Treatment and outcome of 370 cases with spontaneous or post-laser twin anemia-polycythemia sequence managed in 17 fetal therapy centers.

OBJECTIVE: To investigate the antenatal management and outcome in a large international cohort of monochorionic twin pregnancies with spontaneous or post-laser twin anemia-polycythemia sequence (TAPS). METHODS: This study analyzed data of monochorionic twin pregnancies diagnosed antenatally with spontaneous or post-laser TAPS in 17 fetal therapy centers, recorded in the TAPS Registry between 2014 and 2019. Antenatal diagnosis of TAPS was based on fetal middle cerebral artery peak systolic velocity > 1.5 multiples of the median (MoM) in the TAPS donor and < 1.0 MoM in the TAPS recipient. The following antenatal management groups were defined: expectant management, delivery within 7 days after diagnosis, intrauterine transfusion (IUT) (with or without partial exchange transfusion (PET)), laser surgery and selective feticide. Cases were assigned to the management groups based on the first treatment that was received after diagnosis of TAPS. The primary outcomes were perinatal mortality and severe neonatal morbidity. The secondary outcome was diagnosis-to-birth interval. RESULTS: In total, 370 monochorionic twin pregnancies were diagnosed antenatally with TAPS during the study period and included in the study. Of these, 31% (n = 113) were managed expectantly, 30% (n = 110) with laser surgery, 19% (n = 70) with IUT (± PET), 12% (n = 43) with delivery, 8% (n = 30) with selective feticide and 1% (n = 4) underwent termination of pregnancy. Perinatal mortality occurred in 17% (39/225) of pregnancies in the expectant-management group, 18% (38/215) in the laser group, 18% (25/140) in the IUT (± PET) group, 10% (9/86) in the delivery group and in 7% (2/30) of the cotwins in the selective-feticide group. The incidence of severe neonatal morbidity was 49% (41/84) in the delivery group, 46% (56/122) in the IUT (± PET) group, 31% (60/193) in the expectant-management group, 31% (57/182) in the laser-surgery group and 25% (7/28) in the selective-feticide group. Median diagnosis-to-birth interval was longest after selective feticide (10.5 (interquartile range (IQR), 4.2-14.9) weeks), followed by laser surgery (9.7 (IQR, 6.6-12.7) weeks), expectant management (7.8 (IQR, 3.8-14.4) weeks), IUT (± PET) (4.0 (IQR, 2.0-6.9) weeks) and delivery (0.3 (IQR, 0.0-0.5) weeks). Treatment choice for TAPS varied greatly within and between the 17 fetal therapy centers. CONCLUSIONS: Antenatal treatment for TAPS differs considerably amongst fetal therapy centers. Perinatal mortality and morbidity were high in all management groups. Prolongation of pregnancy was best achieved by expectant management, treatment by laser surgery or selective feticide. © 2020 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.

Doppler abnormalities in monochorionic diamniotic twin pregnancies with discordant growth.

OBJECTIVE: We studied whether abnormal umbilical artery (UA) Doppler flow velocity waveforms occur with higher frequency in monochorionic diamniotic (MCDA) twin gestations with discordant fetal growth and whether this impacted neonatal outcome. STUDY DESIGN: We performed a retrospective study of MCDA twin pairs. We collected data from an electronic medical record. We classified pregnancies as discordant if there was at least 20% birth weight discordance. Abnormal UA Doppler velocity waveforms included absent or reversed end diastolic flow. We analyzed the data with chi square, Student's t-test and analysis of variance as appropriate. RESULT: Seventy-three twin pairs met criteria for inclusion, including 16 with discordant growth. The discordant group was significantly more affected with twin-to-twin transfusion syndrome (TTTS) (P=0.02). The smaller fetuses in discordant pairs were more likely to display abnormal UA Doppler flow velocity waveforms (P<0.01). These neonates also had lower Apgar scores (P=0.03) and were more likely to require care in a neonatal intensive care unit. Our findings persisted after excluding pregnancies with TTTS. CONCLUSION: In MCDA twin gestations complicated by discordant growth, there is an increased frequency of abnormal UA Doppler flow velocity waveforms in small fetuses, and these neonates face clinical challenges after birth.

