[Peculiarities of treatment of ulcerative gastrointestinal hemorrhage in pregnant women].

The occurrence rate of gastrointestinal hemorrhage (GIH) of nonvaricosal genesis in pregnant women was analyzed. The risk of complications occurrence in the pregnancy course while performing local endoscopic hemostasis and prophylaxis of the hemorrhage recurrence occurrence was established. Application of elaborated treatment method for GIH of nonvaricosic genesis in pregnant women have promoted reduction of the severe complications rate in the pregnancy course, applying elimination of the vasoconstrictor and uterotonic effects of adrenalin, reduction of esophagogastroduodenoscopy duration. While application of this procedure in pregnant women of a main group operative cessation of GIH was not applied. In a comparison group a hemostasis, using operative way, was done in 2 (13.3%) women patients with subsequent occurrence of preeclampsy, what resulted in antenathal fetal death.

[Management of reproductive-age women with epilepsy].

Medical treatment of epilepsy is quite different for women than for men. It is known that estrogen facilitates while progesterone inhibits the generation of epileptic seizures. Due to the direct neuronal effects of estrogen, progesterone, and their metabolites, as well as the cyclical nature of sex hormone release, women are particularly susceptible to the effects of these hormones on seizure frequency and severity. Antiepileptic drugs (AEDs) may result in reproductive endocrine disorders, decreased effects of oral contraceptives, or congenital malformations. On the other hand, if AED treatment is insufficient, seizures may influence reproductive endocrine disorders or cause fetal death. Physicians should minimize these risks through preconception counseling and appropriate treatment of women with epilepsy who are of reproductive age.

Possible role of the α7 nicotinic receptors in mediating nicotine's effect on developing lung - implications in unexplained human perinatal death.

BACKGROUND: It is well known that maternal smoking during pregnancy is very harmful to the fetus. Prenatal nicotine absorption, in particular, is associated with alterations in lung development and functions at birth and with respiratory disorders in infancy. Many of the pulmonary disorders are mediated by the interaction of nicotine with the nicotinic receptors (nAChRs), above all with the α7 nAChR subunits that are widely expressed in the developing lung. To determine whether the lung hypoplasia frequently observed in victims of sudden fetal and neonatal death with a smoker mother may result from nicotine interacting with lung nicotinic receptors, we investigated by immunohistochemistry the possible presence of the α7 nAChR subunit overexpression in these pathologies. METHODS: In lung histological sections from 45 subjects who died of sudden intrauterine unexplained death syndrome (SIUDS) and 15 subjects who died of sudden infant death syndrome (SIDS), we applied the radial alveolar count (RAC) to evaluate the degree of lung maturation, and the immunohistochemical technique for nAChRs, in particular for the α7 nAChR subunit identification. In the same cases, an in-depth study of the autonomic nervous system was performed to highlight possible developmental alterations of the main vital centers located in the brainstem. RESULTS: We diagnosed a "lung hypoplasia", on the basis of RAC values lower than the normal reference values, in 63% of SIUDS/SIDS cases and 8% of controls. In addition, we observed a significantly higher incidence of strong α7 nAChR immunostaining in lung epithelial cells and lung vessel walls in sudden fetal and infant death cases with a smoker mother than in age-matched controls. Hypoplasia of the raphe, the parafacial, the Kölliker-Fuse, the arcuate and the pre-Bötzinger nuclei was at the same time present in the brainstem of these victims. CONCLUSIONS: These findings demonstrate that when crossing the placenta, nicotine can interact with nicotinic receptors of both neuronal and non-neuronal cells, leading to lung and nervous system defective development, respectively. This work stresses the importance of implementing preventable measures to decrease the noxious potential of nicotine in pregnancy.

Group B Streptococcus ß-hemolysin/cytolysin breaches maternal-fetal barriers to cause preterm birth and intrauterine fetal demise in vivo.

