Conventional ICSI vs. physiological selection of spermatozoa for ICSI (picsi) in sibling oocytes.

BACKGROUND: Physiological selection of spermatozoa for ICSI (PICSI) is a sperm selection method based on sperm binding to hyaluronic acid. Previous studies on the effect of hyaluronic acid binding assays on fertilization and embryo quality have shown inconsistent results. Previous sibling oocyte studies have not found a significant improvement in fertilization or embryo development with hyaluronic acid binding assays. OBJECTIVE: To compare fertilization and embryo development between standard intracytoplasmic sperm injection (ICSI) and PICSI in sibling oocytes. MATERIALS AND METHODS: This is a retrospective analysis of all in vitro fertilization (IVF) cycles between January 2017 and April 2020 in which sibling oocytes were randomly fertilized by both ICSI and PICSI. Fertilization rate and the rate of embryos eligible for transfer were compared. RESULTS: Forty-five IVF cycles, in which 257 oocytes were fertilized with PICSI and 294 with standard ICSI, were compared. Most of the patients included in the study had previous failures of fertilization, poor embryonic development, implantation failure, or miscarriage. All but two of the patients had at least one previous unsuccessful IVF cycle. Both fertilization rates (71% vs. 83%) and transfer eligible embryo rates (38% vs. 51%) were significantly higher in PICSI fertilized oocytes (p = 0.008 and p = 0.01 respectively). DISCUSSION: Our study is the largest sibling oocyte study comparing ICSI and PICSI, and the first to find a significant improvement in fertilization and embryo quality with PICSI using sibling oocytes. The fact our cohort included almost exclusively couples with previous unsuccessful IVF cycles might suggest that PICSI should be used in selected cases. CONCLUSION: PICSI improves fertilization rates and transfer eligible embryo rates in sibling oocytes in a selected study group.

Ovarian stimulation for oocyte cryopreservation for prevention of age-related fertility loss: one in five is a low responder.

Oocyte cryopreservation for age-related fertility loss is gaining interest considering the tendency to postpone motherhood in many societies. Little is currently known about the actual efficiency of this approach. We aimed to explore ovarian response of presumably fertile women undergoing in vitro fertilization for this indication. A total of 105 women underwent 151 stimulation cycles at mean age 37.7 ± 2.4. None had known infertility. Mean daily starting FSH dose was 371 ± 110 (225-600). Mean number of mature oocytes cryopreserved at the first completed cycle was 9.7 ± 7.5 (0-43). However, 21% of started cycles were either cancelled before egg retrieval or resulted in 0-3 mature oocytes retrieved. Therefore, women considering oocyte cryopreservation for prevention of age-related fertility decline should be encouraged to perform this procedure at younger age than, preferably before 35.

Frozen-Thawed Embryo Transfer Success Rate is Affected by Age and Ovarian Response at Oocyte Aspiration Regardless of Blastomere Survival Rate.

OBJECTIVE: To identify the factors influencing the success of frozen-thawed embryo transfers, whether originating directly from current cycles or from their matching fresh cycles. METHODS: Analysis of 273 frozen-thawed embryo transfer cycles and their matching fresh embryo transfer cycles, with respect to maternal, embryological and clinical factors, comparing successful to unsuccessful cycles. RESULTS: The cumulative clinical pregnancy and live birth rates following fresh ET and corresponding FETs were 50.5% and 38.8%, respectively. No outcome measure differed between fresh and frozen ET's. Only maternal age, number of oocytes retrieved and fertilized, and number of cleaved embryos in the fresh cycle were correlated with a higher pregnancy or live birth rate in the FET cycle. None of the other parameters had any effect on the outcome. Pre-freezing embryo quality and blastomere survival rate had no effect on pregnancy/live birth rates. CONCLUSION: Clinical pregnancy and live birth rates of fresh and frozen ETs were not significantly different. The only parameters that affected FET success were those resulting from the patient's age and ovarian reserve at the time of oocyte aspiration. Post-thawing blastomere survival rate and type of endometrial preparation for FET did not affect the success rate.

