cryopreserved-thawed Embryos) OR (Embryo Transfer OR Embryo Transfers OR Tubal Embryo Transfer OR Tubal Embryo Stage Transfer) OR (Vitrification OR Slow Freeze OR Slow Frozen OR Slow Freezing) with (In Vitro Fertilizations/IVF OR Fertilization in Vitro) OR (ICSI OR Injections, Sperm, Intracytoplasmic OR Injections, Intracytoplasmic Sperm OR Intracytoplasmic Sperm Injection OR Sperm Injection, Intracytoplasmic OR Intracytoplasmic Sperm Injections) AND (Pregnancy induced hypertension OR Preeclampsia). We also searched the references of the relevant articles.

Eligibility criteria and data extraction

The review included RCTs that reported perinatal outcomes in pregnancies after IVF and compared FET to fresh ET cycles. Data were also obtained on secondary outcomes of RCTs in which the primary outcomes were live birth or ongoing pregnancy. Studies including only frozen and donor oocytes were excluded. In a first screening, two authors (J.M, P.S) independently assessed all of the abstracts retrieved from the search, and then obtained the full manuscripts of citations that met the inclusion criteria. They judged study eligibility and quality, and extracted data. Any discrepancies were resolved by agreement, and if needed, by reaching a consensus with a third author (M.C). The summarized results were critically appraised; the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to evaluate the quality of the evidence for each outcome [28]. We contacted the authors of the primary studies for additional information, but were able to obtain further data only from some of the studies.

Outcome measures

The primary outcome measure was HDP. According to the International Society for the Study of Hypertension in Pregnancy, HDP include chronic hypertension, white-coat hypertension, masked hypertension, gestational hypertension and preeclampsia [29]. The articles included in the current study refer to gestational hypertension and preeclampsia. Gestational hypertension is defined as hypertension arising de novo after 20 weeks’ gestation in the absence of proteinuria and without biochemical or hematological abnormalities. Preeclampsia is diagnosed by the presence of de novo hypertension after 20 weeks’ gestation accompanied by proteinuria and/or evidence of maternal acute kidney injury, liver dysfunction, neurological features, hemolysis or thrombocytopenia, and/or fetal growth restriction [29].

Risk of bias assessment

Risk of bias for RCTs was evaluated according to the Cochrane Handbook recommendations [30]. The quality of the studies was assessed by two investigators independently in reference to five categories: adequate sequence generation; allocation concealment; blinding of the outcome assessors; handling of missing data (intention-to-treat or per-protocol analysis); selective outcome reporting (Supplementary Data - A).  


A Mantel-Haenszel model was used to determine the pooled effect of each variable. Estimates of effect for dichotomous data accompanied by the relative 95% confidence intervals (CIs) were calculated with a fixed effects model and expressed as risk ratios (RRs). Statistical significance was set at p<.05. The degree of variation across studies attributable to heterogeneity was evaluated with the I2 statistic. The random-effects model was applied when the heterogeneity was greater than 50% (I2 >50%) [31]. Sub-analyses were performed to assess the effect of FET on the outcomes, stratifying PCOS patients and hyper-responder patients for comparison with non-PCOS/normo-responders. At the time of the search, there were no published RCTs that focused on poor responders. Finally, publication bias was evaluated using funnel plots (Supplementary Data - B). Sensitivity analysis was performed to investigate the effect of a single study on the results by omitting one study at a time (Supplementary Data - C) [31]. We conducted a meta-analysis using Review Manager Software 5.3.


A total of 371 records were initially identified according to the search strategy. Of these, 191 were excluded owing to duplication; a further 160 were then excluded after screening of the titles and abstracts showed that they were irrelevant to our study. The remaining 20 studies underwent full-text review. On the basis of the inclusion and exclusion criteria, 15 studies were removed, because they were cohort studies. The other five RCTs assessing HDP in pregnancies after FET versus fresh ET met the inclusion criteria and were thus deemed eligible. Figure 1 is a flow diagram detailing the study selection process.

Synthesis of results

The characteristics of the five studies are summarized in Table 1. A summary of their findings is given in Table 2.

