Compiled by Zhu Mo
Source｜Medical World Obstetrics and Gynecology Channel
1
Does frozen embryo transfer always increase the baby's birth weight?
The birth of Louise Brown, the world's first test-tube baby, in 1978 heralded a technological breakthrough in frozen-thawed embryo transfer. While in-vitro fertilization (IVF) technology has brought good news to tens of millions of families, recent research results have also prompted much reflection among colleagues.
In IVF, since implantation is not guaranteed to be successful on the first transfer, several extra embryos are usually prepared in advance for the next transfer. The remaining embryos then need to be cryopreserved.
In the early days, cryopreservation technology was not perfect (low survival rate, low implantation rate). However, with improvements in embryo vitrification technology, we can now achieve survival and implantation rates of 100%, comparable to or even higher than those of fresh embryo transfer. Therefore, some centers recommend cryopreserving all eligible embryos before performing single or double embryo transfer during routine embryo transfer. This method also avoids complications associated with fresh cycle transfer (such as ovarian hyperstimulation syndrome), and improves endometrial receptivity and synchronicity before transfer.
While clinical efficacy is important, safety is even more crucial. Multiple studies have found that babies conceived through IVF have lower birth weights and a higher risk of preterm birth. Previous research has also reported that babies conceived through frozen embryo transfer (FET) have higher birth weights and an increased risk of macrosomia.
Researchers Litzky and colleagues used the National Centers for Disease Control and Prevention's Assisted Reproductive Technology (ART) Surveillance Database to assess whether frozen embryo transfer was associated with fetal birth weight, the risk of macrosomia, and sex differences. After analyzing data from singleton full-term deliveries using autologous donor eggs (124,286 fresh cycles and 54,698 FETs), they found that, with no difference in confounding factors between the two groups, women in the FET group were more likely to be primiparous.
Both groups of patients had a gestational age exceeding 39 weeks. Single embryo transfer accounted for approximately 21.5% of fresh embryo transfers, compared to 40.8% in FET. The average birth weight gain in the FET group was 142 grams. In contrast, male infants in fresh embryo transfers experienced an average weight loss of 150 grams, and female infants an average weight loss of 143 grams. The FET group had fewer low birth weight infants (adjusted relative risk/aRR: 0.5; 95% confidence interval/CI: 0.48–0.56), while the risk of macrosomia increased approximately 1.7 times after FET (aRR: 1.7; 95% CI: 1.64–1.76).
The exact cause of these differences remains unclear, but it is speculated that they may be related to epigenetic changes during cryopreservation. Other possibilities include the implantation occurring during a non-stimulated endometrial cycle, or individual differences; further research is needed.
The main risk of macrosomia lies in its potential to cause delivery complications, especially during planned vaginal deliveries. Some reports suggest that higher average birth weights at FET (Follicular Unit Delivery) are associated with an increased risk of macrosomia. The direct impact of this 100-200 gram difference is currently unclear, and long-term follow-up of potential metabolic risks is needed.
2
Preventing premature birth: Is there a safest method?
Prematurity is defined as birth before 37 weeks of gestation, occurring in approximately 10% of births. In the United States, the prematurity rate decreased to 9.54% between 2007 and 2014, but has slightly increased since 2014. Prematurity is a leading cause of neonatal morbidity and mortality, impacting a child's health and well-being.
Currently known risk factors for preterm birth include advanced or young maternal age, smoking, low income, overweight or underweight, chronic diseases, uterine abnormalities, multiple pregnancies, and infections. However, the two most important risk factors are a history of preterm birth and a short cervix (<2.5 cm).
Various methods exist for preventing preterm birth, including the use of tocolytics, early cervical assessment, and vaginal progesterone. However, tocolytics are not very effective in preventing preterm birth; they merely delay the onset of labor to allow time for transfer to a better-equipped hospital and the use of steroids. A previous meta-analysis showed that vaginal progesterone and cervical cerclage are both effective in preventing preterm birth.
However, a recent meta-analysis showed that early cervical assessment and vaginal progesterone administration can prevent preterm birth in women with a history of preterm singleton pregnancies and/or cervical shortening. The study compared vaginal progesterone and cerclage after adjusting for individual differences (10 trials; 769 women: 265 in the progesterone trial and 504 in the cerclage trial). The following findings were obtained:
Vaginal progesterone can effectively prevent preterm birth at <35 weeks (RR: 0.68; 95% CI: 0.50-0.93) and <32 weeks (RR: 0.60; 95% CI: 0.39-0.92).
Vaginal progesterone can effectively reduce the incidence of neonatal sepsis, the rate of admission to intensive care, and perinatal morbidity/mortality.
Cervical cerclage is effective in preventing preterm birth at <37 weeks (RR: 0.70; 95% CI: 0.58-0.83), <35 weeks (RR: 0.70; 95% CI: 0.55-0.89), and <32 weeks (RR: 0.66; 95% CI: 0.48-0.91).
