Vitamin-D dysregulation in early- and late-onset preeclampsia: A gestational-age matched study.

Vitamin D deficiency has been associated with preeclampsia, however, vitamin D supplementation studies have shown equivocal data on amelioration of this disease. We hypothesize that women with preeclampsia have an altered endogenous vitamin D homeostasis that counteracts the beneficial effects of vitamin D supplementation. Our study population consisted of 66 maternal/neonate dyads: 16 early-onset (<34 weeks) preeclampsia (EOP), 16 early-onset controls (EOC), 17 late-onset (≥34 weeks) preeclampsia (LOP), and 17 late-onset controls (LOC). Plasma levels of 25-OH-D and the bioactive metabolite 1α,25-(OH)2-D were studied by ELISA. Placental expression of vitamin D transporters (cubulin and megalin), metabolic genes (CYP2R1, CYP27B1, CYP24A1), and vitamin D binding protein (GC), were studied by real-time PCR, and the nuclear and cytosolic levels of the vitamin D receptor (VDR) protein were analyzed by immunoblotting. Maternal admission, maternal postpartum, and umbilical cord blood levels of 1α,25-(OH)2-D and placental nuclear vitamin D receptor protein levels, were significantly lower in EOP compared to EOC. In contrast LOP was characterized by lower 25-OH-D levels in maternal postpartum and cord blood, and decreased placental cubulin expression compared to LOC. Both EOP and LOP showed decreased placental expression of CYP2R1 and GC compared to controls. Multivariable linear regression analysis demonstrated that preeclampsia was a significant predictor of decreased 1α,25-(OH)2-D levels in early-onset subjects, while maternal BMI, but not preeclampsia, was the main predictor of decreased 25-OH-D in late-onset subjects. The highest positive correlation between the two vitamin D metabolites was observed in LOC umbilical cord blood. Finally, paired analysis of maternal metabolites before and after delivery indicated that women without preeclampsia had better maintenance of vitamin D levels. We conclude that EOP is characterized by decreased bioactivation of vitamin D and VDR in association with fetal growth restriction (FGR). In contrast, LOP is characterized by decreased 25-OH-D levels in association with decreased placental CYP2R1 and cubulin expression; and uncoupling of the 25-OH-D with the 1α,25-(OH)2-D metabolite.

Effect of antepartum meconium staining on perinatal and neonatal outcomes among pregnancies with gastroschisis.

OBJECTIVE: To investigate the association between meconium staining and perinatal and neonatal outcomes in pregnancies with gastroschisis. METHODS: Retrospective analysis of infants with prenatally diagnosed gastroschisis born in two academic medical centers between 2008 and 2013. Neonatal outcomes of deliveries with and without meconium staining were compared. Primary outcome was defined as any of the following: neonatal sepsis, prolonged mechanical ventilation, bowel atresia or death. Secondary outcomes were preterm delivery, preterm-premature rupture of membranes (PPROM) and prolonged hospital length of stay. RESULTS: One hundred and eight infants with gastroschisis were included of which 56 (52%) had meconium staining at delivery. Infants with meconium staining had a lower gestational age at delivery (36.3 (±1.4) versus 37.0 (±1.2) weeks, p = 0.007), and a higher rate of PPROM (25% versus 8%, p = 0.03) than infants without meconium. Meconium staining was not significantly associated with the primary composite outcome or with any of its components. After adjustments, meconium staining remained significantly associated with preterm delivery at <36 weeks [odds ratio OR = 4.0, 95% confidence intervals (CI): 1.5-11.4] and PPROM (OR = 3.8, 95%CI: 1.2-14.5). CONCLUSIONS: Among infants with gastroschisis, meconium staining was associated with prematurity and PPROM. No significant increase in other adverse neonatal outcomes was seen among infants with meconium staining, suggesting a limited prognostic value of this finding.

Third trimester tubal pregnancy. A case report.

BACKGROUND: A viable tubal pregnancy is an extremely rare occurrence with an increased risk of fetal as well as maternal morbidity and mortality. We report a third trimester tubal pregnancy occurring after an interval tubal ligation. CASE: A 43-year-old woman, gravida 2 para 1, presented at 29 weeks' gestation with an asymptomatic extrauterine pregnancy and was managed expectantly in the antepartum unit. At 33 weeks the fetus was delivered for worsening umbilical artery velocimetry. Despite aggressive resuscitative efforts, the neonate did not survive. CONCLUSION: In managing an advanced extrauterine pregnancy, imaging with MRI may help diagnose and confirm suspicion raised by ultrasonography and may aid in presurgical planning and management. This case illustrates the diagnostic challenge and high neonatal mortality of an advanced tubal pregnancy.

Peripartum and neonatal outcomes of small-for-gestational-age infants with gastroschisis.

