The Efficacy of Traditional Chinese Medicine Shoutai Pill Combined with Western Medicine in the First Trimester of Pregnancy in Women with Unexplained Recurrent Spontaneous Abortion: A Systematic Review and Meta-Analysis.

BACKGROUND: Shoutai Pill (STP), a famous classic herbal formula documented in traditional Chinese medicine (TCM), is widely available in China for treating unexplained recurrent spontaneous abortion (URSA). This systematic review and meta-analysis aims at evaluating the efficacy and safety of STP in the first trimester of pregnancy in women with a history of unexplained recurrent spontaneous abortion. METHODS: The following eight databases were searched from their establishment to Dec 31, 2019, for randomized controlled trials (RCTs): PubMed, Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure (CNKI), the Chinese BioMedical database (CBM), Chinese Scientific Journal Database (VIP), and the Wanfang database. The quality of evidence was estimated by the Grading of Recommendations Assessment, Development, and Evaluation (GRADE). RESULTS: A total of 12 studies (916 patients) with URSA were contained in this meta-analysis. The forest plot showed that patients treated with Shoutai Pill and western medicine had a significantly lower incidence of early pregnancy loss (RR: 0.42; 95% CI: 0.34-0.52; P < 0.01, I 2 = 0%). Subgroup analysis revealed that different types of TCM syndrome differentiation had the similar results. Also, in the combined group, patients had a lower TCM syndromes and symptoms and serum D-dimer level, while higher incidence of live birth. CONCLUSIONS: Our findings suggest that cotreatment with STP and western medicine might be superior to western medicine alone in the first trimester of pregnancy to prevent miscarriage in women with unexplained recurrent spontaneous abortion, and there was no adverse event in the experimental group reported. However, the methodological quality of included RCTs was unsatisfactory; it is necessary to verify its effectiveness with further more standardized researches of rigorous design.

Association between hereditary predisposition to common cancers and congenital multimalformations.

In a previous article we reported that mutations favoring cancer at adulthood seemed to improve fertility and limit miscarriages. Because spontaneous abortion may result from anomalies in embryo, we questioned if an increased frequency of congenital malformation could be evidenced among cancer-prone families. Oncogenetics database (≈193 000 members) of the comprehensive cancer center Jean Perrin was crossed with regional registry of congenital malformations (≈10 000). Among children born between 1986 and 2011, 176 children with malformation matched in both databases. In breast/ovaries cancer-prone families, the risk for malformations was multiplied by 2.4 [1.2-4.5] in case of a BRCA1 mutation. Frequencies of malformation in BRCA2 and MMR mutated families were similar to families without a cancer syndrome. In comparison to malformations concerning a unique anatomical system, multimalformations were significantly more frequent in case of BRCA or MMR mutations: compared to families without cancer syndrome, the risk of multimalformations was multiplied by 4.1 [0.8-21.7] for cancer-prone families but with no known deleterious mutation, by 6.9 [1.2-38.6] in families with a known mutation but an unknown parental mutational status and by 10.4 [2.3-46.0] when one parent carried the familial mutation. No association with the type of anatomical system was found, nor with multiple births. These results suggest that BRCA and MMR genes play an important role in human embryogenesis and that if their function is lowered because of heterozygote mutations, congenital malformations are either more likely (BRCA1 mutations) and/or more susceptible to concern several anatomical systems.

Why AMPK agonists not known to be stressors may surprisingly contribute to miscarriage or hinder IVF/ART.

