Abstract Study question Does age and AMH impact early pregnancy outcomes in euploid single embryo transfers using NGS-based PGT-A for individuals aged 35 and above? Summary answer In this NGS-based PGT-A study, no significant differences in early pregnancy rates were observed based on age or AMH among individuals aged 35 and above. What is known already A recent meta-analysis suggest a decline in pregnancy rates with advancing age in the context of euploid embryo transfer following PGT-A. However, it’s crucial to acknowledge variations in PGT-A techniques across studies. While individuals with low AMH levels may encounter challenges in obtaining euploid embryos, the precise impact of AMH on pregnancy rates post-embryo acquisition remains unclear. Study design, size, duration A retrospective cohort study was conducted on 428 cycles of single euploid embryo transfers in patients aged 35 and above, performed at the single infertility center from January to December 2022. Participants/materials, setting, methods The study examined frozen-thawed embryo transfer cycles in patients aged 35 and above, analyzing early pregnancy outcomes in single euploid embryo transfers. Participants were grouped by age(35-38, 38-42, 42 and above) and AMH levels(<1, 1-3, >3 ng/ml). NGS-based PGT-A conducted embryo biopsy. The analysis aimed to detect differences in initial pregnancy rates among age and AMH subgroups. The differences between groups were compared using Pearson’s chi-squared test. Main results and the role of chance The average age at transfer was 39.05 ± 2.53 years, with a mean AMH of 2.60 ± 1.86(ng/ml). The mean number of prior frozen embryo transfer (FET) cycles was 1.9 ± 2.04, with 119 patients (27.8%) having undergone three or more transfer cycles. Transfer cycles comprised 363 (84.8%) artificial cycles and 65 (15.2%) ovulatory cycles, with an average endometrial thickness of 8.95 ± 1.73 mm at the time of transfer. The β-hCG positive rate was 57.7% (247/428), and the clinical pregnancy rate was 53.5% (229/428). When analyzing positive b-hCG results by age, rates were 59.9% (82/137) for ages 35-38, 55.5% (121/218) for ages 38-42, and 60.3% (44/73) for ages 42 and above (p = 0.641). In terms of AMH, β-hCG positive rates were 52.1% (37/71) for <1, 59.1% (120/203) for 1-3, and 58.0% (83/143) for ≥3, with no statistically significant differences (p = 0.584). Clinical pregnancy rates were 54.0% for ages 35-38, 51.8% for ages 38-42, and 57.5% for ages 42 and above. For AMH, rates were 50.7% for <1, 53.2% for 1-3, and 54.5% for ≥3, with no statistically significant differences (p = 0.869). Limitations, reasons for caution Being a retrospective study analyzing patients undergoing embryo transfer, our study overlooks variables related to oocyte retrieval. Given the challenges of obtaining euploid embryos in advanced age, further investigation is warranted to explore the probability and duration of embryo acquisition in this population. Wider implications of the findings In this study, utilizing NGS-based PGT-A after generating euploid embryos, no significant differences in early pregnancy outcomes were observed for women aged 35 and older, considering age and AMH levels. The study suggests further research is needed to explore if NGS-based PGT-A can address limitations of traditional chromosomal testing methods. Trial registration number not applicable