Tumefactive demyelination following in vitro fertilization (IVF).

Tumefactive demyelination (TD) is a solitary cerebral demyelinating lesion clinically and radiologically mimicking brain tumors. It can occur in isolation or may be rarely associated with other demyelinating diseases. The underlying pathogenic mechanisms are unknown. We present the first report of TD following in-vitro fertilization (IVF) in a 36-year-old healthy woman who developed subacute right hemiparesis shortly after a scheduled IVF cycle. Evaluation revealed left hemispheric space-occupying lesion pathologically diagnosed as TD. Treatment with intravenous methylprednisolone promptly resulted in a clinical and radiological improvement maintained thereafter. This report confirms and expands the spectrum of inflammatory demyelinating conditions associated with IVF and suggests possible hormonal influence in the development of TD.

Knowledge, attitudes and practices of physicians and nurses regarding the link between IVF treatments and breast cancer.

PURPOSE: The ovarian stimulating hormones used in In-Vitro Fertilization may increase the incidence of breast cancer. Little research has been conducted to ascertain health professionals' knowledge or practices regarding this possible connection and if they communicate this risk to their patients. This study described the knowledge, attitudes and practices of doctors and nurses regarding the causative link between In-Vitro Fertilization treatments and breast cancer, and to determine if these health professionals were assessing or communicating this possible risk to their patients. METHOD: Seventy gynecologists and nurses who worked in fertility clinics, had at least one year of experience in fertility and were literate in Hebrew were asked to complete the questionnaires. Ten clinics around the country were contacted and the questionnaires were distributed and collected on the same day. RESULTS: 35 Nurses and 35 gynecologists completed the survey. Although the majority of the physicians (68%) and nurses (69%) thought that there was a possible connection between the hormonal treatment of IVF and breast cancer, physicians were significantly more likely to inform their patients about the connection than were nurses. CONCLUSIONS: There is a gap between the attitudes and practices of both physicians and nurses in communicating possible cancer risk to IVF clients. It would be beneficial to create a standardized risk communication protocol that would include information and guidelines for practice. More research must be conducted in this area, as there is almost no data on possible maternal risk from IVF treatment.

Relationship between nulliparity and preeclampsia may be explained by altered circulating soluble fms-like tyrosine kinase 1.

OBJECTIVE: To test the hypothesis that the risk of preeclampsia in nulliparous women may be due to an anti-angiogenic state. METHODS: Maternal serum samples obtained in the third trimester from nulliparous (n = 86) and multiparous (n = 165) singleton uncomplicated pregnancies were analyzed for levels of angiogenic factors - soluble fms like tyrosine kinase 1 (sFlt1) and placental growth factor (PlGF) by enzyme-linked immunosorbent assay (ELISA). RESULTS: For nulliparous and multiparous pregnancies, serum sFlt1 levels were 12 732 ± 832 and 10 162 ± 666 (p = 0.020), serum PlGF levels were 215 ± 15 and 249 ± 14 (p = 0.093) (all reported as mean SD in pg/ml) and mean ratios of sFlt1/PlGF were 93 ± 12 and 62 ± 5 (p = 0.023), respectively. Adjustment for maternal age and fetal birth weight did not alter the results. CONCLUSIONS: Nulliparous pregnancies had higher circulating sFlt1 levels and sFlt1/PlGF ratios than multiparous pregnancies, suggesting an association with an angiogenic imbalance. Taken together with the pathogenic role of anti-angiogenic factors in preeclampsia, our data may be one explanation for the epidemiological observation that nulliparity is a risk factor for the development of preeclampsia.

Is the quality of donated semen deteriorating? Findings from a 15 year longitudinal analysis of weekly sperm samples.