Evaluating the cost-effectiveness of prenatal surgery for myelomeningocele: a decision analysis.

OBJECTIVE: To determine whether prenatal myelomeningocele repair is a cost-effective strategy compared to postnatal repair. METHODS: Decision-analysis modeling was used to calculate the cumulative costs, effects and incremental cost-effectiveness ratio of prenatal myelomeningocele repair compared with postnatal repair in singleton gestations with a normal karyotype that were identified with myelomeningocele between T1 and S1. The model accounted for costs and quality-adjusted life years (QALYs) in three populations: (1) myelomeningocele patients; (2) mothers carrying myelomeningocele patients; and (3) possible future siblings of these patients. Sensitivity analysis was performed using one-way, two-way and Monte Carlo simulations. RESULTS: Prenatal myelomeningocele repair saves $ 2 066 778 per 100 cases repaired. Additionally, prenatal surgery results in 98 QALYs gained per 100 repairs with 42 fewer neonates requiring shunts and 21 fewer neonates requiring long-term medical care per 100 repairs. However, these benefits are coupled to 26 additional cases of uterine rupture or dehiscence and one additional case of neurologic deficits in future offspring per 100 repairs. Results were robust in sensitivity analysis. CONCLUSION: Prenatal myelomeningocele repair is cost effective and frequently cost saving compared with postnatal myelomeningocele repair despite the increased likelihood of maternal and future pregnancy complications associated with prenatal surgery.

Assessment of the fetal thymus by two- and three-dimensional ultrasound during normal human gestation and in fetuses with congenital heart defects.

OBJECTIVES: Our objectives were to compare the size and volume of the developing fetal thymus obtained by two-dimensional ultrasound (2D-US) and three-dimensional ultrasound (3D-US), develop normative data for thymus volume (TV), and investigate TV in fetuses with congenital heart disease (CHD) and normal twin gestations. METHODS: We studied 321 fetuses (gestational age (GA): 17-39 weeks) including 238 normal singletons, 64 normal twins and 19 singleton fetuses with CHD. We used 2D-US to assess fetal thymus maximum transverse diameter (MTD), maximum transverse area (MTA), anteroposterior diameter (APD) and superoinferior diameter (SID). TV was obtained by 3D-US using virtual organ computer-aided analysis. Measurements were adjusted for estimated fetal weight where appropriate. Linear regression analysis, general linear models and Fisher's Z-transformation were used where appropriate. A nomogram of fetal TV based on singleton gestations was produced according to previously published methods. RESULTS: Ultrasound assessment of the fetal thymus was possible in 95.3% (306/321) of cases. Both 3D-US and 2D-US measurements were significantly correlated with GA (TV r = 0.989; MTA r = 0.918; MTD r = 0.884; APD r = 0.849; and SID r = 0.816; all P < 0.05). After Fisher's Z-transformation, the correlation between the TV and GA was significantly stronger than that between any individual 2D-US measurement and GA (P < 0.05). Normal twin fetuses had TVs similar to those of singletons adjusted for estimated fetal weight and GA (P = 0.85). TV adjusted for estimated fetal weight and GA was significantly lower in fetuses with CHD than in normal singletons (P < 0.05). CONCLUSION: 2D-US and 3D-US are useful tools for evaluation of the size and volume of the human fetal thymus through gestation. Fetal TV by 3D-US seems to reflect normal development of the thymus in utero better than do 2D-US measurements. Lower TV should be expected in association with CHDs.

The role of urinary soluble endoglin in the diagnosis of pre-eclampsia: comparison with soluble fms-like tyrosine kinase 1 to placental growth factor ratio.