Abstract Study question Is there still a significant impact of embryo-related characteristics on pregnancy rates in NGS based PGT-A euploid embryo transfers for advanced-age patients? Summary answer In single frozen euploid embryo transfers, priority of embryo transfer and grade significantly influence clinical pregnancy rates in women over 35 years old with PGT-A. What is known already It is widely recognized that better embryo grades and a shorter duration of blastulation are associated with favorable reproductive outcomes. Recent meta-analyses have affirmed these findings even in the context of transfer with euploid embryos. However, the impact of prioritizing the highest-ranked embryo among multiple vitrified euploid embryos on pregnancy rates remains unclear. The lack of research in this area implies a gap in understanding whether selecting embryos for transfer among multiple viable euploid embryos could enhance reproductive success. Study design, size, duration Throughout the year 2022, a retrospective review was conducted on 428 cycles of single frozen-thawed euploid embryo transfers performed at a single institution, targeting patients aged 35 and older. The study aimed to explore potential differences in clinical pregnancy rates based on embryo grade, embryo freezing date, and embryo selection priority. Participants/materials, setting, methods Women ≥ 35 years old with single frozen euploid blastocyst transfer cycles was categorized into three groups: (a) with one blastocyst (1/1), (b) with ≥ two blastocysts having the top-priority(½ or higher), and (c) lower-priority blastocysts (lower than ½) to examine potential differences in clinical pregnancy rates among groups based on embryo characteristics, including Gardner grading and day of embryo freezing. Results highlight the impact of both selection criteria and freezing conditions on pregnancy outcomes. Main results and the role of chance This study analyzed a total of 428 frozen embryo transfer (FET) cycles. In the context of frozen-thawed single embryo transfer, the clinical pregnancy rate was 52.2% (128/245) when only one euploid embryo was frozen and subsequently thawed for transfer (a). For cases where two or more euploid embryos were frozen, and embryos with a higher priority (½ or higher) were selected for transfer (b), the clinical pregnancy rate significantly increased to 71.3% (62/87). Conversely, when embryos with a lower priority (lower than ½ in order) were chosen for transfer (c), the clinical pregnancy rate was lower at 38.5% (15/38), indicating a statistically significant difference between the groups (p = 0.001). Categorizing embryos based on Gardner grading, “good” embryos (>3BB) demonstrated a clinical pregnancy rate of 66.8% (141/211), while embryos with lower quality (3BB or below) showed a significantly lower clinical pregnancy rate of 40.6% (88/217) (p < 0.001). The analysis of clinical pregnancy rates based on the embryo freezing day revealed significant differences among embryos freezing on 5 days (71.9%, 133/185), 6 days (39.9%, 71/178), 7 days (25%, 2/8), and thawing PGT-A embryos (38.2%, 21/55) (P < 0.001). Limitations, reasons for caution One limitation of this study is its retrospective nature, and the potential confounding effect of the close association between embryo selection and embryo grading. Further analysis will be conducted to confirm correlations and address this potential confounding effect. Wider implications of the findings In single euploid frozen embryo transfers, selecting the highest-quality embryo through careful embryo selection remains relevant. Morphological indicators of embryos significantly impact early pregnancy outcomes, highlighting the continued importance of strategic embryo accumulation for enhanced procedural success. Trial registration number not applicable

This study aimed to elucidate the effect of hatching status on in vitro fertilization (IVF) outcomes in frozen–thawed blastocyst transfer cycles. Frozen–thawed embryo transfer (FET) cycles performed at a single fertility center between 2016 and 2021 were retrospectively assessed. Analyses were restricted to 6,821 frozen–thawed blastocyst transfers in women aged 24–47 years. For optimal comparability, double embryo transfer (ET) cycles consisting of one hatching and one hatched blastocyst were excluded. The implantation and pregnancy rates were evaluated and compared between the hatching and hatched blastocyst transfer groups based on patients’ age (<38 vs. ≥38 years), blastocyst grade (good vs. bad grade), and the number of transferred embryos (single ET vs. double ET). Hatched blastocyst transfer was associated with higher implantation and clinical pregnancy rates in the single ET group (15.7