Circumcision can effectively reduce perinatal morbidity and mortality.
A meta-analysis also found that vaginal progesterone combined with cerclage was equally effective in preventing preterm birth at <35 weeks of gestation (RR: 0.97; 95% CI: 0.66–1.44).
Researchers concluded that cervical cerclage and/or vaginal progesterone use should be considered for women with a history of preterm singleton pregnancies and/or cervical shortening. Preterm birth is estimated to cause approximately one million perinatal deaths worldwide. Cervical cerclage and vaginal progesterone use can prevent about one-third of preterm births, thus reducing perinatal fetal mortality. Cervical cerclage is a surgical procedure requiring anesthesia and is associated with many complications (injury, rupture of membranes, infection), and often requires a cesarean section for delivery.
Since vaginal progesterone is equally effective in preventing preterm birth with fewer side effects/complications, it should be the preferred treatment for patients, and guidelines may need to be adjusted accordingly. Further research is needed to directly compare the two methods and their combined use.
3
Cervical cancer surgery: Minimally invasive may not be the best surgical option?
Among female cancers, the reproductive tract is the third most common organ affected. Cervical cancer is the third most common reproductive tract cancer, affecting 7.4 women per 100,000 between 2011 and 2015, a significant decrease compared to 13.45 women per 100,000 between 1975 and 1979.
Between 1975 and 2015, the age-adjusted mortality rate for cervical cancer also declined (from approximately 5.07 per 100,000 women to 2.26 per 100,000 women). However, the 5-year overall survival rate did not change significantly between 1975 and 2014 (69.1% vs. 68.9%). Survival rates are higher for localized cancers, exceeding 90%.
With innovations in cancer treatment technologies, such as new, safer, and better-tolerated chemotherapy regimens, as well as the combination of local radiotherapy with minimally invasive procedures (laparoscopy and robotic surgery), the incidence of perioperative complications can be reduced, hospital stays can be shortened, and recovery can be faster.
The main surgical approaches for early-stage cervical cancer include radical hysterectomy and pelvic lymph node dissection. Surgery can be performed via open laparotomy or minimally invasive procedures based on laparoscopic techniques or robotic surgery. In a recent meta-analysis, Jin and colleagues concluded that while minimally invasive methods reduce bleeding, shorten hospital stays, and lower the incidence of postoperative complications, their survival and recurrence rates are slightly higher than those of open surgery.
Ramirez and his team conducted a multicenter randomized controlled trial to evaluate 4.5-year cancer-free survival following open radical hysterectomy (n = 312) or laparoscopic/robotic radical hysterectomy (n = 319) for early-stage cervical cancer (IA1, IA2, IB1 stages). There were no statistically significant differences in baseline characteristics between the two groups. The minimally invasive treatment group had a relatively shorter operative hospital stay (3 days vs. 5 days). The incidence of intraoperative and postoperative complications was similar in both groups.
Of the 34 patients, 34 experienced cancer recurrence (7 in the open surgery group and 27 in the minimally invasive surgery group), and 22 died (3 in the open surgery group and 19 in the minimally invasive surgery group). The cancer-free survival rate was significantly higher in the open surgery group than in the minimally invasive surgery group (96.5% vs 86%), with a relative risk (HR) of 3.74 for recurrence or death in the minimally invasive group (95% CI: 1.63–8.58). The overall survival rate was also lower in the minimally invasive surgery group (93.8% vs 99.0%; HR for death from all causes: 6; 95% CI: 1.77–20.30).
The exact cause is still unclear. It may be due to insufficient surgical experience and techniques (using uterine manipulators, insufflation, cancer resection, etc.), inappropriate non-invasive procedures during the operation leading to tumor spread, or individual patient differences. Further research is needed to determine the specific cause.
4
Can aspirin be used as a primary preventative medication to maintain women's health?
Obstetricians and gynecologists typically consider routine check-ups, primary screening programs, and immunizations as primary preventative healthcare measures. When women are over 65, doctors recommend regular check-ups to check for conditions such as diabetes or dyslipidemia, and to assess their individual cardiovascular disease (CVD) risk.
Among women aged 65-74, heart disease is the second leading cause of death (18.3%), and stroke is the fourth (6.7%). Therefore, any intervention that reduces the risk of cardiovascular disease can affect mortality and disability-free survival.
Aspirin is well known to have anti-inflammatory and antithrombotic effects. It is currently widely used for secondary prevention of cardiovascular disease (CVD). However, whether it can be used for primary prevention remains unclear.
A multicenter randomized controlled trial investigated the efficacy of aspirin in elderly individuals aged 79 years and older (without chronic or cardiovascular disease and a life expectancy > 5 years). Volunteers were randomized to either the experimental group (receiving 100 mg aspirin daily, n = 9525) or the control group (receiving a placebo, n = 9589), with a median follow-up of 4.7 years. The results (including disability-free survival, all-cause mortality, and cardiovascular events including major hemorrhage) were published in three separate articles.
