Poor ovarian response and the possible role of natural and modified natural cycles

About 20% of women undergoing in vitro fertilization struggle with poor ovarian response, indicating a poor prognosis related to low response following ovarian stimulation. Indeed, poor ovarian response, that is associated with both high cancelation rates and low live birth rates, still represents one of the most important therapeutic challenges in in vitro fertilization. In this context, natural cycle/modified natural cycle– in vitro fertilization, as a ‘milder’ approach, could be a reasonable alternative to high-dose/conventional ovarian stimulation in poor ovarian responders, with the aim to retrieve a single oocyte with better characteristics that may result in a single top-quality embryo, transferred to a more receptive endometrium. Moreover, modified natural cycle– in vitro fertilization may be cost-effective because of the reduced gonadotropin consumption. Several studies have been published during the last 20 years reporting conflicting results regarding the use of natural cycle/modified natural cycle– in vitro fertilization in women with poor ovarian response; however, while most of the studies concluded that mild stimulation regimens, including natural cycle/modified natural cycle– in vitro fertilization, have low, but acceptable success rates in this difficult group of patients, others did not replicate these findings. The aim of this narrative review is to appraise the current evidence regarding the use of natural cycle/modified natural cycle– in vitro fertilization in poor ovarian responders.

Preimplantation genetic testing for aneuploidy in uterus transplant patients

Uterus transplantation is an emerging treatment for uterine factor infertility. In vitro fertilization with cryopreservation of embryos prior is required before a patient can be listed for transplant. Whether or not to perform universal preimplantation genetic testing for aneuploidy should be addressed by centers considering a uterus transplant program. The advantages and disadvantages of preimplantation genetic testing for aneuploidy in this unique population are presented. The available literature is reviewed to determine the utility of preimplantation genetic testing for aneuploidy in uterus transplantation protocols. Theoretical benefits of preimplantation genetic testing for aneuploidy include decreased time to pregnancy in a population that benefits from minimization of exposure to immunosuppressive agents and decreased chance of spontaneous abortion requiring a dilation and curettage. Drawbacks include increased cost per in vitro fertilization cycle, increased number of required in vitro fertilization cycles to achieve a suitable number of embryos prior to listing for transplant, and a questionable benefit to live birth rate in younger patients. Thoughtful consideration of whether or not to use preimplantation genetic testing for aneuploidy is necessary in uterus transplant trials. Age is likely a primary factor that can be useful in determining which uterus transplant recipients benefit from preimplantation genetic testing for aneuploidy.

Subarachnoid haemorrhage in pregnancy after in vitro fertilisation with egg donation: a case report and review of the literature

We report a rare case of in vitro fertilisation (IVF) with egg donation complicated by a subarachnoid haemorrhage (SAH). Haemostatic changes related to IVF are known to increase risk of venous thrombosis; however, less is known regarding the risk of arterial events such as cerebrovascular accidents (CVA). Matrix metalloprotease-9 (MMP-9) upregulated in IVF patients may have a role in arterial aneurysm formation, which is the most common cause of SAH. Further research is required to assess the benefit of screening for risk of CVA and the best way to manage this in the IVF population. This may have implications for the ethics of offering certain procedures such as egg donation to women with pre-existing risk factors.

Mitochondrial enrichment in infertile patients: a review of different mitochondrial replacement therapies

Poor ovarian responders exhibit a quantitative reduction in their follicular pool, and most cases are also associated with poor oocyte quality due to patient’s age, which leads to impaired in vitro fertilisation outcomes. In particular, poor oocyte quality has been related to mitochondrial dysfunction and/or low mitochondrial count as these organelles are crucial in many essential oocyte processes. Therefore, mitochondrial enrichment has been proposed as a potential therapy option in infertile patients to improve oocyte quality and subsequent in vitro fertilisation outcomes. Nowadays, different options are available for mitochondrial enrichment treatments that are encompassed in two main approaches: heterologous and autologous. In the heterologous approach, mitochondria come from an external source, which is an oocyte donor. These techniques include transferring either a portion of the donor’s oocyte cytoplasm to the recipient oocyte or nuclear material from the patient to the donor’s oocyte. In any case, this approach entails many ethical and safety concerns that mainly arise from the uncertain degree of mitochondrial heteroplasmy deriving from it. Thus the autologous approach is considered a suitable potential tool to improve oocyte quality by overcoming the heteroplasmy issue. Autologous mitochondrial transfer, however, has not yielded as many beneficial outcomes as initially expected. Proposed mitochondrial autologous sources include immature oocytes, granulosa cells, germline stem cells, and adipose-derived stem cells. Presently, it would seem that these autologous techniques do not improve clinical outcomes in human infertile patients. However, further trials still need to be performed to confirm these results. Besides these two main categories, new strategies have arisen for oocyte rejuvenation by improving patient’s own mitochondrial function and avoiding the unknown consequences of third-party genetic material. This is the case of antioxidants, which may enhance mitochondrial activity by counteracting and/or preventing oxidative stress damage. Among others, coenzyme-Q10 and melatonin have shown promising results in low-prognosis infertile patients, although further randomised clinical trials are still necessary.