Abstract Study question Can intrauterine infusion of autologous platelet-rich plasma(PRP) for patients with refractory thin endometrium in euploid frozen embryo transfer(FET) cycles improve pregnancy outcomes? Summary answer Intrauterine infusion of autologous platelet-rich plasma(PRP) for patients with refractory thin endometrium in euploid FET cycles improve pregnancy outcomes. What is known already Previous studies have reported a positive correlation between endometrial thickness and pregnancy rate, which has led to the common clinical practice of canceling embryo transfer in cycles where the patient’s endometrial thickness remains below 7mm.One of the novel and promising treatments to improve pregnancy outcomes in patients with refractory thin endometrium is intrauterine infusion of autologous PRP.Recent studies demonstrated that intrauterine infusion of PRP improve pregnancy outcomes in these patients.Thus, to better assess the efficacy of intrauterine PRP treatment, further studies involving euploid embryos are necessary to rule out failed implantation or pregnancy loss due to aneuploidy of the embryos. Study design, size, duration This retrospective study analyzed all cycles(n = 131) of euploid FET in women with refractory thin endometrium at the CHA Fertility Center in Seoul Station from January 2022 to August 2023.Patients were divided into two groups according to whether they received PRP intrauterine infusion before embryo transfer in euploid FET cycles.Group A(n = 88) received intrauterine infusion of PRP at least once before transfer of euploid FET,and Group B(n = 43) underwent euploid FET without PRP infusion. Participants/materials, setting, methods Intrauterine infusion of autologous PRP was performed on patients who had more than two canceled FET cycles due to thin endometrial thickness(<7mm). Endometrial preparation was executed according to a standardized protocol for hormone replacement therapy. Group A received the last autologous PRP infusion 48 hours before euploid FET. PRP preparation was carried using an aseptic PRP centrifuge kit (PROSYS PRP; Prodizen, Korea). All embryos transferred were tested for genetic abnormalities using next-generation sequencing. Main results and the role of chance There was no significant difference in mean age and maximum endometrial thickness between the two groups. (38.1±3.1 vs. 38.3±3.2, p = 0.986 and 6.6±1.1 vs. 6.0±0.8, p = 0.320, respectively) Group A had significantly higher clinical pregnancy rates and ongoing pregnancy rates than Group B. (51.1% vs. 30.2%, p = 0.024 and 44.3 vs. 16.3%, p = 0.0017, respectively) Implantation rate and beta HCG positivity were also higher in group A, but there was no statistical difference. (63.6% vs. 46.5%, p = 0.063 and 37.2 vs. 23.2%, p = 0.064, respectively) Limitations, reasons for caution This is a retrospective study and results must be confirmed on a well-designed randomized controlled study. Also, follow-up study consisting of larger number of patients is necessary. Wider implications of the findings Autologous PRP intrauterine infusion has shown positive effects in assisting implantation in patients with refractory thin endometrium. In particular, euploid frozen embryo transfer in these patients excludes failed implantation and pregnancy loss due to embryo aneuploidy, suggesting that intrauterine PRP treatment contributes to successful implantation and pregnancy. Trial registration number not applicable

Does double-dose hCG triggering improve oocyte quality and pregnancy outcomes compared to single-dose hCG triggering and dual trigger with GnRH-Agonist with hCG in advanced-age women undergoing IVF-ICSI cycles? This retrospective study was conducted from January 2020 to October 2022 at a CHA hospital seoulstation. Women aged ≥35 years undergoing IVF/ICSI treatment, receiving a non-pituitary down-regulation protocol, and with low risk of OHSS, were included in the study. A total of 656 cycles were divided into three groups according to different trigger protocols: group A received r-hCG 250 μg (n=185), group B received r-hCG 500 μg (n=461), and group C received GnRHa 0.2 mg and r-hCG 250 μg (n=86). The clinical pregnancy rate (28.1% vs. 36.0% vs. 29.1%) and ongoing pregnancy rate (24.3% vs. 33.4% vs. 22.1%) was the highest in group B, but there was a significant difference compared to group A , but no significant difference from group C. Biochemical pregnancy rates were also the highest in group B with 40.5%, 45.6%, and 37.2%, but there was no significant difference. In addition, although the average number of retrieved oocytes(5.6±3.2 vs. 8.9±3.4 vs.7.8±3.4) and average number of mature oocytes(3.9±2.4 vs. 7.1±2.5 vs.5.2±3.1) were the highest in group B, there was a significant difference compared to group A, but no significant difference compared to group C. The average number of embryos (3.8±2.3 vs. 6.9±2.3 vs.4.4±2.6) was also the highest in group B, but there was no significant difference. Double-dose hCG triggering improves oocyte quality and pregnancy outcomes compared to single-dose hCG triggering and dual trigger with GnRH-Agonist with hCG in advanced-age women undergoing IVF-ICSI cycles.

