Browse

Graphical Abstract

Abstract

Studies evaluating pregnancy outcomes after assisted reproductive treatment (ART) in women with high-normal (2.5–4.5 mIU/L) thyroid-stimulating hormone (TSH) levels are conflicting, possibly due to different patient charactistics and subfertility indications. The aim of this study was to examine the hypothesis that high-normal compared to low-normal TSH levels are associated with adverse implications for pregnancy outcomes in conventional in vitro fertilization (IVF)-treated women. Therefore, we analyzed retrospectively the characteristics and pregnancy outcomes of 949 subfertile women with TSH 0.3–4.5 mIU/L, treated with conventional IVF between January 2008 and March 2012. Demographic and baseline characteristics were compared between groups of patients based on TSH quartiles, using one-way Anova, Kruskal–Wallis ANOVA and chi-square test. Women with high-normal quartile TSH were significantly more likely to be primary subfertile (P = 0.01), with a higher prevalence of unexplained subfertility and with 15% fewer live births after IVF compared to lower TSH quartiles (P = 0.02). In secondary subfertile women with high-normal TSH, male factor subfertility prevailed (P = 0.01), with more live births (P = 0.01). When analyzing primary and secondary subfertile women as one group, these differences failed to be observed, showing no differences in cumulative pregnancy outcomes of IVF between TSH quartiles (I: 0.3–1.21 mIU/L; II: 1.22–1.68 mIU/L; III: 1.69–2.31 mIU/L; IV: 2.32–4.5 mIU/L). In conclusion, primary subfertile women predominate in the high-normal TSH quartile, associated with significantly fewer live births in a subgroup of primary unexplained subfertile women (9%; n  = 87/949), while in secondary subfertile women, dominated by male factor subfertility, high-normal TSH is associated with more live births.

Lay summary

Thyroid hormones are required for all cell processes in the body. An underactive thyroid gland, in which insufficient thyroid hormones are produced and thyroid-stimulating hormone (TSH) rises, is associated with a lower chance of pregnancy. It is not yet clear above which TSH level, 4.5 or also 2.5 mIU/L, this lower probability occurs. Therefore, in 949 couples treated with conventional IVF, we examined whether high-normal TSH levels (TSH: 2.5–4.5 mIU/L) compared to low normal TSH levels (0.3–2.5 mIU/L) affect the live birth rate. We found that women who were trying to become pregnant for the first time, especially without any other cause, that is unexplained subfertility, were more likely to have higher TSH levels. These women had a much lower chance of having a baby compared to women with low-normal TSH levels.

Lay summary

Mitochondria are small parts of cells called organelles that generate the chemical energy needed for life. Hundreds of thousands of mitochondria in the developing eggs of the mother support the initial growth and development of the fertilized egg. However, due to increasingly diminished function over time, mitochondria generate less energy as we age, posing real problems for older women considering pregnancy. It is possible that this declining energy could be responsible for declining fertility as women age. Energy may decline because mitochondria fail and the cell’s way of keeping them healthy become less efficient as we age. This review summarizes what is known about mitochondrial quality control in developing eggs as they age. In the future, understanding how the best mitochondria are selected and maintained in the egg, and hence the future baby, may enable older women with or without mitochondrial problems, to have healthy children.

Lay summary

Early identification during pregnancy of small for gestational age (SGA) babies would enable interventions to lower risk of complications around birth (perinatal), but current detection rates of these at risk babies is low. Pregnancy hormones, prolactin and placental lactogen, are involved in metabolic changes that are required for the mother to support optimal growth and development of her offspring during pregnancy. The levels of these hormones may provide a measurable indicator (biomarker) to help identify these at risk pregnancies. Levels of these hormones were measured in samples from week 20 of gestation from women who went on to have SGA babies and control pregnancies where babies were born at a size appropriate for gestation age. Despite the implications of prolactin and placental lactogen in maternal metabolism, no significant differences were detected suggesting that single measures of either prolactin or placental lactogen at 20 weeks gestation are unlikely to be useful biomarker to help detect SGA pregnancies.

Objectives

Pouch of Douglas (POD) obliteration is a severe consequence of inflammation in the pelvis, often seen in patients with endometriosis. The sliding sign is a dynamic transvaginal ultrasound (TVS) test that can diagnose POD obliteration. We aimed to develop a deep learning (DL) model to automatically classify the state of the POD using recorded videos depicting the sliding sign test.