BACKGROUND: Studies suggest that global semen quality is declining, but the debate remains open owing to geographic variation. OBJECTIVES: To evaluate temporal trends of sperm parameters - namely concentration, motility and total motile sperm count - in sperm donated during the period 1995-2009. METHODS: In a retrospective longitudinal cohort study we analyzed the sperm count and motility of 2182 semen samples provided on a weekly basis by 58 young, healthy, fertile, university-educated, paid donors. RESULTS: Despite the lowering of criteria for sperm parameters satisfactory for donation that were implemented in 2004, 38% of applicants for sperm donation are now rejected based on semen quality as compared to a third of applicants 10-15 years ago (P < 0.001). If the old strict criteria were in place 88% of candidates would be rejected today (P < 0.0001). Over the study period, the average sperm parameters dropped from a concentration of 106 +/- 25 million spermatozoa/ml with 79% +/- 4.3% motility to 68 +/- 14 million/ ml with 66% +/- 4.5% motile sperm (P < 0.0001, P < 0.0001, respectively). The total motile sperm count per ejaculate also decreased, from 66.4 +/- 18.2 million to 48.7 +/- 12 million (P < 0.005). When the previous criteria were implemented for the analysis of the latest group of sperm donors, only 18% of donors had an acceptable sperm quality, with an average concentration of 87 +/- 12 million spermatozoa/ml, 73% +/- 2.6% motile sperm and total motile sperm count of 53.1 +/- 3.8 million per ejaculate - still significantly lower than 15 years ago (P= 0.01, P= 0.003, P= 0.058 respectively). CONCLUSIONS: The rapid deterioration of sperm quality among fertile semen donors is alarming and may lead to cessation of sperm donation programs.

Reproductive outcome of fresh or frozen-thawed embryo transfer is similar in high-risk patients for ovarian hyperstimulation syndrome using GnRH agonist for final oocyte maturation and intensive luteal support.

BACKGROUND: Triggering ovulation by GnRH agonist (GnRHa) in GnRH antagonist IVF protocols coupled with adequate luteal phase support has recently been suggested as a means to prevent ovarian hyperstimulation syndrome (OHSS). Our objective was to examine the outcome of fresh embryo transfer (f-ET) after triggering ovulation by GnRHa and providing intensive luteal phase supplementation, compared with that of the next first frozen-thawed embryo transfer (ft-ET) after cycles with the same protocol and cryopreservation of all the embryos. METHODS: We performed a cohort study at a university-based IVF clinic. The study population was patients at high risk for OHSS. A daily dose of 50 mg i.m. progesterone in oil and 6 mg of oral 17-ß-estradiol initiated on oocyte retrieval day in the f-ET group (n= 70). In the ft-ET group (n= 40) the embryos were cryopreserved and transferred in the next cycle. RESULTS: The live birth rate per f-ET was 27.1 versus 20% in the ft-ET groups [P = 0.4; rate ratio = 1.36 (0.65-2.81)]. The implantation, pregnancy and spontaneous abortion rates were comparable in both groups. None of the patients developed OHSS. CONCLUSIONS: In this observational cohort study, we showed that triggering ovulation with GnRHa and intensive luteal phase support is a promising new modality to prevent OHSS without the cost of cycle cancellation, ET deferral and reduced clinical pregnancy rates. Confirmation of these findings by RCTs is now required.

Technical modification of testicular sperm extraction expedites testicular sperm retrieval.

OBJECTIVE: To determine the predictive value and the quality of supernatant sperm (SS) achieved by a simple laboratory technical modification after testicular sperm extraction (TESE). DESIGN: A retrospective analysis. SETTING: An IVF unit in a university medical center. PATIENT(S): Azoospermic patients undergoing TESE between January 2001 and December 2006. INTERVENTION(S): Before the mechanical shredding, the testicular specimen in toto was placed in medium. The medium was spun and the pellet resuspended and transferred for SS detection. Then a wet preparation of the testicular tissue was shredded roughly and inspected for tissue sperm (TS) as described. MAIN OUTCOME MEASURE(S): Detection of SS versus TS, fertilization and pregnancy rates (PR) after intracytoplasmic sperm injection (ICSI) with SS versus TS. RESULT(S): The SS was detected in all specimens where TS was eventually found, independent of their testicular pathology. When the supernatant was spermatozoa-negative, no spermatozoa were detected in the tissue. For embryos derived from ICSI the fertilization rate of SS was significantly higher than TS (52% vs. 44%), whereas the PR was comparable. CONCLUSION(S): The SS serves as an excellent predictor of TESE outcome and as a superior source for fertilization. This modified technique enables faster decision of TESE outcome and an easier switch to donor sperm when available.