Abstract Study question Is natural cycle the best protocol for endometrial preparation in frozen-thawed single euploid blastocyst transfers? Summary answer Clinical and ongoing pregnancy were comparable between endometrial preparation methods although programmed cycle was associated with a higher risk of miscarriage compared to natural cycle. What is known already Utilization of frozen-thawed single euploid embryo transfers based on PGT-A have been substantially increased recently, but there are still no firm conclusions on the optimal protocol in frozen-thawed embryo transfers (FETs). Even so, significant concerns have been raised about maternal and fetal safety associated with the programmed cycles and several favorable outcomes of natural cycles and letrozole use in FETs have been suggested in recent years. Pregnancy outcomes after endometrial preparation with natural cycle, letrozole use, programmed cycles have not been compared in euploid blastocyst FETs. Study design, size, duration This was a retrospective cohort study at a single center including FET cycles from January 2019 to October 2021. Participants/materials, setting, methods A total of 708 frozen-thawed single euploid blastocyst transfer cycles were analyzed. Endometrial preparation was performed using natural cycle with hCG trigger (n = 60), ovulation induction with letrozole (n = 32), or programmed cycle (n = 616) at the discretion of each attending physician. Pregnancy outcomes including clinical pregnancy, ongoing pregnancy, and miscarriage were calculated using multivariable logistic regression. Main results and the role of chance The three groups were similar for age, BMI, basal FSH, TSH, AMH levels, PGT-A indications, presence of ovulatory dysfunction, endometrial thickness on the starting day of progesterone supplementation, and the proportion of good quality embryo transferred. The crude clinical pregnancy rate, ongoing pregnancy rate, and miscarriage rate were not different among the groups (55.0% vs. 68.9% vs. 61.9%, p = 0.40; 51.7% vs. 59.4% vs. 50.0%, p = 0.58; 6.1% vs. 13.6% vs. 20.4%, p = 0.11, respectively). After adjusting for confounders, clinical pregnancy and ongoing pregnancy outcomes of natural cycle were similar to that of letrozole cycle and programmed cycle. However, programmed cycle was associated with significantly higher odds of miscarriage compared to natural cycle (aOR 4.33, 95% CI 1.01-18.58). Limitations, reasons for caution This was not an intention-to-treat study due to its retrospective design. Another limitation of this study includes a small sample size and risk of patient selection bias for indication of PGT-A. Wider implications of the findings Natural cycle and ovulation induction with letrozole may be safely and effectively carried out for endometrial preparation in patients undergoing single euploid FETs. Trial registration number not applicable

Karyomapping is a method for analyzing genome-wide parental haplotypes using single nucleotide polymorphism (SNP) genotyping. It provides a comprehensive method for linkage-based diagnosis of single gene defects. Genetic recombination at the target gene can affect accurate diagnosis in preimplantation genetic testing for monogenic disorders (PGT-M). In this study, we aimed to analyze genetic recombination to overcome for the diagnostic limitations of PGT-M. Karyomapping was performed on 1,638 embryos from 348 cycles of 187 couples for 50 single gene disorders from July 2020 to December 2022. Karyomapping was performed by the HumanKaryomap-12 BeadChip protocol (Illumina, USA) and analyzed using BlueFuse Multi software (Illumina). Recombinant embryos in 5’ flanking region (46 embryos), main region (9 embryos), and 3’ flanking region (58 embryos) were analyzed using direct sequencing and short tandem repeat (STR) linked markers based on polymerase chain reaction (PCR). Among a total of 1,638 embryos from 348 cycles, 1,577 (96.3%) embryos were successfully diagnosed. Eleven (0.7%) recombinant embryos were found. At least one recombinant embryo was found in nine (2.6%) PGT cycles. Recombination was detected in genes on all chromosomes except 9, 10, 18, 21 and Y in this study. The occurrences of recombinant embryos were the highest in DMD, 11.0% (8/73). Others showed low rate of recombination: 1.4% (1/72), 0.5% (1/201), 50.0% (1/2) in FBN1, NF1 and SMAD3 genes, respectively. Nine out of 11 recombinant embryos were further tested using PCR for confirmation. As a result, all 9 embryos (100%) of the PCR results were concordant to the results of Karyomapping: 5 normal, 2 carrier and 2 abnormal. There were 104 embryos which had recombination in 5’ or’ flanking regions adjacent to the gene, and 47 embryos were further tested with PCR. In three embryos (6.4%), the results of PCR were not concordant with the those of karyomapping. Our study shows that recombination occurs in most of the chromosomes, not in a specific chromosome. In some of the embryos which had cross over in 5' or 3' flanking regions, karyomapping and PCR results may be inconsistent. Therefore, when cross over is found in karyomapping, it may be necessary to add PCR methods such as direct sequencing or linkage analysis using STR markers to increase the accuracy of PGT-M.