Methods

Two expert sonologists performed, interpreted, and recorded videos of consecutive patients from September 2018 to April 2020. The sliding sign was classified as positive (i.e. normal) or negative (i.e. abnormal; POD obliteration). A DL model based on a temporal residual network was prospectively trained with a dataset of TVS videos. The model was tested on an independent test set and its diagnostic accuracy including area under the receiver operating characteristic curve (AUC), accuracy, sensitivity, specificity, and positive and negative predictive value (PPV/NPV) was compared to the reference standard sonologist classification (positive or negative sliding sign).

Results

In a dataset consisting of 749 videos, a positive sliding sign was depicted in 646 (86.2%) videos, whereas 103 (13.8%) videos depicted a negative sliding sign. The dataset was split into training (414 videos), validation (139), and testing (196) maintaining similar positive/negative proportions. When applied to the test dataset using a threshold of 0.9, the model achieved: AUC 96.5% (95% CI: 90.8–100.0%), an accuracy of 88.8% (95% CI: 83.5–92.8%), sensitivity of 88.6% (95% CI: 83.0–92.9%), specificity of 90.0% (95% CI: 68.3–98.8%), a PPV of 98.7% (95% CI: 95.4–99.7%), and an NPV of 47.7% (95% CI: 36.8–58.2%).

Conclusions

We have developed an accurate DL model for the prediction of the TVS-based sliding sign classification.

Lay summary

Endometriosis is a disease that affects females. It can cause very severe scarring inside the body, especially in the pelvis − called the pouch of Douglas (POD). An ultrasound test called the 'sliding sign' can diagnose POD scarring. In our study, we provided input to a computer on how to interpret the sliding sign and determine whether there was POD scarring or not. This is a type of artificial intelligence called deep learning (DL). For this purpose, two expert ultrasound specialists recorded 749 videos of the sliding sign. Most of them (646) were normal and 103 showed POD scarring. In order for the computer to interpret, both normal and abnormal videos were required. After providing the necessary inputs to the computer, the DL model was very accurate (almost nine out of every ten videos was correctly determined by the DL model). In conclusion, we have developed an artificial intelligence that can interpret ultrasound videos of the sliding sign that show POD scarring that is almost as accurate as the ultrasound specialists. We believe this could help increase the knowledge on POD scarring in people with endometriosis.

Lay summary

Due to ethical limitations involving humans, the female horse (mare) has recently emerged as an alternative model for reproductive comparisons with women to optimize fertility restoration using ovarian tissue transplantation techniques. This study determined if ovarian tissue from donor mares (n = 3), exposed or not to vascular endothelial growth factor (VEGF) before transplantation, better survives for 7 days after transplantation into mouse hosts (n = 12). Tissues submitted to different combinations of cooling, freezing, and transplanting treatments, along with control groups, were evaluated using the parameters morphology, development, the density of immature eggs (follicles), the density of supportive (stromal) cells, collagen protein proportions, and density of blood vessels. Frozen-thawed treatments had lower percentages of normal follicles. Exposure to VEGF increased blood vessel densities in frozen tissue and favored adequate collagen levels in cooled-transplanted treatments. In conclusion, VEGF exposure seems to be beneficial for mare ovarian tissue transplantation and warrants further investigation.

Lay summary

The term ‘nocebo’ describes the undesirable effects of a medication or treatment that patients may experience which are not directly caused by the treatment (e.g. tiredness from a sugar pill). These arise from pre-existing expectations toward a treatment and are influenced by multiple external factors, including past experiences, online media, personal beliefs, and personality factors. Endometriosis is a disease characterized by cells like those from the inside of the uterus growing outside of the uterus. The complex nature of endometriosis diagnosis and management creates an environment where nocebo effects may affect treatment outcomes. We may be able to limit nocebo effects through awareness and simple actions that strengthen patient–doctor relationships. Effective therapeutic relationships with doctors are crucial in limiting negative expectations and are established through empathy, honesty, and support. Therapeutic relationships built on trust may allow healthcare providers to address negative expectations, nocebo effects, and the misinformation affecting endometriosis management.

