Obstetric and perinatal outcomes following programmed compared to natural frozen-thawed embryo transfer cycles: a systematic review and meta-analysis

STUDY QUESTION Is there an association between the different endometrial preparation protocols for frozen embryo transfer (FET) and obstetric and perinatal outcomes? SUMMARY ANSWER Programmed FET protocols were associated with a significantly higher risk of hypertensive disorders of pregnancy (HDP), pre-eclampsia (PE), post-partum hemorrhage (PPH) and cesarean section (CS) when compared with natural FET protocols. WHAT IS KNOWN ALREADY An important and growing source of concern regarding the use of FET on a wide spectrum of women, is represented by its association with obstetric and perinatal complications. However, reasons behind these increased risks are still unknown and understudied. STUDY DESIGN, SIZE, DURATION Systematic review with meta-analysis. We systematically searched PubMed, MEDLINE, Embase and Scopus, from database inception to 1 November 2021. Published randomized controlled trials, cohort and case control studies were all eligible for inclusion. The risk of bias was assessed using the Newcastle-Ottawa Quality Assessment Scale. The quality of evidence was also evaluated using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. PARTICIPANTS/MATERIALS, SETTING, METHODS Studies were included only if investigators reported obstetric and/or perinatal outcomes for at least two of the following endometrial preparation protocols: programmed FET cycle (PC-FET) (i.e. treatment with hormone replacement therapy (HRT)); total natural FET cycle (tNC-FET); modified natural FET cycle (mNC-FET); stimulated FET cycle (SC-FET). MAIN RESULTS AND THE ROLE OF CHANCE Pooled results showed a higher risk of HDP (12 studies, odds ratio (OR) 1.90; 95% CI 1.64-2.20; P < 0.00001; I-2 = 50%) (very low quality), pregnancy-induced hypertension (5 studies, OR 1.46; 95% CI 1.03-2.07; P = 0.03; I-2 = 0%) (very low quality), PE (8 studies, OR 2.11; 95% CI 1.87-2.39; P < 0.00001; I-2 = 29%) (low quality), placenta previa (10 studies, OR 1.27; 95% CI 1.05-1.54; P = 0.01; I-2 = 8%) (very low quality), PPH (6 studies, OR 2.53; 95% CI 2.19-2.93; P < 0.00001; I-2 = 0%) (low quality), CS (12 studies, OR 1.62; 95% CI 1.53-1.71; P < 0.00001; I-2 = 48%) (very low quality), preterm birth (15 studies, OR 1.19; 95% CI 1.09-1.29; P < 0.0001; I-2 = 47%) (very low quality), very preterm birth (7 studies, OR 1.63; 95% CI 1.23-2.15; P = 0.0006; I-2 = 21%) (very low quality), placenta accreta (2 studies, OR 6.29; 95% CI 2.75-14.40; P < 0.0001; I-2 = 0%) (very low quality), preterm premature rupture of membranes (3 studies, OR 1.84; 95% CI 0.82-4.11; P = 0.14; I-2 = 61%) (very low quality), post-term birth (OR 1.90; 95% CI 1.25-2.90; P = 0.003; I-2 = 73%) (very low quality), macrosomia (10 studies, OR 1.18; 95% CI 1.05-1.32; P = 0.007; I-2 = 45%) (very low quality) and large for gestational age (LGA) (14 studies, OR 1.08; 95% CI 1.01-1.16; P = 0.02; I-2 = 50%) (very low quality), in PC-FET pregnancies when compared with NC (tNC + mNC)-FET pregnancies. However, after pooling of ORs adjusted for the possible confounding variables, the endometrial preparation by HRT maintained a significant association in all sub-analyses exclusively with HDP, PE, PPH (low quality) and CS (very low quality). LIMITATIONS, REASONS FOR CAUTION The principal limitation concerns the heterogeneity across studies in: (i) timing and dosage of HRT; (ii) embryo stage at transfer; and (iii) inclusion of preimplantation genetic testing cycles. To address it, we undertook subgroup analyses by pooling only ORs adjusted for a specific possible confounding factor. WIDER IMPLICATIONS OF THE FINDINGS Endometrial preparation protocols with HRT were associated with worse obstetric and perinatal outcomes. However, because of the methodological weaknesses, recommendations for clinical practice cannot be made. Well conducted prospective studies are thus warranted to establish a safe endometrial preparation strategy for FET cycles aimed at limiting superimposed risks in women with an 'a priori' high-risk profile for obstetric and perinatal complications. STUDY FUNDING/COMPETING INTEREST(S) None. REGISTRATION NUMBER CRD42021249927.