OBJECTIVE: Endoglin, an anti-angiogenic glycoprotein expressed on endothelial cells, has been proposed recently as a biomarker of pre-eclampsia (PE). Given that PE is characterised by an imbalance of angiogenic factors, we sought to determine the clinical utility of urinary soluble endoglin, relative to the soluble fms-like tyrosine kinase 1 to placental growth factor (PlGF) ratio, in the diagnosis of PE during gestation. DESIGN: Prospective observational cohort. SETTING: Tertiary referral university hospital. POPULATION: Two hundred and thirty-four pregnant women were enrolled prospectively in the following groups: healthy controls, n = 63; gestational age (GA), median (interquartile range), 33 weeks (27-39 weeks); chronic hypertension, n = 27; GA, 33 weeks (30-36 weeks); mild PE, n = 38; GA, 37 weeks (34-40 weeks); severe PE, n = 106; GA, 32 weeks (29-37 weeks). METHODS: Free urinary levels of soluble endoglin, soluble fms-like tyrosine kinase 1 and PlGF were measured by sensitive and specific immunoassay. Levels for all urinary analytes were normalised to creatinine. MAIN OUTCOME MEASURES: Urinary soluble endoglin, and the soluble fms-like tyrosine kinase 1 to PlGF ratio. RESULTS: In healthy controls, urinary soluble endoglin levels were increased significantly at term relative to those earlier in gestation. Severe PE was characterised by an increased urinary level of soluble endoglin, soluble fms-like tyrosine kinase 1, protein to creatinine ratio and soluble fms-like tyrosine kinase 1 to PlGF ratio compared with all other groups. There was a direct correlation between urinary soluble endoglin and proteinuria that remained after GA correction (R = 0.382, P < 0.001). Urinary soluble endoglin could not differentiate mild PE from severe preterm PE. Overall, soluble endoglin had the ability to discriminate PE from chronic hypertension and healthy controls only in women who were evaluated at <37 weeks of GA. The sensitivity, specificity and accuracy of urinary soluble endoglin alone in the diagnosis of PE or in the identification of women with PE requiring a mandated delivery before 37 weeks of gestation were 70%, 86% and 76%, respectively. These values were inferior to those of the soluble fms-like tyrosine kinase 1 to PlGF ratio (P < 0.001). The addition of urinary soluble endoglin did not improve the diagnostic accuracy of the soluble fms-like tyrosine kinase 1 to PlGF ratio alone. CONCLUSIONS: We have provided evidence that soluble endoglin is present and elevated in the urine of women who develop preterm PE. Urinary soluble endoglin has only limited ability to determine the severity of PE and to distinguish between PE and chronic hypertension both preterm and at term. Compared with urinary soluble endoglin, the soluble fms-like tyrosine kinase 1 to PlGF ratio remains a better marker of disease presence, severity and outcome.

Regulation of monocyte chemotactic protein-1 expression in human endometrial stromal cells by estrogen and progesterone.

There is a cyclicity in the number of endometrial macrophages that is most likely secondary to changes in steroid hormone levels. One cytokine that controls macrophage migration is monocyte chemotactic protein-1 (MCP-1). In the endometrium, highest levels of MCP-1 are detected perimenstrually, when estrogen levels are low; however, when estrogen levels are high (around the time of ovulation), MCP-1 levels are lowest. We hypothesized that sex steroids may be involved in the regulation of macrophage migration by regulating MCP-1 expression. We investigated the regulation of MCP-1 expression in human endometrial stromal cells by estradiol 17beta (E2) and progestins. We found that MCP-1 mRNA levels decreased in response to E2 (5 x 10(-8) M), with biphasic nadirs at 8 h and 24 h. MCP-1 protein production was also inhibited by E2 in a concentration-dependent manner. Tamoxifen, an anti-estrogen, alone (10(-7) M) did not affect MCP-1 expression, but it reversed the E2-induced inhibition up to 80%. Progesterone (10(-7) M) alone slightly decreased MCP-1 levels, and the combination of E2 and progesterone further decreased them, but that decrease was not different from that observed using E2 treatment alone. In summary, we found that E2 inhibits MCP-1 expression in endometrial stromal cells, and we speculate that E2 may control endometrial macrophage migration by regulating MCP-1 expression.

Follicular fluid of women with endometriosis stimulates the proliferation of endometrial stromal cells.