Primary outcome

Hypertensive disorders of pregnancy

Four studies, including 3,757 patients, were pooled in this analysis. Overall, they evaluated 1,705 deliveries after FET and 1,596 after fresh ET. The risk of HDP was significantly higher in pregnancies resulting from FET than in those resulting from fresh ET cycles (RR 1.60; 95% CI 1.15-2.22; I2=34%; Fig. 2). A subgroup analysis, dividing patients by ovarian response, indicated that in PCOS/hyper-responder patients (two studies; n = 1,643 patients) FET led to an increase in HDP, with an RR of 1.98 (95% CI: 1.11–3.51; I2 = 63%; low quality of evidence; Fig. 2). However, in non-PCOS/normo-responders (two studies; n = 2,114 patients) there was no significant difference in HDP between the treatment groups (RR = 1.44; 95% CI: 0.97–2.14; I2 = 12%; low quality of evidence; Fig. 2).

Secondary outcomes


Five studies were included in this analysis. Overall, they evaluated 2,290 deliveries after FET and 2,154 after fresh ET. The fixed effects analysis showed an RR of 2.11 (95% CI 1.44–3.11; I2=0%) when comparing pregnancies after FET versus fresh ET (Fig. 3). We again performed a sub-analysis according to ovarian response. Compared with fresh ET, FET was associated with an increase in preeclampsia both in PCOS/hyper-responder (three studies; n = 2,330 patients; RR = 2.86; 95% CI: 1.54–5.32; I2 = 0%; moderate quality of evidence; Fig. 3) and in non-PCOS/normo-responder patients (two studies; n = 2,114 patients; RR = 1.69; 95% CI: 1.03–2.80; I2 = 44%; moderate quality of evidence; Fig. 3).

Gestational hypertension

Four studies were pooled in this analysis. The fixed effects analysis revealed no significant differences between the groups with regard to gestational hypertension (RR 0.92, 95% CI 0.56-1.52; I2=0%; Fig. 4). The ovarian response did not affect the risk of gestational hypertension

among patients undergoing FET (PCOS/hyper-responder: RR = 0.80; 95% CI: 0.39–1.66, I2 = 0%; non-PCOS/normo-responders: RR = 1.05; 95% CI: 0.53–2.08, I2 = 0%, moderate quality of evidence; Fig. 4).

Sensitivity analyses

Sensitivity analyses were performed to examine the influence of between-study variance on overall risk estimates. No significant impact was noted on the pooled effect size (Supplementary Data).



Main findings

This systematic review and meta-analysis showed that pregnancies after FET are associated with an increased risk of HDP and preeclampsia. However, subgroup analyses from RCTs investigating PCOS/hyper-responders and non-PCOS/normo-responders indicated that FET is associated with a significantly higher HDP risk than fresh ET in the PCOS/hyper-responder group only. By contrast, no effect was noted in the non-PCOS/normo-responders group. The GRADE quality of evidence was low, mainly due to the substantial interstudy heterogeneity, which was presumed to be caused by differences in the study populations, multiple pregnancies, and the use of different types of luteal phase support in the FET cycles.

Regarding preeclampsia, moderate quality evidence indicated that FET is associated with an increased risk of preeclampsia both in PCOS/hyper-responder patients and in non-PCOS/normo-responders. Lastly, moderate quality evidence also indicated that there are no differences in the risk of gestational hypertension linked to the use of FET in preference to fresh ET in the population undergoing IVF.


This study is, to our knowledge, the most up-to-date review on this subject, and the largest meta-analysis of RCTs comparing HDP between pregnancies after FET and fresh ET. In addition, the study shows narrow confidence levels and low I2 values for preeclampsia and gestational hypertension, suggesting that the precision of the meta-analysis is good and that the estimated value is relatively stable for these variables. Moreover, this systematic review and meta-analysis study was performed according to the PRISMA statement, thereby ensuring high methodological quality. Finally, the strength of the evidence was rated with reference to GRADE. These factors significantly increase the validity of our findings.



The most important source of bias of this study is that there was no stratification by natural or medicated cycle, including different estradiol schemes for endometrial proliferation and different progesterone regimens for luteal phase support; this was mainly because the studies included in the analysis did not provide subset analyses of outcomes based on these characteristics of FET. A recently published study [32], which showed no increased risk of HDP and preeclampsia in FET using natural cycles, confirmed the bias deriving from not separating natural cycles from artificial ones in FET. In addition, there was no stratification by singleton and multiple pregnancies, as not all the authors provided additional information when contacted. Hence, we cannot exclude that the pooled effect estimates reported in this meta-analysis were confounded by multiple pregnancies or different estradiol or progesterone regimens. For this reason, our findings should be interpreted with caution. A further limitation was that only English language articles were allowed.