BACKGROUND: Maternal vaginal colonization with Streptococcus agalactiae (Group B Streptococcus [GBS]) is a precursor to chorioamnionitis, fetal infection, and neonatal sepsis, but the understanding of specific factors in the pathogenesis of ascending infection remains limited. METHODS: We used a new murine model to evaluate the contribution of the pore-forming GBS ß-hemolysin/cytolysin (ßH/C) to vaginal colonization, ascension, and fetal infection. RESULTS: Competition assays demonstrated a marked advantage to ßH/C-expressing GBS during colonization. Intrauterine fetal demise and/or preterm birth were observed in 54% of pregnant mice colonized with wild-type (WT) GBS and 0% of those colonized with the toxin-deficient cylE knockout strain, despite efficient colonization and ascension by both strains. Robust placental inflammation, disruption of maternal-fetal barriers, and fetal infection were more frequent in animals colonized with WT bacteria. Histopathologic examination revealed bacterial tropism for fetal lung and liver. CONCLUSIONS: Preterm birth and fetal demise are likely the direct result of toxin-induced damage and inflammation rather than differences in efficiency of ascension into the upper genital tract. These data demonstrate a distinct contribution of ßH/C to GBS chorioamnionitis and subsequent fetal infection in vivo and showcase a model for this most proximal step in GBS pathogenesis.

Detection of S100B in maternal blood before and after fetal death.

BACKGROUND: S100B is a brain damage biomarker. When measured immediately after birth, it reflects neonatal brain damage following asphyxia. In this study, we used feticide as a novel model of fetal brain damage. We examined whether such damage is reflected by a rise in S100B in maternal blood before delivery. METHODS: Eight pregnant women were recruited between January and July 2012. Maternal blood samples were drawn before and after feticide at predetermined time points (0, 15, 30, 60, 120, and 240 min). S100B, lactate dehydrogenase, creatine kinase, and creatinine concentrations were measured by standard human ELISA and chemical analyzer. RESULTS: No significant difference was noted between S100B levels before and after feticide, neither in non-specific cell death markers (lactate dehydrogenase and creatine kinase), which remained within normal range. S100B ranged between 0.015-0.04 µg/L through all the predetermined time points. CONCLUSION: No statistically significant differences were demonstrated in S100B levels before and after feticide.

Folic acid protects against lipopolysaccharide-induced preterm delivery and intrauterine growth restriction through its anti-inflammatory effect in mice.

Increasing evidence demonstrates that maternal folic acid (FA) supplementation during pregnancy reduces the risk of neural tube defects, but whether FA prevents preterm delivery and intrauterine growth restriction (IUGR) remains obscure. Previous studies showed that maternal lipopolysaccharide (LPS) exposure induces preterm delivery, fetal death and IUGR in rodent animals. The aim of this study was to investigate the effects of FA on LPS-induced preterm delivery, fetal death and IUGR in mice. Some pregnant mice were orally administered with FA (0.6, 3 or 15 mg/kg) 1 h before LPS injection. As expected, a high dose of LPS (300 µg/kg, i.p.) on gestational day 15 (GD15) caused 100% of dams to deliver before GD18 and 89.3% of fetuses dead. A low dose of LPS (75 µg/kg, i.p.) daily from GD15 to GD17 resulted in IUGR. Interestingly, pretreatment with FA prevented LPS-induced preterm delivery and fetal death. In addition, FA significantly attenuated LPS-induced IUGR. Further experiments showed that FA inhibited LPS-induced activation of nuclear factor kappa B (NF-κB) in mouse placentas. Moreover, FA suppressed LPS-induced NF-κB activation in human trophoblast cell line JEG-3. Correspondingly, FA significantly attenuated LPS-induced upregulation of cyclooxygenase (COX)-2 in mouse placentas. In addition, FA significantly reduced the levels of interleukin (IL)-6 and keratinocyte-derived cytokine (KC) in amniotic fluid of LPS-treated mice. Collectively, maternal FA supplementation during pregnancy protects against LPS-induced preterm delivery, fetal death and IUGR through its anti-inflammatory effects.