Couples with chromosomal structural rearrangements have an increased risk of having unbalanced embryos which results in poor reproductive outcomes. PGT-SR allows these couples to select normal or balanced embryos. The rate of transferrable embryos is varying according to the couples. In this study, we aimed to evaluate the proportion of unbalanced embryos in NGS setting according to the types of structural rearrangement and the gender of carriers. This retrospective study conducted in all PGT-SR cycles performed between January 2021 and December 2022. PGT-SR was performed on 2,237 embryos from 608 cycles of 333 couples: 239 Reciprocal translocation (REC-T), 56 Robertsonian translocation (ROB-T), 21 Inversion (INV). Couples were divided into female carrier group (357 cycles, 1,305 embryos) and male carrier group (251 cycles, 932 embryos). The rate of unbalanced embryos was compared according to the types of rearrangement in each group. The unbalanced embryo rate and sporadic aneuploid (diagnosed as aneuploid but balanced for structural rearrangement) were compared according to the maternal age. NGS-based PGT-SR was performed using Veriseq NGS (Illumina, San Diego, USA) platform. The results were analyzed by BlueFuse Multi v4.3 software (Illumina). The rate of unbalanced embryos after NGS-based PGT-SR was significantly higher in female carrier group than in male carrier group (58.5% vs 48.0% respectively, p<0.001). According to the types of rearrangement, the rate of unbalanced embryos was significantly higher in REC-T (64.2% female, 58.2% male, p<0.02) than ROB-T (45.5% Female, 17.1% male, p<0.001) and INV-T (18.4% female, 18.9% male, p>0.05). Interestingly enough, the unbalanced embryo rate was very low in male carrier of ROB-T. Paternally derived translocations led to lower rate of unbalanced embryos in ROB-T (45.5% maternal vs. 17.1% paternal, p<0.001) than in REC-T (64.2% maternal vs. 58.2% paternal, p<0.02). In contrast to the translocation carriers, the inversion carriers had significantly lower rate of unbalanced rearrangement. Regardless of the female age, the unbalanced embryos rate was relatively constant (mean rate: 58.5%, <35 years: 58.6%; 35–37 years: 58.6%; 38–40 years: 56.3%; and >40 years: 54.1% in female carriers and mean rate: 48.0%, <35 years: 45.2%; 35–37 years: 51.3%; 38–40 years: 47.6%; and >40 years: 50.0% in male carriers. In this study, reciprocal translocation carrier, especially female carriers, were found to have a higher risk of having unbalanced embryos than ROB-T and INV. Although the unbalanced embryo rate can be predicted according to the gender and type of the rearrangements in couples with chromosomal structural rearrangements, the feasibility of getting transferrable embryo from PGT-SR would be heavily dependent upon the age of female due to aneuploidy of other chromosomes.

Does the duration of incubation after warming between thawing and embryo transfer affect reproductive outcomes in IVF patients? 1856 single frozen blastocyst transfer cycles from January 2021 to December 2021 were analyzed. And were divided into two groups, 1704 Group A (or "Day Before"), in which blastocysts were warmed on the day before transfer, cultured for approximately 18 hours (range 16–22 hours), and then transferred. And 152 group B (or "ET-Day"), in which embryos were warmed on the day of transfer, kept in culture during approximately 4 hour, and then transferred. IVF cycles using donor oocyte, TESE sperm, PGT, or those lacking follow-up were excluded. For group A, if the blastocyst had not re-expanded or degenerated prior to embryo transfer, additional warming was performed when possible. All women underwent standard IVF protocols following usual individualized practice in our IVF clinic. All blastocyst transfers were performed under ultrasound guidance during an ovulatory or a hormonal replacement therapy (HRT) cycle. The clinical pregnancy rate and pregnancy rate of cryopreserved embryos transferred after overnight culture was significantly higher than after 4 hours culture after thawing. (56.9% vs. 39.5% p<0.05, 67.0% vs. 48.5% p<0.05 ) The ongoing pregnancy rate was also higher in group A, but there was no significant difference. (48.9% vs. 31.6% p>0.05) Cryopreserved embryos transferred after overnight cultureafter thawing provided a better success rate than culture after 4 hours culture after thawing.

[This corrects the article DOI: 10.1371/journal.pone.0267652.].