Comparison with other studies

Some recent reviews showed that pregnancies following FET had significantly higher odds of HDP [15-17], but only one performed a specific analysis of preeclampsia separately [17], finding FET to be associated with an elevated risk for this outcome compared with fresh ET (RR 1.79; 95% CI: 1.03–3.09). Our study includes a larger study population and we performed subgroup stratification by ovarian response. Lastly, no previous studies have assessed the risk of gestational hypertension comparing fresh ET and FET.

Interpretation of the results

Different mechanisms could explain the origin of adverse obstetric outcomes, such as HDP in ART patients, including infertility per se, or aspects related to the IVF treatment [5].

The etiology of HDP and preeclampsia is commonly associated with abnormal placentation and evidence of a maternal inflammatory response [33,34]. Utero-placental ischemia, probably as a consequence of partial myometrial spiral artery remodeling, is considered a marker of abnormal placentation [6,7]. This is supported by Doppler velocimetry alterations of uterine and umbilical arteries [35-37], biochemical factors associated with angiogenesis [38-43], and placental histological findings [44,45].

Different studies have supported the idea that COS may impact decidualization and placentation, contributing to the development of placental insufficiency, and consequently increasing the risk of adverse outcomes related to ischemic placental disease [46,47], although they did not specifically evaluate differences between fresh and frozen cycles. Subsequent studies have confirmed different placental alterations in patients after both FET and fresh ET [48,49].

In fresh ET, the supraphysiological hormone levels achieved during COS may be associated with alterations in endometrial receptivity [50-52] and endometrial gene expression [53] that could affect remodeling and angiogenesis, leading to impaired extravillous trophoblast invasion of spiral arteries and finally abnormal placentation [54,55]. However, the mechanisms underlying the increased risk of preeclampsia in pregnancies after FET are not clearly understood. Some cryoprotectants or the vitrification and thawing process per se could lead to certain metabolic or epigenetic changes related to alterations in methylation of regulatory genes involved in implantation [56]. Differences in gene expression, mostly in the trophectoderm, may lead to abnormal placentation and eventually to preeclampsia [57,58]. Other current research links pleiotrophin, a heparin-binding protein expressed in trophoblasts that has a role in angiogenesis, with preeclampsia in ART. The knockdown of pleiotrophin increases the risk of preeclampsia following vitrified-thawed ET [59,60].

Another etiological theory assigns more weight to impaired development of the placenta due to prolonged exposure to hormone replacement in protocols used for endometrial priming for the reception of embryos, and not necessarily to characteristics and manipulations of the embryo [61,62]. In programmed FET cycles, the estradiol supplementation used for endometrial priming suppresses the pituitary-ovarian axis, resulting in the absence of a corpus luteum, which has a key function as a major source of reproductive hormones. Although estradiol and progesterone are replaced during these artificial FET protocols, other products of the corpus luteum are not administered in the first trimester. Some recent studies have reported a crucial role of hormones such as relaxin, mainly in maternal cardiovascular adaptation to pregnancy [63]. Early gestation after FET was found to be linked to an increased incidence of deficient circulatory adaptations related to adverse pregnancy outcomes, including preeclampsia [64,65]. Probably, other unknown factors may be related to the risk of developing a future placental dysfunction in the absence of a corpus luteum. A natural cycle before FET allows more physiological development of the corpus luteum, as suggested in a retrospective study that reported higher rates of preeclampsia in artificial FET cycles compared with modified natural FET cycles [63]. A recent RCT found no increased risk of preeclampsia in pregnancies after FET compared with pregnancies following fresh ET, but it is important to note that most of the FET cycles were performed in natural cycles [20]. Further investigations are needed to compare maternal and perinatal outcomes of stimulated cycles versus natural modified cycles in FET in order to clarify this matter.