The value of repeat testicular sperm retrieval in azoospermic men.

To determine the predictive value of a previous testicular biopsy to the chance of sperm retrieval in the next testicular sperm extraction (TESE) procedure, we retrospectively analyzed the outcome of past sperm collection procedures and histopathology diagnoses of patients with nonobstructive azoospermia. Repeated TESE ensured a high recovery rate (96%) when the first recovery procedure had been successful and when hypospermatogenesis was diagnosed (77%); when no spermatozoa were found on the first attempt, a repeat TESE procedure was successful in one-third of the patients.

Endometrial NK cells are special immature cells that await pregnancy.

NK cells populate the human endometrium before pregnancy. Unlike decidual NK cells that populate the decidua during pregnancy, the NK cells present in the human endometrium, before pregnancy, have not been fully characterized. In this study, we provide a detailed analysis of the origin, phenotype, and function of endometrial NK cells (eNK). We show that eNK cells have a unique receptor repertoire. In particular, they are negative for NKp30 and chemokine receptor expression, which distinguishes them from any other NK subset described so far. We further show that eNK cells lack NK-specific functional phenotype and activity such as cytokine secretion and cytotoxicity, before IL-15 stimulation. Following such stimulation, endometrial NK cells acquire phenotype and function that are similar to those of decidual NK cells. We therefore suggest that eNK cells are inactive cells (before IL-15 activation and in relation to the known NK activity) that are present in the endometrium before conception, waiting for pregnancy.

Adolescent infertility--to treat or not to treat.

OBJECTIVE: To present the set of reasons for and against fertility treatment for a very young patient. DESIGN: An expert opinion based on clinical experience. SETTING: An academic-affiliated fertility clinic situated in East Jerusalem. PATIENT(S): A 16-year-old married teenager with 2 years' duration of infertility due to polycystic ovarian syndrome was referred to our infertility center after treatment with six cycles of clomiphene citrate and ovarian drilling. INTERVENTION(S): Counseling of the options of fertility treatments, weight reduction, physical exercise, metformin intake, and an additional gonadotropins-intrauterine insemination cycle with IVF backup. MAIN OUTCOME MEASURE(S): Successful pregnancy while avoiding the risk of ovarian hyperstimulation syndrome. RESULT(S): The patient conceived a single embryo and on the 30th week of gestation suffered premature uterine contractions and gave birth to a 1,330-g preterm male newborn. CONCLUSION(S): Adolescent contraception and unintended pregnancies are prevalent issues in the Western world, whereas adolescent infertility is unheard of. Early age of marriage and conception imposes tremendous dilemma to the society of reproductive endocrinologists. This important cultural issue ought to be debated regarding the age at marriage, the age at first pregnancy, and the treatment of infertility in married "minors" who need treatment. Such a debate is likely to encourage development of formal guidelines for practitioners, which would clearly be beneficial.

Acute renal failure may lead to reversible azoospermia.

OBJECTIVE: To report a possible association between azoospermia and acute renal failure. DESIGN: A case report. SETTING: An in vitro fertilization unit in an academic medical center. PATIENT(S): A patient with high-gonadotropin azoospermia and a history of acute obstructive renal failure because of bilateral renal calculi, who was referred for testicular sperm extraction. INTERVENTION(S): Deferral of the surgical procedure. MAIN OUTCOME MEASURE(S): Return of sperm into the patient's ejaculate. RESULT(S): Four months after normalization of his renal function tests, the sperm analysis showed reversal of the azoospermic state. CONCLUSION(S): Azoospermic patients with recent history of acute renal failure would be followed up for several months after renal function normalization, awaiting reappearance of sperm in the ejaculate.