Here we examine recent evidence suggesting that many drugs and diet supplements (DS), experimental AMP-activated protein kinase (AMPK) agonists as well as energy-depleting stress, lead to decreases in anabolism, growth or proliferation, and potency of cultured oocytes, embryos, and stem cells in an AMPK-dependent manner. Surprising data for DS and drugs that have some activity as AMPK agonists in in vitro experiments show possible toxicity. This needs to be balanced against a preponderance of evidence in vivo that these drugs and DS are beneficial for reproduction. We here discuss and analyze data that leads to two possible conclusions: First, although DS and drugs that have some of their therapeutic mechanisms mediated by AMPK activity associated with low ATP levels, some of the associated health problems in vivo and in vitro fertilization/assisted reproductive technologies (IVF/ART) may be better-treated by increasing ATP production using CoQ10 (Ben-Meir et al., Aging Cell 14:887-895, 2015). This enables high developmental trajectories simultaneous with solving stress by energy-requiring responses. In IVF/ART, it is ultimately best to maintain handling and culture of gametes and embryos in the quietest state with low metabolic activity (Leese et al., Mol Hum Reprod 14:667-672, 2008; Leese, Bioessays 24 (9):845-849, 2002) using back-to-nature or simplex algorithms to identify optima (Biggers, Reprod Biomed Online 4 Suppl 1:30-38, 2002). Stress markers, such as checkpoint proteins like TRP53 (aka p53) (Ganeshan et al., Exp Cell Res 358:227-233, 2017); Ganeshan et al., Biol Reprod 83:958-964, 2010) and a small set of kinases from the protein kinome that mediate enzymatic stress responses, can also be used to define optima. But, some gametes or embryos may have been stressed in vivo prior to IVF/ART or IVF/ART optimized for one outcome may be suboptimal for another. Increasing nutrition or adding CoQ10 to increase ATP production (Yang et al., Stem Cell Rev 13:454-464, 2017), managing stress enzyme levels with inhibitors (Xie et al., Mol Hum Reprod 12:217-224, 2006), or adding growth factors such as GM-CSF (Robertson et al., J Reprod Immunol 125:80-88, 2018); Chin et al., Hum Reprod 24:2997-3009, 2009) may increase survival and health of cultured embryos during different stress exposure contexts (Puscheck et al., Adv Exp Med Biol 843:77-128, 2015). We define "stress" as negative stimuli which decrease normal magnitude and speed of development, and these can be stress hormones, reactive oxygen species, inflammatory cytokines, or physical stimuli such as hypoxia. AMPK is normally activated by high AMP, commensurate with low ATP, but it was recently shown that if glucose is present inside the cell, AMPK activation by low ATP/high AMP is suppressed (Zhang et al., Nature 548:112-116, 2017). As we discuss in more detail below, this may also lead to greater AMPK agonist toxicity observed in two-cell embryos that do not import glucose. Stress in embryos and stem cells increases AMPK in large stimulation indexes but also direness indexes; the fastest AMPK activation occurs when stem cells are shifted from optimal oxygen to lower or high levels (Yang et al., J Reprod Dev 63:87-94, 2017). CoQ10 use may be better than risking AMPK-dependent metabolic and developmental toxicity when ATP is depleted and AMPK activated. Second, the use of AMPK agonists, DS, and drugs may best be rationalized when insulin resistance or obesity leads to aberrant hyperglycemia and hypertriglyceridemia, and obesity that negatively affect fertility. Under these conditions, beneficial effects of AMPK on increasing triglyceride and fatty acid and glucose uptake are important, as long as AMPK agonist exposures are not too high or do not occur during developmental windows of sensitivity. During these windows of sensitivity suppression of anabolism, proliferation, and stemness/potency due to AMPK activity, or overexposure may stunt or kill embryos or cause deleterious epigenetic changes.

Interactive Effects of Snps Located Within CD28/B7Pathway and Environment on Susceptibility to Recurrent Spontaneous Abortion.