On the other hand, the findings of the current study showed that PCOS/hyper-responder patients have an increased risk of developing HDP compared with non-PCOS/normo-responder patients. A large retrospective population-based study reported that HDP have a higher prevalence among PCOS than non-PCOS women (16.1% vs 7.45%) [66]. The underlying relationship between PCOS and HDP is thought to be related to the negative impact on placental function of two clinical hallmarks of PCOS: androgen excess and insulin resistance [67,68]. Epigenetic alterations such as DNA methylation and miRNA expression may occur in certain endocrine and metabolic tissues of women with PCOS, including the ovaries and placenta [69,70]. These epigenetic modifications are thought to have an important role in the development of HDP and preeclampsia [67,71], but an improved understanding of placental development and function in the pregnancies of PCOS women is needed. At present, there are significant methodological challenges in investigating placental dysfunction in PCOS, mainly due to variability in PCOS phenotypic expression, the use of ART, and confounding comorbidities, including obesity, diabetes and chronic hypertension [67].

Although gestational hypertension is usually associated with good outcomes, the notion that gestational hypertension is intrinsically less concerning than preeclampsia is incorrect. Gestational hypertension is associated with adverse pregnancy outcomes [72] and may not represent a separate entity from preeclampsia [25]. Up to 50% of women with gestational hypertension will eventually develop preeclampsia, and this progression is more likely when hypertension is diagnosed before 32 weeks of gestation [73]. In the current study, the risk of gestational hypertension was not increased with FET. The reason for these findings is unknown, but probably the cryopreservation process does not influence the placentation mechanisms that trigger gestational hypertension in the same way as it influences other mechanisms that contribute to the development of preeclampsia.

Clinical considerations and future research

Our findings represent a detailed assessment of the risk of HDP after fresh ET and FET leading to live births, and it contributes to the ongoing discussion on which transfer type is safer for each patient circumstance. The increased risk of HDP after FET observed in this study emphasizes that the freeze-all policy should be implemented weighing up the overall benefits and risks for mothers and their children.

It is imperative to clarify in future research whether the increase in HDP is due to the cryopreservation process or to the artificial preparation of the endometrium. Since recently published data revealed that the increased risk of HDP and preeclampsia was not observed in FET using natural cycles [32,65], future RCTs or individual patient data meta-analysis should further explore pregnancy outcomes between autologous FET natural cycles and artificial cycles. Furthermore, studying the influence of cryopreservation on metabolic and epigenetic changes associated with abnormal decidualization, implantation and placentation could be revealing.

An improved understanding of the association between dysregulated decidualization and preeclampsia in pregnancies following FET and fresh ET is also warranted, in order to design prophylactic or therapeutic interventions that optimize decidualization before and during early pregnancy.

The prediction of pregnancy-related complications after IVF is a crucial topic. From the data obtained in our meta-analysis, practitioners can increase the safety of their interventions, identifying those pregnant women who potentially require additional care [74].  Finally, a panel of biomarkers reflecting endometrial dysfunction (e.g., IGFBP-1 or glycodelin) might be helpful in identifying women at increased risk [75].


The present study found that pregnancies conceived after FET have a higher risk of HDP compared with pregnancies after fresh ET in PCOS/hyper-responders. Both non-PCOS/normo-responders and PCOS/hyper-responders have an increased risk of preeclampsia after FET. The growing concerns about the safety of cryopreservation and subsequent FET, particularly as this procedure has become increasingly used, must be weighed up against the decreased risks of other important conditions in pregnancy, such as low birth weight and preterm delivery. Meanwhile, IVF specialists and obstetricians must be aware of this clinically relevant risk in patients undergoing IVF-FET and implement adequate monitoring strategies during the prenatal care. The development of gestational hypertension in IVF patients seems not to be influenced by FET. Future research focused on the pathophysiology underlying these differences and the study of possible strategies to reduce these risks in IVF pregnancies are warranted.


This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.