Twin pregnancy and the risk of preeclampsia: bigger placenta or relative ischemia?

OBJECTIVE: Twin pregnancies are a risk factor for preeclampsia with a reported incidence of 2-3 times higher than singleton pregnancies. Soluble fms-like tyrosine kinase 1 (sFlt1), which is a circulating antiangiogenic molecule of placental origin, plays a central role in preeclampsia by antagonizing placental growth factor (PlGF) and vascular endothelial growth factor signaling in the maternal vasculature. Increased sFlt1 and the ratio sFlt1/free PlGF have been shown to antedate clinical signs in preeclampsia. Although the cause of the upregulated sFlt1 in preeclampsia still is not understood clearly, placental ischemia with accompanying hypoxia is thought to play an important role. We therefore hypothesized that the higher risk of preeclampsia in twin pregnancies results from high sFlt1 (or sFlt1/PlGF) and that the sFlt1 upregulation was due to either relative placental hypoxia and/or increased placental mass. STUDY DESIGN: Maternal serum samples and placentas from third-trimester twin and singleton pregnancies without preeclampsia were used. Serum samples were analyzed for levels of sFlt1 and free PlGF by enzyme-linked immunosorbent assay and reported as means (in nanograms per milliliter and picograms per milliliter, respectively). Placentas were weighed and examined for content of sFlt1 and PlGF messenger RNA (mRNA) by quantitative polymerase chain reaction and hypoxia inducible factor-1alpha (HIF-1alpha) protein by Western blot. RESULTS: Soluble Flt1 concentrations in twin pregnancy maternal serum were 2.2 times higher than those that were measured in singleton pregnancy maternal serum samples (30.98 +/- 9.78 ng/mL vs 14.14 +/- 9.35 ng/mL, respectively; P = .001). Free PlGF concentrations were not significantly different between twin and singleton maternal serum samples, but the mean sFlt1/PlGF ratio of twin pregnancy maternal serum samples was 2.2 times higher than the equivalent ratio in singleton pregnancy samples (197.58 +/- 126.86 ng/mL vs 89.91 +/- 70.63 ng/mL, respectively; P = .029). Quantitative polymerase chain reaction for sFlt1 and PlGF mRNA revealed no significant differences between the 2 study groups. Western blot analysis of placental samples for HIF-1alpha revealed a mean ratio HIF-1alpha/actin of 0.53 vs 0.87, for the twins vs singletons placental samples respectively (twins showed lower HIF-1alpha, not higher). The mean weights of twin and singleton placentas were 1246 vs 716 g, respectively (P < .001). Importantly, the placental weights correlated very well with the circulating sFlt1 levels (R(2) = .75). CONCLUSION: In twin pregnancies, circulating sFlt1 levels and sFlt1/PlGF ratios were twice as high as those in singleton pregnancies. The increased serum sFlt1 levels in twin pregnancies were not accompanied by any changes in the levels of sFlt1 mRNA and HIF-1alpha protein in the twin placentas but were correlated with increased placental weight. These findings suggest that the increased risk of preeclampsia in twin pregnancies may be due to increased placental mass that leads to increased circulating levels of sFlt1.

Early serum beta-human chorionic gonadotropin in pregnancies after in vitro fertilization: contribution of treatment variables and prediction of long-term pregnancy outcome.