Metoclopramide in pregnancy and risk of major congenital malformations and fetal death.

IMPORTANCE: Metoclopramide, a drug frequently used for nausea and vomiting in pregnancy, is thought to be safe, but information on the risk of specific malformations and fetal death is lacking. OBJECTIVE: To investigate the safety of metoclopramide use in pregnancy. DESIGN, SETTING, AND PARTICIPANTS: Register-based cohort study in Denmark, 1997-2011. From a cohort of 1,222,503 pregnancies, metoclopramide-exposed and unexposed women were matched (1:4 ratio) on the basis of age, calendar year, and propensity scores. MAIN OUTCOMES AND MEASURES: Primary outcomes were major congenital malformations overall, 20 individual malformation categories (selected according to power criteria), spontaneous abortion, and stillbirth. In matched analyses, logistic regression was used to estimate prevalence odds ratios of malformations and Cox regression to estimate hazard ratios (HRs) of spontaneous abortion. RESULTS: Among 28,486 women exposed to metoclopramide in the first trimester, 721 had an infant with a major congenital malformation (25.3 [95% CI, 23.5-27.1] cases per 1000 births), compared with 3024 among 113,698 unexposed women (26.6 [95% CI, 25.7-27.5] per 1000 births). There were no significant associations between metoclopramide use and malformations overall (prevalence odds ratio, 0.93 [95% CI, 0.86-1.02]) or any of the 20 individual malformation categories, eg, neural tube defects, transposition of great vessels, ventricular septal defect, atrial septal defect, tetralogy of Fallot, coarctation of the aorta, cleft lip, cleft palate, anorectal atresia/stenosis, and limb reduction (upper limit of 95% CI below 2.0 for 17 of 20 categories). Metoclopramide was not associated with increased risk of spontaneous abortion (757 cases [20.0 {95% CI, 18.5-21.4} per 1000] among 37,946 metoclopramide-exposed women and 9414 cases [62.1 {95% CI, 60.9-63.3} per 1000] among 151,661 unexposed women; HR, 0.35 [95% CI, 0.33-0.38]) and stillbirth (142 cases [3.5 {95% CI, 2.9-4.1} per 1000] among 40,306 metoclopramide-exposed women and 634 cases [3.9 {95% CI, 3.6-4.2} per 1000] among 161,098 unexposed women; HR, 0.90 [95% CI, 0.74-1.08]). CONCLUSIONS AND RELEVANCE: Metoclopramide use in pregnancy was not associated with increased risk of major congenital malformations overall, any of the 20 individual malformation categories assessed, spontaneous abortion, or stillbirth. These safety data may help inform decision making when treatment with metoclopramide is considered in pregnancy.

Synergistic effects of pyrrolizidine alkaloids and lipopolysaccharide on preterm delivery and intrauterine fetal death in mice.

Preterm birth is the leading cause of death for newborn infants, and lipopolysaccharide (LPS) is commonly used to induce preterm delivery in experimental animals. Pyrrolizidine alkaloids (PAs) are widespread and occur in foods, herbs, and other plants. This study was to investigate the synergistic effects of LPS and two representative PAs, retrorsine (RTS) and monocrotaline (MCT), on preterm delivery and fetal death. Pregnant Kunming mice were divided into seven groups: control, RTS, MCT, LPS, RTS+LPS and two MCT+LPS groups. Animals in PAs and PAs+LPS groups were dosed intragastrically with RTS (10mg/kg) or MCT (20 mg/kg or 60 mg/kg) from gestational day (GD) 9 to GD16; mice given LPS were injected intraperitoneally with 150 µg/kg on GD15.5. Latencies to delivery, numbers of pups live and dead at birth were recorded, and livers of live neonates were collected. The incidence of LPS-induced preterm birth was enhanced in dams pretreated with MCT, and combination of PAs and LPS increased fetal mortality from PAs. The enhancement of LPS-induced preterm delivery and fetal demise in animals exposed chronically to PAs and other substances found in foods and beverages consumed widely by humans merits further focused investigation.