  1. De Geyter C, Calhaz-Jorge C, Kupka MS, et al; European IVF-monitoring Consortium (EIM) for the European Society of Human Reproduction and Embryology (ESHRE). ART in Europe, 2015: results generated from European registries by ESHRE. Hum Reprod Open. 2020;2020:hoz038.
  2. Helmerhorst FM, Perquin DA, Donker D, Keirse MJ. Perinatal outcome of singletons and twins after assisted conception: a systematic review of controlled studies. BMJ. 2004;328:261.
  3. Qin J, Liu X, Sheng X, Wang H, Gao S. Assisted reproductive technology and the risk of pregnancy-related complications and adverse pregnancy outcomes in singleton pregnancies: a meta-analysis of cohort studies. Fertil Steril. 2016;105:73-85.e856.
  4. Pandey S, Shetty A, Hamilton M, Bhattacharya S, Maheshwari A. Obstetric and perinatal outcomes in singleton pregnancies resulting from IVF/ICSI: a systematic review and meta-analysis. Hum Reprod Update. 2012;18:485-503.
  5. Berntsen S, Söderström-Anttila V, Wennerholm UB, et al. The health of children conceived by ART: ‘the chicken or the egg?’. Hum Reprod Update. 2019;25:137-58.
  6. Ananth CV, Vintzileos AM. Ischemic placental disease: epidemiology and risk factors. Eur J Obstet Gynecol Reprod Biol. 2011;159:77-82.
  7. Brosens I, Pijnenborg R, Vercruysse L, Romero R. The “Great Obstetrical Syndromes” are associated with disorders of deep placentation. Am J Obstet Gynecol. 2011;204:193-201.
  8. Helmerhorst FM, Keirse M. Assisted reproductive technology and pregnancy outcomes. BJOG. 2016;123:1329.
  9. Pereira N, Elias RT, Christos PJ, et al. Supraphysiologic estradiol is an independent predictor of low birth weight in full-term singletons born after fresh embryo transfer. Hum Reprod. 2017;32:1410-7.
  10. Pereira N, Reichman DE, Goldschlag DE, Lekovich JP, Rosenwaks Z. Impact of elevated peak serum estradiol levels during controlled ovarian hyperstimulation on the birth weight of term singletons from fresh IVF-ET cycles. J Assist Reprod Genet. 2015;32:527-32.
  11. Wennerholm UB, Söderström-Anttila V, Bergh C, et al. Children born after cryopreservation of embryos or oocytes: a systematic review of outcome data. Hum Reprod. 2009;24:2158-72.
  12. Maheshwari A, Pandey S, Shetty A, Hamilton M, Bhattacharya S. Obstetric and perinatal outcomes in singleton pregnancies resulting from the transfer of frozen thawed versus fresh embryos generated through in vitro fertilization treatment: a systematic review and meta-analysis. Fertil Steril. 2012;98:368-77.e1-9.
  13. Pinborg A, Wennerholm UB, Romundstad LB, et al. Why do singletons conceived after assisted reproduction technology have adverse perinatal outcome? Systematic review and meta-analysis. Hum Reprod Update. 2013;19:87-104.
  14. Zhao J, Xu B, Zhang Q, Li YP. Which one has a better obstetric and perinatal outcome in singleton pregnancy, IVF/ICSI or FET? A systematic review and meta-analysis. Reprod Biol Endocrinol. 2016;14:51.
  15. Maheshwari A, Pandey S, Amalraj Raja E, Shetty A, Hamilton M, Bhattacharya S. Is frozen embryo transfer better for mothers and babies? Can cumulative meta-analysis provide a definitive answer? Hum Reprod Update. 2018;24:35-58.
  16. Sha T, Yin X, Cheng W, Massey IY. Pregnancy-related complications and perinatal outcomes resulting from transfer of cryopreserved versus fresh embryos in vitro fertilization: a meta-analysis. Fertil Steril. 2018;109:330-42.e9.
  17. Roque M, Haahr T, Geber S, Esteves SC, Humaidan P. Fresh versus elective frozen embryo transfer in IVF/ICSI cycles: a systematic review and meta-analysis of reproductive outcomes. Hum Reprod Update. 2019;25:2-14.
  18. Chen ZJ, Shi Y, Sun Y, et al. Fresh versus frozen embryos for infertility in the polycystic ovary syndrome. N Engl J Med. 2016;375:523-33.