Human growth hormone use in poor ovarian response – caution and opportunities

Human growth hormone has found favour as a co-gonadotrophin in assisted reproduction particularly in the circumstances of a poor response to stimulation. Its use has been based on animal studies suggesting insulin-like growth factor-1 enhances granulosa and cumulus cell function and possibly oocyte quality. While there is limited ovarian cellular information in women, the use of human growth hormone is alleged to improve egg numbers, embryo quality, clinical pregnancies and live birth in women with a poor ovarian response. A number of cohort studies have claimed these benefits compared with prior nil treatment, but there are a limited number of quality randomised controlled studies. The few good randomised trials indicate an enhanced ovarian response in terms of oestradiol secretion and oocyte maturity with controversial improvement in ongoing pregnancy and live birth. Given the cost of the medication, the lack of convincing data on enhanced clinical outcomes and the theoretical possibility of side effects, we propose it is still too early to determine human growth hormone’s true cost-benefit for widespread use. However, a number of emerging randomised trials may tilt the equation to a positive outlook in the future. Meanwhile, the hormone should only be used after full informed consent from the patient as to its effectiveness and efficacy.

Air quality in the clinical embryology laboratory: a mini-review

The scope of the clinical embryology laboratory has expanded over recent years. It now includes conventional in vitro fertilization (IVF) techniques and complex and time-demanding procedures like blastocyst culture, processing of surgically retrieved sperm, and trophectoderm biopsy for preimplantation genetic testing. These procedures require a stable culture environment in which ambient air quality might play a critical role. The existing data indicate that both particulate matter and chemical pollution adversely affect IVF results, with low levels for better outcomes. As a result, IVF clinics have invested in air cleaning technologies with variable efficiency to remove particulates and volatile organic compounds. However, specific regulatory frameworks mandating air quality control are limited, as are evidence-based guidelines for the best air quality control practices in the embryology laboratory. In this review, we describe the principles and existing solutions for improving air quality and summarize the clinical evidence concerning air quality control in the embryology laboratory. In addition, we discuss the gaps in knowledge that could guide future research to improve clinical outcomes.

A review of maternal overweight and obesity and its impact on cardiometabolic outcomes during pregnancy and postpartum

The rates of maternal overweight and obesity, but also excess gestational weight gain, are increasing. Pregnancy complications, including gestational diabetes mellitus, gestational hypertension, pre-eclampsia and delivery of a preterm or growth restricted baby, are higher for both women with overweight and obesity and women who gain excess weight during their pregnancy. Other conditions such as polycystic ovary syndrome are also strongly linked to overweight and obesity and worsened pregnancy complications. All of these conditions place women at increased risk for future cardiometabolic diseases. If overweight and obesity, but also excess gestational weight gain, can be reduced in women of reproductive age, then multiple comorbidities associated with pregnancy complications may also be reduced in the years after childbirth. This narrative review highlights the association between maternal overweight and obesity and gestational weight gain, with gestational diabetes, pre-eclampsia, polycystic ovary syndrome and delivery of a preterm or growth restricted baby. This review also addresses how these adverse conditions are linked to cardiometabolic diseases after birth. We report that while the independent associations between obesity and gestational weight gain are evident across many of the adverse conditions assessed, whether body mass index or gestational weight gain is a stronger driving factor for many of these is currently unclear. Mechanisms linking gestational diabetes mellitus, gestational hypertension, pre-eclampsia, preterm delivery and polycystic ovary syndrome to heightened risk for cardiometabolic diseases are multifactorial but relate to cardiovascular and inflammatory pathways that are also found in overweight and obesity. The need for post-partum cardiovascular risk assessment and follow-up care remains overlooked. Such early detection and intervention for women with pregnancy-related complications will significantly attenuate risk for cardiovascular disease.