In utero phthalate effects in the female rat: a model for MRKH syndrome.

Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome is characterized by uterine and vaginal canal aplasia in normal karyotype human females and is a syndrome with poorly defined etiology. Reproductive toxicity of phthalate esters (PEs) occurs in rat offspring exposed in utero, a phenomenon that is better studied in male offspring than females. The current study reports female reproductive tract malformations in the Sprague-Dawley rat similar to those characteristic of MRKH syndrome, following in utero exposure to a mixture of 5 PEs. We determined that females are ∼2-fold less sensitive to the effects of the 5-PE mixture than males for reproductive tract malformations. We were not fully successful in defining the critical exposure period for females; however, incidence of malformations was 88% following dosing from GD8 to 19 versus 22% and 0% for GD8-13 and GD14-19, respectively. Overall, this study provides valuable information regarding female vulnerability to in utero phthalate exposure and further characterizes a potential model for the human MRKH syndrome.

Exposure of mares to processionary caterpillars (Ochrogaster lunifer) in early pregnancy: an additional dimension to equine amnionitis and fetal loss.

REASONS FOR PERFORMING STUDY: Equine amnionitis and fetal loss (EAFL) is an unusual form of abortion in mid- to late-gestation mares, first identified in Australia in 2004. It has been shown that both whole processionary caterpillars (Ochrogaster lunifer) and their shed exoskeletons can induce abortion in mares during midgestation. These abortions exhibited gross pathology and bacteriology results consistent with field cases of EAFL. OBJECTIVES: To determine whether exposure of mares to the shed exoskeletons of processionary caterpillars can induce abortion in the preplacentation (<35 days' gestation) and early placentation (45-60 days) stages of pregnancy. STUDY DESIGN: In vivo experimental study. METHODS: Mares less than 35 days' gestation and between 45 and 60 days' gestation were exposed to a slurry of shed processionary caterpillar exoskeletons by nasogastric intubation. Mares were monitored by clinical examination daily. Transrectal ultrasonography was performed daily (control and treated preplacentation mares, treated early placentation mares) or every second day (control early placentation mares). Uterine swabs were collected from mares that aborted. All live foals underwent a clinical examination. Placentas were examined, with sampling for bacteriology and histopathology if appropriate. RESULTS: Abortions occurred in treated mares in both experiments without signs of impending abortion. One mare aborted in the embryonic stage experiment and 2 in the early placentation experiment. Embryonic and fetal death was detected on transrectal ultrasonography prior to abortion. In the early placentation experiment, one foal was born 5 weeks preterm and was very small, with laxity of the tendons in all limbs. Enteric or environmental bacteria, consistent with EAFL, were isolated from the mares that aborted. Focal mucoid placentitis lesions were present on the placentas of 2 treated mares, one from each experiment. CONCLUSIONS AND POTENTIAL RELEVANCE: Processionary caterpillar exposure may be associated with EAFL-related embryonic and early fetal loss in mares. Processionary caterpillars may also play a role in the occurrence of focal mucoid placentitis.

[The use of foeticide in late termination of pregnancies in Denmark]. / Brug af foetocidium ved sene provokerede aborter i Danmark.

As a result of prenatal screening the number of late terminations of pregnancy is increasing in Denmark. The fact that the foetus sometimes shows signs of life after the termination is a large concern for health-care staff and parents. In other countries foeticide is performed intrauterinely to ensure that the foetus is dead before the delivery. In Denmark this method is legally used in foetal reduction, but not in late termination of pregnancy. In the light of international literature on the subject, perspectives on foeticide in late termination of pregnancy are explored.