  19. Zhang B, Wei D, Legro RS, et al. Obstetric complications after frozen versus fresh embryo transfer in women with polycystic ovary syndrome: results from a randomized trial. Fertil Steril. 2018;109:324-9.
  20. Shi Y, Sun Y, Hao C, et al. Transfer of fresh versus frozen embryos in ovulatory women. N Engl J Med. 2018;378:126-36.
  21. Vuong LN, Dang VQ, Ho TM, et al. IVF Transfer of fresh or frozen embryos in women without polycystic ovaries. N Engl J Med. 2018;378:137-47.
  22. Wei D, Liu JY, Sun Y, et al. Frozen versus fresh single blastocyst transfer in ovulatory women: a multicentre, randomised controlled trial. Lancet. 2019;393:1310-8.
  23. Aronow WS. Hypertensive disorders in pregnancy. Ann Transl Med. 2017;5:266.
  24. Shih T, Peneva D, Xu X, et al. The rising burden of preeclampsia in the United States impacts both maternal and child health. Am J Perinatol. 2016;33:329-38.
  25. ACOG Practice Bulletin No. 202: Gestational Hypertension and Preeclampsia. Obstet Gynecol. 2019;133:1.
  26. Hao J, Hassen D, Hao Q, et al. Maternal and infant health care costs related to preeclampsia. Obstet Gynecol. 2019;134:1227-33.
  27. Shamseer L, Moher D, Clarke M, et al; PRISMA-P Group. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015: elaboration and explanation. BMJ. 2016;354:i4086
  28. Schünemann H, Brożek J, Guyatt G, Oxman A, eds. Handbook for grading quality of evidence and strength of recommendations using the Grade approach. Updated October 2013. Available at: https://med.mahidol.ac.th/ceb/sites/default/files/public/pdf/journal_club/2017/GRADE%20handbook.pdf.
  29. Brown MA, Magee LA, Kenny LC, et al; International Society for the Study of Hypertension in Pregnancy (ISSHP). Hypertensive disorders of pregnancy: ISSHP classification, diagnosis, and management recommendations for international practice. Hypertension. 2018;72:24-43.
  30. Higgins JP, Altman DG, Gøtzsche PC, et al; Cochrane Bias Methods Group; Cochrane Statistical Methods Group. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ. 2011;343:d5928.
  31. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327:557-60.
  32. Ginström Ernstad E, Wennerholm UB, Khatibi A, Petzold M, Bergh C. Neonatal and maternal outcome after frozen embryo transfer: Increased risks in programmed cycles. Am J Obstet Gynecol. 2019;221:126.e1-126.e18.
  33. Bartsch E, Medcalf KE, Park AL, Ray JG; High Risk of Pre-eclampsia Identification Group. Clinical risk factors for pre-eclampsia determined in early pregnancy: systematic review and meta-analysis of large cohort studies. BMJ. 2016;353:i1753.
  34. Falco ML, Sivanathan J, Laoreti A, Thilaganathan B, Khalil A. Placental histopathology associated with pre-eclampsia: systematic review and meta-analysis. Ultrasound Obstet Gynecol. 2017;50:295-301.
  35. Espinoza J, Romero R, Nien JK, et al. Identification of patients at risk for early onset and/or severe preeclampsia with the use of uterine artery Doppler velocimetry and placental growth factor. Am J Obstet Gynecol. 2007;196:326.e1-13.
  36. Savasan ZA, Goncalves LF, Bahado-Singh RO. Second- and third-trimester biochemical and ultrasound markers predictive of ischemic placental disease. Semin Perinatol. 2014;38:167-76.
  37. Turan OM, Turan S, Gungor S, et al. Progression of Doppler abnormalities in intrauterine growth restriction. Ultrasound Obstet Gynecol. 2008;32:160-7.
  38. Medina-Bastidas D, Guzmán-Huerta M, Borboa-Olivares H, et al. Placental microarray profiling reveals common mRNA and lncRNA expression patterns in preeclampsia and intrauterine growth restriction. Int J Mol Sci. 2020;21:3597.
  39. Stepan H, Hund M, Andraczek T. Combining biomarkers to predict pregnancy complications and redefine preeclampsia: the angiogenic-placental syndrome. Hypertension. 2020;75:918-26.