OBJECTIVE: Low initial serum beta hCG is a good predictor of early pregnancy failure. We sought to determine the contribution of treatment variables and the predictive value of early serum beta hCG after IVF on long-term pregnancy outcome. DESIGN: A retrospective case-control study. SETTING: An academic IVF unit. PATIENT(S): Five hundred thirty-three IVF cycles performed between 1999 and 2004, which resulted in a positive serum beta hCG level (> 10 mIU/mL) on day 13 after embryo transfer (ET). INTERVENTION(S): The study group included 281 pregnancies with initial beta hCG < or = 150 mIU/mL on day 13 after ET. Randomly selected 252 IVF cycles with initial beta hCG > 150 mIU/mL comprised the control group. Characteristics of the patients and the treatment protocols were analyzed using logistic regression, Pearson's chi-square, and Fisher's exact test. MAIN OUTCOME MEASURE(S): Primary pregnancy outcome was defined as favorable when a fetal pulse was detected, testifying to a viable gestation. Unfavorable outcome referred to chemical or ectopic pregnancies, as well as spontaneous abortions. Additionally, the two groups were followed throughout gestation. Secondary pregnancy outcome was based on the following parameters: gestational age at delivery, method of delivery, and birth weight. RESULT(S): Poor primary pregnancy outcome was encountered in 64.8% of the study group and in 22.2% of the control group. Predictors of unfavorable primary pregnancy outcome were older age, use of a short protocol, and shorter than anticipated crown-rump length. No difference was found in the secondary pregnancy outcome between the groups. Preterm labor was more prevalent in the study group, but the difference did not reach statistical significance. CONCLUSION(S): Pregnancy viability can be predicted by measuring serum beta hCG as early as on day 13 after ET. Older age, use of a short protocol, and shorter than anticipated crown-rump length are associated with early pregnancy loss. Of those who reach delivery, no significant adverse outcome is anticipated in IVF pregnancies with low initial serum beta hCG.

Atrophy-related ubiquitin ligases atrogin-1 and MuRF-1 are associated with uterine smooth muscle involution in the postpartum period.

The regulation of cell size depends on a delicate balance between protein synthesis and breakdown. Skeletal and cardiac muscle adapt to hormonal and neuronal stimuli and can rapidly hypertrophy and atrophy; however, the extent to which these processes occur in smooth muscle is less clear. Atrophy in striated muscle results from enhanced protein breakdown and is associated with a common transcriptional profile and activation of the ubiquitin-proteasome pathway, including induction of the muscle-specific ubiquitin protein ligases atrogin-1 and muscle ring-finger protein 1 (MuRF-1). Here we show that atrogin-1 is also expressed in smooth muscle, and that both atrogin-1 and MuRF-1 are upregulated in the uterus following delivery, as rapid involution occurs. While these two genes are similarly induced in all types of muscle during rapid loss of cell mass, other striated muscle atrophy-specific transcriptional changes are not observed during uterine involution, suggesting different underlying molecular mechanisms. These results raise the possibility that activation of atrogin-1 and MuRF-1 may be a common general adaptation in cells undergoing a rapid reduction in size.

Soluble endoglin contributes to the pathogenesis of preeclampsia.

Preeclampsia is a pregnancy-specific hypertensive syndrome that causes substantial maternal and fetal morbidity and mortality. Maternal endothelial dysfunction mediated by excess placenta-derived soluble VEGF receptor 1 (sVEGFR1 or sFlt1) is emerging as a prominent component in disease pathogenesis. We report a novel placenta-derived soluble TGF-beta coreceptor, endoglin (sEng), which is elevated in the sera of preeclamptic individuals, correlates with disease severity and falls after delivery. sEng inhibits formation of capillary tubes in vitro and induces vascular permeability and hypertension in vivo. Its effects in pregnant rats are amplified by coadministration of sFlt1, leading to severe preeclampsia including the HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome and restriction of fetal growth. sEng impairs binding of TGF-beta1 to its receptors and downstream signaling including effects on activation of eNOS and vasodilation, suggesting that sEng leads to dysregulated TGF-beta signaling in the vasculature. Our results suggest that sEng may act in concert with sFlt1 to induce severe preeclampsia.

Circulating angiogenic proteins in trisomy 13.