The peritoneal environment in endometriosis is known to have growth-promoting effects on endometrial cells. To investigate whether follicular fluid, a contributor to the peritoneal fluid, stimulates endometrial cell proliferation, we incubated endometrial stromal cells in culture with various dilutions of follicular fluid obtained from women with or without endometriosis undergoing oocyte retrieval for in-vitro fertilization. Cell proliferation assays were performed using follicular fluid from 28 women (without endometriosis, n = 13; with endometriosis, n = 15) in eight different endometrial stromal cell culture set-ups. Cell proliferation was assessed by a colorimetric method. Maximum cell proliferation was detected when endometrial cells were incubated with 50% dilution of follicular fluid for 48 h. Follicular fluid from women with endometriosis induced significantly higher cell proliferation than follicular fluid from women without endometriosis (P < 0.05). Our findings indicate that follicular fluid contents may contribute to the growth-promoting factors in the peritoneal fluid of women with endometriosis.

Growth-regulated alpha expression in human preovulatory follicles and ovarian cells.

PROBLEM: Around the time of ovulation the number of neutrophils increases in the theca of the leading follicle. We hypothesized that growth-regulated alpha (GRO alpha), a neutrophil chemoat-tractant/activating factor, may be a modulator of periovulatory neutrophil chemotaxis. METHOD: GRO alpha levels were measured in follicular fluids (n = 61). Granulosa-lutein and ovarian stromal cells were also cultured. After experimental paradigms, GRO alpha mRNA was evaluated by Northern analysis, GRO alpha in follicular fluids, and culture supernatants were quantified using ELISA. RESULTS: In follicular fluids the mean pre-human chorionic gonadotropin (hCG) GRO alpha level was 51 +/- 24 (+/- SEM) pg/ml, post-hCG it was 210 +/- 20 pg/ml (P = 0.04). GRO was produced constitutively by ovarian stromal and granulosa-lutein cells. Interleukin-alpha (IL-1 alpha) and tumor necrosis factor-alpha (TNF-alpha) further stimulated GRO alpha production. Treatment of stromal cells with hCG also stimulated GRO alpha production. CONCLUSION: GRO alpha is a constituent of periovulatory follicular fluid. Ovarian stromal and granulosa-lutein cells express the GRO alpha mRNA and produce the protein. The regulation of GRO alpha by cytokines and hCG suggests that GRO alpha may play a role in the process of ovulation.

Growth-regulated alpha expression in the peritoneal environment with endometriosis.

OBJECTIVE: To investigate the presence and modulation of growth-regulated alpha, a member of the chemokine family with neutrophil chemotactic activity, in the peritoneal fluid of women with or without endometriosis. METHODS: Peritoneal fluid samples were obtained at laparoscopy from 63 women with endometriosis and 19 fertile women without endometriosis. Endometrial tissue was obtained from uteri after hysterectomy for reasons other than endometrial disease or from endometrial biopsies of reproductive-age women. Cellular RNA was extracted and northern blots were hybridized with an oligonucleotide probe complementary to a specific sequence of growth-regulated alpha messenger RNA. Growth-regulated alpha in peritoneal fluid and culture supernatant was quantified using enzyme-linked immunosorbent assay. Statistical analyses were performed using Kruskal-Wallis and Mann-Whitney tests. RESULTS: The median (range) concentration of growth-regulated alpha in peritoneal fluid samples from 19 normal fertile women was 27 pg/mL (0-108), from 24 women with moderate endometriosis 34 pg/mL (8-150), and from seven with severe endometriosis was 73 pg/mL (10-221) (P = .04, P = .01, respectively). In the moderate and severe endometriosis groups, the levels of growth-regulated alpha were significantly higher in the peritoneal fluid of women with untreated endometriosis (73 pg/mL [10-221]) than in women with medically treated endometriosis (25 pg/mL [8-47]). In mesothelial and endometrial stromal cells in culture, growth-regulated alpha messenger RNA and protein were detectable constitutively; however, both interleukin-1 alpha and tumor necrosis factor-alpha induced higher levels of growth-regulated alpha messenger RNA and protein in a dose- and time-dependent manner. CONCLUSIONS: Growth-regulated alpha levels are elevated in the peritoneal fluid of women with moderate and severe endometriosis. This chemotactic factor, which acts via the interleukin-8 receptor, may play a role in the pathogenesis of endometriosis.