  40. Ciobanou A, Jabak S, De Castro H, Frei L, Akolekar R, Nicolaides KH. Biomarkers of impaired placentation at 35-37 weeks’ gestation in the prediction of adverse perinatal outcome. Ultrasound Obstet Gynecol. 2019;54:79-86.
  41. Kwiatkowski S, Kwiatkowska E, Rzepka R, Dołegowska B, Torbe A, Bartosik-Sławińska A. Using Doppler ultrasound of the uterine and umbilical arteries and disordered angiogenesis markers (sFlt-1/PlGF) in unified monitoring of ischemic placental syndrome patients. Hypertens Pregnancy. 2016;35:490-8.
  42. Kwiatkowski S, Kwiatkowska E, Rzepka R, Torbe A, Dolegowska B. Ischemic placental syndrome–prediction and new disease monitoring. J Matern Fetal Neonatal Med. 2016;29:2033-9.
  43. Vintzileos AM, Ananth CV. First trimester prediction of ischemic placental disease. Semin Perinatol. 2014;38:159-66.
  44. Mayhew TM, Manwani R, Ohadike C, Wijesekara J, Baker PN. The placenta in pre-eclampsia and intrauterine growth restriction: studies on exchange surface areas, diffusion distances and villous membrane diffusive conductances. Placenta. 2007;28:233-8.
  45. Sacha CR, Harris AL, James K, et al. Placental pathology in live births conceived with in vitro fertilization after fresh and frozen embryo transfer. Am J Obstet Gynecol. 2020;222:360.e1-360.e16.
  46. Imudia AN, Awonuga AO, Doyle JO, et al. Peak serum estradiol level during controlled ovarian hyperstimulation is associated with increased risk of small for gestational age and preeclampsia in singleton pregnancies after in vitro fertilization. Fertil Steril. 2012;97:1374-9.
  47. Vermey BG, Buchanan A, Chambers GM, et al. Are singleton pregnancies after assisted reproduction technology (ART) associated with a higher risk of placental anomalies compared with non-ART singleton pregnancies? A systematic review and meta-analysis. BJOG. 2019;126:209-18.
  48. Healy DL, Breheny S, Halliday J, et al. Prevalence and risk factors for obstetric haemorrhage in 6730 singleton births after assisted reproductive technology in Victoria Australia. Hum Reprod. 2010;25:265-74.
  49. Rombauts L, Motteram C, Berkowitz E, Fernando S. Risk of placenta praevia is linked to endometrial thickness in a retrospective cohort study of 4537 singleton assisted reproduction technology births. Hum Reprod. 2014;29:2787-93.
  50. Dunietz GL, Holzman C, Zhang Y, et al. Correction: Assisted reproductive technology and newborn size in singletons resulting from fresh and cryopreserved embryos transfer. PLoS One. 2018;13:e0196767.
  51. Kondapalli LA, Perales-Puchalt A. Low birth weight: is it related to assisted reproductive technology or underlying infertility? Fertil Steril. 2013;99:303-10.
  52. Shapiro BS, Daneshmand ST, Garner FC, Aguirre M, Hudson C, Thomas S. Evidence of impaired endometrial receptivity after ovarian stimulation for in vitro fertilization: a prospective randomized trial comparing fresh and frozen-thawed embryo transfer in normal responders. Fertil Steril. 2011;96:344-8.
  53. Senapati S, Wang F, Ord T, Coutifaris C, Feng R, Mainigi M. Superovulation alters the expression of endometrial genes critical to tissue remodeling and placentation. J Assist Reprod Genet. 2018;35:1799-1808.
  54. Bonagura TW, Babischkin JS, Aberdeen GW, Pepe GJ, Albrecht ED. Prematurely elevating estradiol in early baboon pregnancy suppresses uterine artery remodeling and expression of extravillous placental vascular endothelial growth factor and α1β1 and α5β1 integrins. Endocrinology. 2012;153:2897-906.
  55. Oron G, Hiersch L, Rona S, et al. Endometrial thickness of less than 7.5 mm is associated with obstetric complications in fresh IVF cycles: a retrospective cohort study. Reprod Biomed Online. 2018;37:341-8.
  56. Hiura H, Hattori H, Kobayashi N, et al. Genome-wide microRNA expression profiling in placentae from frozen-thawed blastocyst transfer. Clin Epigenetics. 2017;9:79.