The main observations are as follows:
The incidence of disability (including death, dementia and physical disability) was 21.5 per year in the aspirin treatment group and 21.1 per year in the placebo group (HR: 1.01; 95% CI: 0.92-1.11).
The mortality rate was 12.7 per 1,000 in the aspirin group and 11.1 per 1,000 in the placebo group (HR: 1.14; 95% CI: 1.01–1.29).
The incidence of cancer was higher in the aspirin group than in the placebo group (6.7‰ vs 5.1‰; HR: 1.31; 95% CI: 1.10–1.56). Colorectal cancer was the most common cancer in the aspirin group (HR: 1.77; 95% CI: 1.02–3.06). There was no significant difference in the incidence of breast cancer and pancreatic cancer.
There was no difference in CVD events between the two groups (10.7‰ vs 11.3‰; HR: 0.95; 95% CI: 0.83–1.08). However, aspirin treatment could lead to serious bleeding (3.8% vs 2.8%; HR: 1.38; 95% CI: 1.18–1.62).
Researchers concluded that daily intake of 100 mg of aspirin did not prolong disability-free survival in the elderly. Compared to the placebo group, although the incidence of CVD was similar in both groups, the aspirin group had a higher mortality rate, a higher incidence of cancer, and a higher rate of bleeding events. Aspirin is widely used for secondary prevention of CVD, but it does not appear to offer much benefit to patients who do not have pre-existing risk factors.
Therefore, it is recommended that aspirin treatment for low-risk individuals be carefully evaluated before being decided upon, as its routine preventative use seems unreasonable. Thus, the American College of Obstetricians and Gynecologists' recommendations regarding aspirin for CVD prevention require further consideration. However, for patients with pre-existing cardiovascular risk factors (dyslipidemia, hypertension, obesity, sedentary lifestyle), aspirin may offer protective effects against CVD.
5
Does preimplantation genetic testing for aneuploidy improve IVF results?
The key to successful IVF is transferring euploid embryos into receptive endometrium. Typically, morphokinetic parameters are used to identify the one or two embryos in optimal condition for transfer. When clinical outcomes after IVF do not meet expectations, various embryo screening techniques are considered, and the patient is placed under close monitoring.
Preimplantation genetic testing (PGT-A) for aneuploidy involves examining chromosomes extracted from the polar bodies of oocytes or from the inner cell mass of embryos. While this method seemed reasonable, an early report found it to be of no benefit. Subsequently, with improvements in genetic testing technology, biopsy became the preferred method.
A recent randomized controlled trial showed that biopsy genetic testing can improve clinical pregnancy outcomes after embryo transfer in these patients. While this technique can shorten the clinical pregnancy cycle and reduce miscarriage rates, it is now widely believed that PGT-A does not improve clinical outcomes after all embryo transfers. Furthermore, biopsies may have adverse effects on the embryo, and not all tests provide definitive results to aid physician decision-making.
Given the above issues, coupled with the high additional technical costs, the validity of PGT-A testing remains to be verified.
A multicenter randomized controlled trial was conducted to assess the impact of array comparative genomic hybridization assays on clinical outcomes within one year of polar body PGT-A testing and transplantation in newly identified women aged 36–40 years.
Analysis of data from 396 women using the intention-to-treat method revealed that approximately 21% of biopsied oocytes yielded no or indeterminate results, with aneuploid oocytes accounting for one-third. There was no difference in live birth rate between the experimental and control groups (24% vs. 24%; relative risk/RR: 1.07; 95% CI: 0.75–1.51). The risk of miscarriage was lower in the PGT-A group (7% vs. 14%; RR: 0.48; 95% CI: 0.26–0.90). The live birth rate after the first embryo transfer did not significantly increase after PGT-A (30% vs. 22%).
In summary, polar body PGT-A did not increase the live birth rate, but its use required minimal intervention and resulted in a lower miscarriage rate. PGT-A shortened the clinical pregnancy period and prevented adverse pregnancies, but several issues remain.
Questions arise regarding whether all patients should receive PGT-A, or whether testing should be limited to a specific population (e.g., older mothers), and whether a few truly specialized testing centers should be designated to perform embryo biopsies.
Furthermore, how to handle uncertain results and chromosomal mosaicism is also a problem. When euploidy or aneuploidy results are obtained, the choice is easy to make, but how to handle mosaic embryos is still controversial, because this does not necessarily mean that the fetus is unhealthy.
Finally, there is no consensus on at what stage a biopsy should be performed (polar body, day 3, or blastocyst). Perhaps in the future, a biopsy can be performed at any stage, and we may even be able to obtain genetic information by testing the embryo's culture medium.
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