OBJECTIVES: Neonates with gastroschisis are often small for gestational age (SGA) based on population nomograms. Our objective was to evaluate the effect of SGA on perinatal and neonatal outcomes in cases of gastroschisis. METHODS: This is a retrospective study of neonates with prenatally diagnosed gastroschisis from two academic centers between 2008 and 13. Perinatal and neonatal outcomes of neonates with SGA at birth were compared with appropriate-for-gestational-age (AGA) neonates. The primary composite outcome was defined as any of the following: neonatal sepsis, short bowel syndrome at discharge, prolonged mechanical ventilation (upper quartile for the cohort), bowel atresia or death. RESULTS: We identified 112 cases of gastroschisis, 25 of whom (22%) were SGA at birth. There were no differences in adverse peripartum outcomes between SGA and AGA infants. No difference was found in the primary composite neonatal outcome (52% vs 36%, p = 0.21), but SGA infants were more likely to have prolonged mechanical ventilation (44% vs 22%, p = 0.04) and prolonged length of stay (LOS) (52% vs 22%, p = 0.007). After adjusting for GA at delivery, SGA remained associated with prolonged LOS (OR = 4.3, CI: 1.6-11.8). CONCLUSION: Among infants with gastroschisis, SGA at birth is associated with a fourfold increase in odds for prolonged LOS, independent of GA.

A multistate quality improvement program to decrease elective deliveries before 39 weeks of gestation.

OBJECTIVE: Nonmedically indicated (elective) deliveries before 39 weeks of gestation result in unnecessary neonatal morbidity. We sought to determine whether implementation of a process improvement program will decrease the rate of elective scheduled singleton early-term deliveries (37 0/7-38 6/7 weeks of gestation) in a group of diverse community and academic hospitals. METHODS: Policies and procedures for scheduling inductions and cesarean deliveries were implemented and patient and health care provider education was provided. Outcomes for scheduled singleton deliveries at 34 weeks of gestation or higher were submitted through a web-based data entry system. The rate of scheduled singleton elective early-term deliveries as well as the rates of early-term medically indicated and unscheduled deliveries, neonatal intensive care unit admissions, and singleton term fetal mortality rate were evaluated. RESULTS: A total of 29,030 scheduled singletons at 34 weeks of gestation or higher were delivered in 26 participating hospitals between January 2011 and December 2011. Elective scheduled early-term deliveries decreased from 27.8% in the first month to 4.8% in the 12th month (P<.001); rates of elective scheduled singleton early-term inductions (72%, P=.029) and cesarean deliveries (84%; P<.001) decreased significantly. There was no change in medically indicated or unscheduled early-term deliveries. Neonatal intensive care unit admissions among scheduled early-term singletons decreased nonsignificantly from 1.5% to 1.2% (P=.24). There was no increase in the term fetal mortality rate. CONCLUSION: A rapid-cycle process improvement program substantially decreased elective scheduled early-term deliveries to less than 5% in a group of diverse hospitals across multiple states. LEVEL OF EVIDENCE: III.

HPV-16 exposed mouse embryos: a potential model for pregnancy wastage.

PURPOSE: Placentas from spontaneous abortions and preterm deliveries have a higher prevalence of Human papillomavirus (HPV) compared to placentas from elective abortions and term births. The objective was to determine the effects of HPV-16 on the adhesion and implantation properties of early embryo trophoblasts. METHODS: Two-cell mouse embryos were cultured (medium G2, 5 % CO2, 37 °C) for 72-96 h and exposed to either HPV-16 rich SiHa cell lysates which were refrigerated after mechanical lysis, thawed lysates which had been frozen for freeze/thaw lysis method, or control medium, incubated (4-5 days) and evaluated by microscopy (N = 96 embryos, 3 repeated experiments). Trophoblasts were stained and images were digitized. Adhesion and dimension data were analyzed by Chi-square and t test, respectively. RESULTS: HPV-16 exposed embryos exhibited less adhesion through reduced implantation compared with the control (combined lysates 53.8 vs. 85.7 %, P < 0.05). Refrigerated and thawed lysate groups had similar reduced implantations (58.3 vs. 50.0 %). Of the embryos with implantation, 100 % in the refrigerated lysates were noted to have loose or abnormal adhesion. This was measured when embryos were noted to be lost after washes with HTF. There was no difference in trophoblast viability among the groups. Total trophoblast area was greater in the HPV-16 exposed frozen lysate group (1,881.8 ± 605.3 vs. control 848.8 ± 298.0 square units, mean ± SEM). CONCLUSIONS: HPV-16 inhibited trophoblasts adhesion needed for normal implantation, but not embryo development. Total trophoblast spread was increased after HPV-16 exposure suggesting that HPV-16 altered trophoblast migration. These results suggest that HPV-16 may induce abnormal placental growth resulting in pregnancy wastage.