OBJECTIVE: Women who are carrying a trisomy 13 fetus are more prone to develop preeclampsia. Excess circulating soluble fms-like tyrosine kinase-1 has been implicated recently in the pathogenesis of preeclampsia. Since the fms-like tyrosine kinase-1/soluble fms-like tyrosine kinase-1 gene is located on chromosome 13q12, we hypothesized that the extra copy of this gene in trisomy 13 may lead to excess circulating soluble fms-like tyrosine kinase-1, reduced free placental growth factor level, and increased soluble fms-like tyrosine kinase-1/placental growth factor ratio. This may then contribute to the increased risk of preeclampsia that has been observed in these patients. Our objective was to characterize the maternal circulating angiogenic proteins in trisomy 13 pregnancies. STUDY DESIGN: Maternal serum samples of trisomy 13, 18, 21 and normal karyotype pregnancies were obtained from first and second trimester screening programs. We chose 17 cases of trisomy 13 that were matched for maternal age, freezer storage time, and parity with 85 normal karyotype control samples. Additionally, 20 cases of trisomy 18 and 17 cases of trisomy 21 were included. Cases and control samples were assayed for levels of soluble fms-like tyrosine kinase-1 and placental growth factor by enzyme-linked immunosorbent assay in a blinded fashion. Because of the skewed distributions of soluble fms-like tyrosine kinase-1 and placental growth factor, nonparametric analytic techniques were used, and the results are reported as median and ranges. RESULTS: In early pregnancy trisomy 13 cases and control samples, the median circulating soluble fms-like tyrosine kinase-1/placental growth factor ratios were 17.0 (range, 1.2-61.3) and 6.7 (range, 0.8-62.9), respectively (P = .003). The median soluble fms-like tyrosine kinase-1/placental growth factor ratios in trisomy 18 and 21 were 4.8 (range, 0.9-53.9) and 5.1 (range, 1.0-18.1), which were not significantly different than the control samples. Furthermore, the differences between trisomy 13 and control samples were more pronounced in the second trimester specimens than in the specimens from the first trimester. CONCLUSION: These data suggest that alterations in circulating angiogenic factors may be involved intimately in the pathogenesis of preeclampsia in trisomy 13. A larger clinical study that measures these factors longitudinally and correlates them with pregnancy outcomes is needed to further establish the link between trisomy 13, altered angiogenic factors, and preeclampsia.

Recent advances in understanding of preeclampsia.

Despite intensive research, preeclampsia still accounts for significant morbidity and mortality for the mother and the neonate, especially in developing countries. Recent studies have suggested that excess secretion of a naturally occurring anti-angiogenic molecule of placental origin referred to as soluble fms-like tyrosine kinase-1 (sFlt-1, also referred to as sVEGFR-1) may contribute to the pathogenesis of preeclampsia. sFlt-1 acts by antagonizing two pro-angiogenic molecules - vascular endothelial growth factor (VEGF) and placental growth factor (PlGF). Abnormalities in the angiogenic balance have been proposed as having a major role in the molecular cascade leading to proteinuria, hypertension, and endothelial dysfunction. Further evidence supports the hypothesis that angiogenic balance is crucial to differentiation and invasion of cytotrophoblasts. The abnormal placentation and the accompanying hypoxia may, in turn, result in more sFlt-1 production, thus leading to a vicious cycle of sFlt-1 production, eventually causing preeclampsia. These recent discoveries may facilitate the development of novel strategies for the diagnosis and therapy of preeclampsia.

Angiogenic imbalance in the pathophysiology of preeclampsia: newer insights.

Angiogenesis is the process of neovascularization from preexisting blood vessels, whereas vasculogenesis is the process of blood vessel generation from angioblast precursor cells. The human placenta undergoes high levels of angiogenesis and vasculogenesis during fetal development. Additionally, the placenta undergoes a process of vascular mimicry (also referred to as pseudovasculogenesis ) in which the placental cytotrophoblasts convert from an epithelial to an endothelial phenotype during normal fetal development. Failure of placental angiogenesis and pseudovasculogenesis during placental development has been linked to the pathogenesis of preeclampsia. It currently is believed that soluble factors released by the diseased placenta lead to clinical findings of preeclampsia. This article discusses placental vascular development in health and in disease, with a focus on accumulating recent evidence that the maternal clinical syndrome of preeclampsia is an antiangiogenic state resulting from an excess of anti-endothelial factors liberated by the diseased placenta.