The role of midwives and obstetrical nurses in the promotion of healthy lifestyle during pregnancy

Women with maternal obesity, an unhealthy lifestyle before and during pregnancy and excess gestational weight gain have an increased risk of adverse pregnancy and birth outcomes that can also increase the risk of long-term poor health for them and their children. Pregnant women have frequent medical appointments and are highly receptive to health advice. Healthcare professionals who interact with women during pregnancy are in a privileged position to support women to make lasting healthy lifestyle changes that can improve gestational weight gain and pregnancy outcomes and halt the intergenerational nature of obesity. Midwives and obstetrical nurses are key healthcare professionals responsible for providing antenatal care in most countries. Therefore, it is crucial for them to build and enhance their ability to promote healthy lifestyles in pregnant women. Undergraduate midwifery curricula usually lack sufficient lifestyle content to provide emerging midwives and obstetrical nurses with the knowledge, skills, and confidence to effectively assess and support healthy lifestyle behaviours in pregnant women. Consequently, registered midwives and obstetrical nurses may not recognise their role in healthy lifestyle promotion specific to healthy eating and physical activity in practice. In addition, practising midwives and obstetrical nurses do not consistently have access to healthy lifestyle promotion training in the workplace. Therefore, many midwives and obstetrical nurses may not have the confidence and/or skills to support pregnant women to improve their lifestyles. This narrative review summarises the role of midwives and obstetrical nurses in the promotion of healthy lifestyles relating to healthy eating and physical activity and optimising weight in pregnancy, the barriers that they face to deliver optimal care and an overview of what we know works when supporting midwives and obstetrical nurses in their role to support women in achieving a healthy lifestyle.

Double or dual stimulation in poor ovarian responders: where do we stand?

Recent advances in our recognition of two to three follicular waves of development in a single menstrual cycle has challenged the dogmatic approach of ovarian stimulation for in vitro fertilization starting in the early follicular phase. First shown in veterinary medicine and thereafter in women, luteal phase stimulation–derived oocytes are at least as competent as those retrieved following follicular phase stimulation. Poor ovarian responders still remain a challenge for many decades simply because they do not respond to ovarian stimulation. Performing follicular phase stimulation and luteal phase stimulation in the same menstrual cycle, named as double stimulation/dual stimulation, clearly increases the number of oocytes, which is a robust surrogate marker of live birth rate in in vitro fertilization across all female ages. Of interest, apart from one study, the bulk of evidence reports significantly higher number of oocytes following luteal phase stimulation when compared with follicular phase stimulation; hence, performing double stimulation/dual stimulation doubles the number of oocytes leading to a marked decrease in patient drop-out rate which is one of the major factors limiting cumulative live birth rates in such poor prognosis patients. The limited data with double stimulation/dual stimulation-derived embryos is reassuring for obstetric and neonatal outcome. The mandatory requirement of freeze-all and lack of cost-effectiveness data are limitations of this novel approach. Double stimulation/dual stimulation is an effective strategy when the need to obtain oocytes is urgent, including patients with malignant diseases undergoing oocyte cryopreservation and patients of advanced maternal age or with reduced ovarian reserve.

A rational diagnostic approach to the “phantom hCG” and other clinical scenarios in which a patient is thought to be pregnant but is not

The scenario in which a patient tests positive for human chorionic gonadotropin (hCG) in the absence of pregnancy can pose a diagnostic dilemma for clinicians. The term “phantom hCG” refers to persistently positive hCG levels on diagnostic testing in a nonpregnant patient and such results often lead to a false diagnosis of malignancy and subsequent inappropriate treatment with chemotherapy or hysterectomy. There remains a need for a consistent and rational diagnostic approach to the “phantom hCG.” This article aims to review the different etiologies of positive serum hCG testing in nonpregnant subjects and concludes with a practical, stepwise diagnostic approach to assist clinicians encountering this clinical dilemma.