AIMS: This study was aimed to explore the interaction between environment and CD28/B7 pathway to provide the potential epidemiology for prevention and treatment of recurrent spontaneous abortion (RSA). METHODS: The retrospective study included 630 RSA cases and 1320 healthy women during their middle and late prenatal care. Their living environment was investigated, and the influence of environmental factors on pregnancy abortion was analyzed. The genomic DNAs were extracted from the study subjects, and the polymorphisms of CD28 and B7 were analyzed. Finally, the interaction of gene and environment on RSA was analyzed with the logistic regression analyses. RESULTS: The multi-variate regression analysis indicated that vitamin supplement, intake of fresh fruits or vegetables, night shift, staying up late, history miscarriage, as well as history induced abortion were, independently, risk factors for RSA (all P< 0.05). Moreover, rs3116496 (T>C), rs3181098 (G>A) and rs3181100 (G>C) of CD28, rs1915087 (C>T) of B7-2, as well as rs6804441 (A>G) and rs41271391 (G>T) of B7-1 were correlated with modified RSA risk (all P< 0.05). The haplotypes TGT and TAG could also regulate the risk of RSA (both P< 0.05). The synthetic influences of the aforementioned SNPs and environmental factors could also significantly affect the susceptibility to RSA (all P< 0.05). CONCLUSION: The interaction of environment and SNPs of CD28/B7 pathway on RSA risk was distinct from CD28/B7 pathway or environment alone.

Sildenafil (Viagra®) blocks inflammatory injury in LPS-induced mouse abortion: A potential prophylactic treatment against acute pregnancy loss?

INTRODUCTION: Recurrent pregnancy losses (RPL) are common women's health issues. Inflammatory and thrombotic events have been associated with RPL including excessive production of cytokines, in particular TNF-α. However, mechanisms behind gestational losses are not yet fully understood. Sildenafil inhibits phosphodiesterase Type-5 (PDE5). This drug increases intracellular cyclic guanosine monophosphate, having vasodilatory and, more recently described, anti-inflammatory properties. PDE5 is present in murine and human uterus and placenta. Sildenafil is already used clinically for treatment of human fetal growth restriction (FGR). Our objective was to determine if Sildenafil alone or in combination with Heparin had protective effects in pregnant Swiss albino challenged to abort by lipopolysaccharide (LPS). METHODS: Treatments (Sildenafil (50 mg/kg/day), Heparin (500 IU/Kg/day) or Sildenafil + Heparin at the same doses) were initiated the morning of copulation plug detection (gestational day (gd0)). On the 15th day of pregnancy, an intra-peritoneal injection of LPS (100 µg/kg) was administered. Untreated, pregnant mice challenged by LPS served as controls. RESULTS: Assessments at 48 h after LPS revealed that Sildenafil + Heparin prevented fetal loss. Early assessments at 2 h after LPS indicated that the pretreatments prevented induction of inflammatory cytokine production (TNF-α, IL-1ß/NF-κß) and preserved placental histopathology. DISCUSSION: Combined Sildenafil + Heparin therapy was superior to either treatment alone in most analyses. The known safety of Sildenafil and Heparin in human pregnancy suggests that usage of these combined agents may be of value for treatment of patients with impending pregnancy loss or prophylactically in women with a history of recurrent miscarriages.

Morphological criteria for normalization of menstrual function in women with spontaneous abortion.

Normalization of the menstrual function in women with spontaneous abortion receiving sorbent and bioresonance (extremely high-frequency) therapy was evaluated by morphological criteria (correspondence of structural changes in the endometrium to the phase of the menstrual cycle). The absence of microvilli and cilia on the apical surface of surface and glandular epitheliocytes, presence of intranuclear tubules and giant mitochondria in the cytoplasm, and signs of apocrine secretion in epitheliocytes attested to the luteal phase of the cycle.

Alterations of the subcommissural organ in the hydrocephalic human fetal brain.

We have studied the subcommissural organ of two hydrocephalic brains, of 20 and 21 gestational weeks and of two normal brains, aged 19 and 23 gestational weeks. Both hydrocephalic cases presented a size reduction of the subcommissural organ compared to the normal cases; only in one case, there were also alterations of the morphological components of the subcommissural organ, suggesting different pathogenic relationships between hydrocephalus and dysplasia of the subcommissural organ.