Quality improvement opportunities to prevent preterm births.

Quality improvement initiatives have been successfully employed in many areas of medicine, but few have been implemented in preventing prematurity (or preterm birth), which continues to be one of the most common complications in obstetrics, and the leading cause of perinatal morbidity and mortality in the United States. Due to the complex nature of the causes of prematurity, developing and instituting a quality improvement program to prevent prematurity can be challenging. However, using proven quality improvement principles and techniques, along with institutional will and commitment, are invaluable in rapidly implementing evidence-based initiatives for the prevention of preterm births.

Remodeling of the cervix and parturition in mice lacking the progesterone receptor B isoform.

Withdrawal of progestational support for pregnancy is part of the final common pathways for parturition, but the role of nuclear progesterone receptor (PGR) isoforms in this process is not known. To determine if the PGR-B isoform participates in cervical remodeling at term, cervices were obtained from mice lacking PGR-B (PGR-BKO) and from wild-type (WT) controls before or after birth. PGR-BKO mice gave birth to viable pups at the same time as WT controls during the early morning of Day 19 postbreeding. Morphological analyses indicated that by the day before birth, cervices from PGR-BKO and WT mice had increased in size, with fewer cell nuclei/area as well as diminished collagen content and structure, as evidenced by optical density of picrosirius red-stained sections, compared to cervices from nonpregnant mice. Moreover, increased numbers of resident macrophages, but not neutrophils, were found in the prepartum cervix of PGR-BKO compared to nonpregnant mice, parallel to findings in WT mice. These results suggest that PGR-B does not contribute to the growth or degradation of the extracellular matrix or proinflammatory processes associated with recruitment of macrophages in the cervix leading up to birth. Rather, other receptors may contribute to the progesterone-dependent mechanism that promotes remodeling of the cervix during pregnancy and in the proinflammatory process associated with ripening before parturition.

Decreasing elective deliveries before 39 weeks of gestation in an integrated health care system.

OBJECTIVE: The American College of Obstetricians and Gynecologists has recommended that elective deliveries not be performed before 39 weeks of gestation, to minimize prematurity-related neonatal complications. Because a worrisome number of elective deliveries were occurring before 39 weeks of gestation in our system, we developed and implemented a program to decrease the number of these early term elective deliveries. Secondary objectives were to monitor relevant clinical outcomes. METHODS: The electronic medical records of an integrated health care system involving nine labor and delivery units in Utah were queried to establish the incidence of patients admitted for elective induction of labor or planned elective cesarean delivery. These facilities have open staff models with obstetricians, family practitioners, and certified nurse midwives. Guidelines were developed and implemented to discourage early term elective deliveries. The prevalence of early term elective deliveries was tracked and reported back regularly to the obstetric leadership and obstetric departments at each facility. RESULTS: The baseline prevalence of early term elective deliveries was 28% of all elective deliveries before the initiation of the program. Within 6 months of initiating the program, the incidence of near-term elective deliveries decreased to less than 10% and after 6 years continues to be less than 3%. A reduced length of stay in labor and delivery occurred with the introduction of the program, and there were no adverse effects on secondary clinical outcomes. CONCLUSION: With institutional commitment, it is possible to substantially reduce and sustain a decline in the incidence of elective deliveries before 39 weeks of gestation. LEVEL OF EVIDENCE: III.

A novel method of measuring reduction of nitrite-induced methemoglobin applied to fetal and adult blood of humans and sheep.

The reaction of nitrite with deoxyhemoglobin results in the production of nitric oxide and methemoglobin, a reaction recently proposed as an important oxygen-sensitive source of vasoactive nitric oxide during hypoxic and anoxic stress, with several animal studies suggesting that nitrite may have therapeutic potential. Accumulation of toxic levels of methemoglobin is suppressed by reductase enzymes present within the erythrocyte. Using a novel method of measuring methemoglobin reductase activity in intact erythrocytes, we compared fetal and adult sheep and human blood. After nitrite-induced production of 20% methemoglobin, the blood was equilibrated with carbon monoxide, which effectively stopped further production. Methemoglobin disappearance was first order in nature with specific rate constants (k x 1,000) of 12.9 +/- 1.3 min(-1) for fetal sheep, 5.88 +/- 0.26 min(-1) for adult sheep, 4.27 +/- 0.34 for adult humans, and 3.30 +/- 0.15 for newborn cord blood, all statistically different from one another. The effects of oxygen tensions, pH, hemolysis, and methylene blue are reported. Studies of temperature dependence indicated an activation energy of 8,620 +/- 1,060 calories/mol (2.06 kJ/mol), appreciably higher than would be characteristic of processes limited by passive membrane diffusion. In conclusion, the novel methodology permits absolute quantification of the reduction of nitrite-induced methemoglobin in whole blood.