The CRTH2 agonist Pyl A prevents lipopolysaccharide-induced fetal death but induces preterm labour.

We have previously demonstrated that the anti-inflammatory prostaglandin 15-deoxy-Δ 12,14-prostaglandin J(2) (15dPGJ(2)) delays inflammation-induced preterm labour in the mouse and improves pup survival through the inhibition of nuclear factor-κB (NF-κB) by a mechanism yet to be elucidated. 15dPGJ(2) is an agonist of the second prostaglandin D(2) receptor, chemoattractant receptor homologous to the T helper 2 cell (CRTH2). In human T helper cells CRTH2 agonists induce the production of the anti-inflammatory interleukins IL-10 and IL-4. We hypothesized that CRTH2 is involved in the protective effect of 15dPGJ(2) in inflammation-induced preterm labour in the murine model. We therefore studied the effects of a specific small molecule CRTH2 agonist on preterm labour and pup survival. An intrauterine injection of lipopolysaccharide (LPS) was administered to CD1 mice at embryonic day 16, ± CRTH2 agonist/vehicle controls. Mice were killed at 4.5 hr to assess fetal wellbeing and to harvest myometrium and pup brain for analysis of NF-κB, and T helper type 1/2 interleukins. To examine the effects of the CRTH2 agonist on LPS-induced preterm labour, mice were allowed to labour spontaneously. Direct effects of the CRTH2 agonist on uterine contractility were examined ex vivo on contracting myometrial strips. The CRTH2 agonist increased fetal survival from 20 to 100% in LPS-treated mice, and inhibited circular muscle contractility ex vivo. However, it augmented LPS-induced labour and significantly increased myometrial NF-κB, IL-1ß, KC-GRO, interferon-γ and tumour necrosis factor-α. This suggests that the action of 15dPGJ(2) is not via CRTH2 and therefore small molecule CRTH2 agonists are not likely to be beneficial for the prevention of inflammation-induced preterm labour.

Transvaginal administration of intraamniotic digoxin prior to dilation and evacuation.

BACKGROUND: Transabdominal injection of digoxin into the amniotic fluid or fetus to induce fetal demise before dilation and evacuation (D&E) abortion has become common practice since the passage of the Partial-Birth Abortion Ban Act in 2007. STUDY DESIGN: We performed a prospective study to assess the feasibility of transvaginal administration of intraamniotic digoxin the day before D&E. All women between 18 0/7 and 23 5/7 weeks of gestation seeking termination from December 2009 to May 2011 were approached for study participation. Women who declined participation were asked to identify their primary rationale. For women declining study participation, transection of the umbilical cord during D&E was performed to meet the requirements of the ban. RESULTS: Over 18 months, 134 women met study entry criteria and 108 (81%) declined to participate. Of the 26 women who enrolled, 1.0 mg undiluted digoxin was successfully administered transvaginally in 24 (92%, 95% confidence interval 75%-99%). The most common reasons for declining participation were discomfort with preoperatively inducing fetal demise (37%) and desire to avoid a medically unnecessary medication (36%). CONCLUSIONS: Transvaginal administration of digoxin is a feasible alternative to transabdominal administration to induce preoperative fetal demise. The majority of women decline digoxin administration when an alternative is available.

Inflammation or infection at the time of second trimester induced abortion.

BACKGROUND: Induced abortion via dilation and evacuation (D&E) typically involves cervical preparation. Some clinicians also induce fetal death in the second trimester. We designed this study to determine if the combination of intra-amniotic digoxin and osmotic dilators induced intrauterine inflammatory changes. STUDY DESIGN: Twenty-two women requesting abortion at 19-23 weeks gestation had amniotic fluid sent for measurement of interleukin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis factor-α (TNF-α), white blood cell (WBC) count and anaerobic and aerobic cultures on day 1, before dilators and digoxin amnioinjection. Sampling was repeated on Day 2, prior to D&E. RESULTS: All subjects had significantly elevated IL-6, IL-8 and TNF-α in the amniotic fluid on Day 2. The median difference for IL-6 was 19,893.4 pg/mL (p<.0001), 7040.7 pg/mL (p<.0001) for IL-8 and 181.0 pg/mL (p<.0001) for TNF-α. There was no significant difference in WBC count. There were no clinically significant positive cultures and no clinical infections. CONCLUSION: The administration of intra-amniotic digoxin and the placement of osmotic dilators prior to D&E create an intrauterine inflammatory response.