  57. Nelissen EC, van Montfoort AP, Dumoulin JC, Evers JL. Epigenetics and the placenta. Hum Reprod Update. 2011;17:397-417.
  58. Shaw L, Sneddon SF, Brison DR, Kimber SJ. Comparison of gene expression in fresh and frozen-thawed human preimplantation embryos. Reproduction. 2012;144:569-82.
  59. Ball M, Carmody M, Wynne F, et al. Expression of pleiotrophin and its receptors in human placenta suggests roles in trophoblast life cycle and angiogenesis. Placenta. 2009;30:649-53.
  60. Liu S, Wang F, Liu G. Knockdown of pleiotrophin increases the risk of preeclampsia following vitrified-thawed embryo transfer. Int J Oncol. 2018;53:1847-56.
  61. Staff AC, Benton SJ, von Dadelszen P, et al. Redefining preeclampsia using placenta-derived biomarkers. Hypertension. 2013;61:932-42.
  62. Thilaganathan B. Placental syndromes: getting to the heart of the matter. Ultrasound Obstet Gynecol. 2017;49:7-9.
  63. Conrad KP, Baker VL. Corpus luteal contribution to maternal pregnancy physiology and outcomes in assisted reproductive technologies. Am J Physiol Regul Integr Comp Physiol. 2013;304:R69-72.
  64. von Versen-Höynck F, Narasimhan P, Selamet Tierney ES, et al. Absent or excessive corpus luteum number is associated with altered maternal vascular health in early pregnancy. Hypertension. 2019;73:680-90.
  65. von Versen-Höynck F, Schaub AM, Chi YY, et al. Increased preeclampsia risk and reduced aortic compliance with in vitro fertilization cycles in the absence of a corpus luteum. Hypertension. 2019;73:640-9.
  66. Mills G, Badeghiesh A, Suarthana E, Baghlaf H, Dahan MH. Polycystic ovary syndrome as an independent risk factor for gestational diabetes and hypertensive disorders of pregnancy: a population-based study on 9.1 million pregnancies. Hum Reprod. 2020;35:1666-74.
  67. Kelley AS, Smith YR, Padmanabhan V. A narrative review of placental contribution to adverse pregnancy outcomes in women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2019;104:5299-315.
  68. Zaki M, Basha W, El-Bassyouni HT, El-Toukhy S, Hussein T. Evaluation of DNA damage profile in obese women and its association to risk of metabolic syndrome, polycystic ovary syndrome and recurrent preeclampsia. Genes Dis. 2018;5:367-73.
  69. Concha C F, Sir P T, Recabarren SE, Pérez B F. Epigenetics of polycystic ovary syndrome. Rev Med Chil. 2017;145:907-15.
  70. Yu YY, Sun CX, Liu YK, Li Y, Wang L, Zhang W. Genome-wide screen of ovary-specific DNA methylation in polycystic ovary syndrome. Fertil Steril. 2015;104(1):145-53.e6.
  71. Peixoto AB, Rolo LC, Nardozza LMM, Araujo Júnior E. Epigenetics and preeclampsia: programming of future outcomes. Methods Mol Biol. 2018;1710:73-83.
  72. Homer CS, Brown MA, Mangos G, Davis GK. Non-proteinuric pre-eclampsia: a novel risk indicator in women with gestational hypertension. J Hypertens. 2008;26:295-302.
  73. Magee LA, von Dadelszen P, Bohun CM, et al. Serious perinatal complications of non-proteinuric hypertension: an international, multicentre, retrospective cohort study. J Obstet Gynaecol Can. 2003;25:372-82.
  74. Hürter H, Vontelin van Breda S, Vokalova L, et al. Prevention of pre-eclampsia after infertility treatment: preconceptional minimalisation of risk factors. Best Pract Res Clin Endocrinol Metab. 2019;33:127-32.
  75. Conrad KP, Rabaglino MB, Post Uiterweer ED. Emerging role for dysregulated decidualization in the genesis of preeclampsia. Placenta. 2017;60:119-29.


Keywords: , , , ,

Citation: Moreno Sepulveda J.,Santucci P.,Checa M., Higher risk of hypertensive disorders of pregnancy and preeclampsia in pregnancies following frozen embryo transfer: a systematic review and meta-analysis, GREM Gynecological and Reproductive Endocrinology & Metabolism (2021); 02/2021:074-084 doi: 10.53260/GREM.212022

Published: June 14, 2021