Lay summary

Even partway through an IVF cycle, at the point when a woman’s eggs have been collected, it is hard to provide reliable answers to the common question of ‘Am I likely to have a good embryo to transfer?’ Sometimes, it only takes one good egg to be successful. However, doctors and patients are acutely aware that low egg numbers, older age and having conditions such as endometriosis can stack the odds against success. We have developed a model to try and answer this question for those patients who wish for more information to help guide their expectations after egg collection. A new tool is presented to predict whether a woman having IVF treatment will have a good enough embryo either to transfer on day 5 or freeze. It was built using information from all 2015 to 2016 UK cycles and predicts using age, number of eggs collected and cause of subfertility.

Lay summary

In women, a progressive decline and depletion of the primary ovary reserve, which represents the reserve of immature eggs, are a challenging condition in the field of reproductive medicine. This decline, occurring physiological with age, is the main determinant of the age at the onset of menopause. Concomitant with the reduction in their number, the quality of the eggs also decreases with age. Metabolic disorders such as diabetes and obesity can cause ovarian dysfunctions and affect a woman’s fertility mainly by direct targeting the egg stockpile or by indirect interference with the production of reproductive hormones. Here, we report up-to-date data and discuss results about how disturbance of insulin-dependent signalling and increased oxidative stress in the ovary, usually associated to metabolic disorders, can dysregulate the dynamics of the primary ovary reserve and/or impair the survival and quality of the eggs.

Lay summary

The success of IVF has remained stagnant for a decade. The focus of a great deal of research is to improve on the current ~30% success rate of IVF. Artificial intelligence (AI), or machines that mimic human intelligence, has been gaining traction for its potential to improve outcomes in medicine, such as cancer diagnosis from medical images. In this commentary, we discuss whether AI has the potential to improve fertility outcomes in the IVF clinic. Based on existing research, we examine the potential of adopting AI within multiple facets of an IVF cycle, including egg/sperm and embryo selection, as well as formulation of an IVF treatment regimen. We discuss both the potential benefits and concerns of the patient and clinician in adopting AI in the clinic. We outline hurdles that need to be overcome prior to implementation. We conclude that AI has an important future in improving IVF success.

Background

LIN28B plays an important role in early embryonic development, but its role in villous trophoblast implantation and differentiation remains unknown. This study aims to verify the role of LIN28B in trophoblastic villous tissue and cells from women with URSA (unexplained recurrent spontaneous abortion) and artificial termination of pregnancy (negative control, NC).

Methods

The LIN28B gene and its protein expression level were detected with real-time quantitative PCR, Western immunoblotting analysis, and immunocytochemistry. The gene was also overexpressed in chorionic villous cell lines (HTR-8/SVneo and BeWo) to examine its effect on trophoblast function.

Results

The expression of LIN28B mRNA and protein of URSA villi was lower than that in the NC group. At the cellular level, overexpression of LIN28B enhanced cellular migration, and invasion, and inhibited apoptosis. LIN28B may inhibit apoptosis by promoting Akt phosphorylation and by inhibiting Bad phosphorylation and Bcl-2 expression. In addition, LIN28B inhibited cell fusion and reduced cellular syncytia.

Conclusions

LIN28B can inhibit cell invasion and migration in vitro and promote apoptosis and fusion. The low expression of LIN28B in URSA villous trophoblast cells may be one of the causes of abortion. The role of LIN28B in villous trophoblasts needs further study.

Lay summary

Propagation of offspring is of great significance to the continuation of the human race. However, continuous pregnancy is more difficult for some women, especially women who have multiple miscarriages. One important contributor is the cessation of development caused by genetic factors of the embryo, but there are still many unknown reasons. We investigated the LIN28B gene which is a possible pathogenic factor in the placenta. We collected 25 cases of abortion in the experimental group (unexplained recurrent abortion group) and 25 in the control group (artificial termination of pregnancy group): on average at 7–8 weeks of pregnancy. We tested the function of lin28b in these samples and verified its function in cell lines. LIN28B plays an important role in maintaining early pregnancy by promoting the invasion of villous cells, inhibiting apoptosis and fusion, and the reduction of LIN28B expression may lead to the occurrence of early miscarriage.