Background: Various life course factors can affect susceptibility to diseases during adolescence and adulthood, and those relationships are complex. However, few studies have assessed the potential mediating factors. Therefore, we assessed the mediating effects of factors related to growth and inflammation between perinatal factors and metabolic syndrome risk during adolescence.Methods: The study was conducted on adolescents who participated in the follow-up in the Ewha Birth and Growth Cohort. We considered the ponderal index (PI) as a perinatal factor and the continuous metabolic syndrome score (cMetS) as the outcome and confirmed the mediating effects of body mass index (BMI) trajectory pattern in childhood and inflammation levels by using the PROCESS macro for SAS.Results: Although the direct effect of BMI trajectory on the relationship between PI and cMetS was not significant (0.545), the indirect effect was significant (1.044). In addition, the indirect effect was statistically significant in the pathways mediating the BMI trajectory pattern and inflammation (beta = 1.456).Conclusions: The direct and indirect effects on the relationship between PI and cMetS suggest that childhood factors related to growth may be involved in disease susceptibility. Therefore, appropriate interventions for the management of obesity during the growth phase are necessary.I

Not all blastocyst reach the fully expanded stage by day 5; those are the slow developing blastocysts. There is a lack of evidence regarding the implantation potential of slow developing blastocysts that determines the day of TE biopsy. To evaluate the clinical outcomes of not-fully expanded blastocysts biopsied on day 5 and fully expanded blastocysts biopsied on day 6.

Complex chromosomal rearrangements (CCRs) are constitutional structural rearrangements that involve three or more chromosomes with more than two breakpoints. CCR carriers have a high risk of recurrent spontaneous abortion and birth of offspring with abnormal phenotype. The Preimplantation genetic testing for structural rearrangement (PGT-SR) can reduce the miscarriage rate and improve clinical outcomes. However, the odds of normal or balanced embryo for CCR carriers is very low. There are scanty data on the effect of different types of CCR on abnormal embryo rate. Herein, we evaluated the difference in the unbalanced translocation rate in a series of preimplantation embryos from couples with CCR.

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Other SectionsAbstractIntroductionMaterials and MethodsResultsDiscussionConflict of interestAuthors’ ContributionsFigureTableReference

Abstract Study question Does Preconception TSH levels affect the clinical outcomes of Infertile Women Undergoing Fresh Embryo Transfer Cycle? Summary answer Among euthyroid patients, preconceptional TSH values in the high-normal range (between 2.5 and 4.0 mIU/L) are associated with adverse clinical outcomes. What is known already Serum thyroid-stimulating hormone (TSH) levels are routinely screened in women with infertility given the negative impact of thyroid disease on ovarian function and pregnancy is associated with poor outcomes.In fact, an underlying thyroid abnormality was found in 46% for women experiencing IVF failure and TSH levels were inversely proportional to the fertilization rate at IVF. While it is clear that pregnancies complicated by subclinical hypothyroidism in the fertile population have poor outcomes, the relevance of preconception subclinical hypothyroidism in infertile patients undergoing ART has not been thoroughly examined. Study design, size, duration Outcomes of all fresh IVF patients with an embryo transfer from from January 2019 to August 2021 within 1 yr of TSH screening at a our center were studied. IVF cycles using donor oocyte, TESE sperm, PGT, or those lacking follow-up were excluded. For patients with more than one Preconception TSH measurement prior IVF, the most recent measurement before the IVF cycle was used. Participants/materials, setting, methods Cycles were categorized into two groups based on preconceptional TSH values: Euthyroid (0.4–2.5 μIU/mL), subclinical hypothyroidism (>2.5-4.0 μIU/mL). All women underwent standard IVF protocols following usual individualized practice in our IVF clinic. Chi-square test was used to evaluate the differences between the patient cohorts. Main results and the role of chance A total of 2,669 fresh-ET cycles were reviewed retrospectively by dividing them into a euthyroid group (0.4-2.5 uIU/mL, n = 2397) and subclinical hypothyroidism group (2.5-4.0 uIU/mL, n=272). The overall biochemical pregnancy rate and clinical pregnancy rate was significantly lower in women with subclinical hypothyroidism (50.0% vs 43.4%, 40.0% vs 30.9%, p < 0.05). However, biochemical preganacy loss rate and the miscarriage rate was higher in women with subclinical hypothyroidism. (19.6% vs. 28.8%, 17.3% vs. 25.0%, p = 0.079) Limitations, reasons for caution This is a retrospective study and results must be confirmed on a well-designed randomized controlled study. Correlations must be considered with caution since the role of TSH is under study, especially when considering LBR outcome. Wider implications of the findings Among euthyroid patients, preconceptional TSH values in the high-normal range (between 2.5 and 4.0 mIU/L) are associated with adverse clinical outcomes. Our findings suggest that subclinical hypothyroidism may affect clinical outcomes. Trial registration number not applicable