Effect of estrogen on rat placental development depending on gestation stage.

We examined the sequential histopathological changes in the placenta from rats exposed to estrogen. 17 ß-estrogiol-3-benzoate was intraperitoneally administered at 100 µg/animal/day during GD 6 to GD 8 (GD6-8 treated group), GD 9 to GD 11 (GD9-11 treated group) and GD 12 to GD 14 (GD12-14 treated group), and the placentas were sampled on GDs 11, 13, 15, 17, and 21. Fetal mortality rates were increased up to approximately 50% in the GD6-8 and 9-11 treated groups, but there was no change of fetal weight on GD 21. An increase in placental weight and a reduction in fetal/placental weight ratio were detected during GD 17 to GD 21 in the GD6-8 treated group. Histopathologically, hypoplasia of metrial gland was detected with defective development of spiral arteries in the GD6-8 and GD9-11 treated groups. A decrease in the thickness of metrial gland was observed from GD 11 onwards in the GD6-8 treated group and from GD 13 onwards in the GD9-11 treated group. The endovascular trophoblasts invaded into the spiral arteries in the deep part of metrial gland in these treated groups. The number of phospho-histone H3 positive cells was decreased on GD 11 or GD 13 in these groups. In the decidua basalis, transitory necrosis was observed with hemorrhage on GD 13 in the GD6-8 and GD9-11 treated groups. In the labyrinth zone, cystic dilatation of the sinusoid was observed with congestion in the GD6-8 treated group, resulting in an increased placental weight. Therefore, we consider that estrogen inhibits the proliferation of decidualized endometrial stromal cells in the metrial gland, and leads to metrial gland hypoplasia with less development of the spiral arteries. The reduced utero-placental blood flow is supposed to be one of the important factors for poor reproductive performance.

Cancer chemotherapeutic agents as human teratogens.

BACKGROUND: Cancer is the second leading cause of death among women of reproductive age. Although the coincidence of pregnancy and cancer is rare and treatment may sometimes be safely delayed, the use of chemotherapeutic agents in pregnancy is sometimes unavoidable or inadvertent. METHODS: We review the literature for the use of antineoplastic agents in single-agent and combination therapy from 1951 through June 2012. We also summarize the evidence relating to teratogenicity of disorder-specific combination chemotherapy treatments for those malignancies frequently encountered in women of childbearing age. Major endpoints were called "adverse pregnancy outcomes" (APOs), to include structural anomalies (congenital malformations), functional defects, blood or electrolyte abnormalities, stillbirths, spontaneous abortions (miscarriages), and fetal, neonatal, or maternal deaths. RESULTS: The registry totals 863 cases. Rates of APOs (and congenital malformations) after any exposure were 33% (16%), 27% (8%), and 25% (6%), for first, second, and third trimesters. Among the groups of cancer drugs, antimetabolites and alkylating agents have the highest rates of APOs. Mitotic inhibitors and antibiotics seem more benign. Mixed results were observed from single-agent exposure, often because of small numbers of exposures. As a whole, the alkylating agents and antimetabolites are more harmful when given as a single agent rather than as part of a regimen. First-trimester exposure poses a more permanent risk to the fetus. CONCLUSIONS: Systematic ascertainment of women early in pregnancy, preferably in a population base, is needed for assessment of true risks. Long-term follow-up is needed to rule out neurobehavioral effects.