Heparin in pregnant women with previous placenta-mediated pregnancy complications: a prospective, randomized, multicenter, controlled clinical trial.

To assess whether antithrombotic prophylaxis with low-molecular-weight heparin effectively prevents recurrence of late pregnancy complications, 135 women with previous history of preeclampsia, hemolytic anemia, elevated liver enzymes and low platelet count syndrome, intrauterine fetal death, fetal growth restriction, or placental abruption who had been referred within the 12th gestational week were randomized to medical surveillance alone (n = 68) or combined to open-label nadroparin (3800 IU daily subcutaneous injections) treatment (n = 67) in the setting of a randomized, parallel-group, superiority trial, run in Italy from April 2007 to April 2010. Primary outcome was a composite end point of late-pregnancy complications. Analysis was by intention to treat. The study was stopped for futility at the time of the first planned interim analysis. Among the 128 women eventually available for final analyses, 13 of the 63 (21%) randomized to nadroparin compared with 12 of the 65 (18%) on medical surveillance alone progressed to the primary end point. The absolute event risk difference between treatment arms (2.2; -1.6 to 16.0) was not statistically significant (P = .76). Thus, nadroparin did not prevent late-pregnancy complications in women at risk of recurrence. This finding challenges the role of antithrombotic prophylaxis with low-molecular-weight heparin in the prevention of recurrent late pregnancy complications The trial was registered at http://ricerca-clinica.agenziafarmaco.it as EudraCT 2006-004205-26.

Lactate detection in the brain of growth-restricted fetuses with magnetic resonance spectroscopy.

OBJECTIVE: The objective of the study was to determine the feasibility of detecting fetal brain lactate, a marker of fetal metabolic acidemia, using a noninvasive technique, proton magnetic resonance spectroscopy ((1)H MRS), in intrauterine growth-restricted (IUGR) fetuses. STUDY DESIGN: In vivo human fetal brain lactate detection was determined by (1)H MRS in 5 fetuses with IUGR. Oxygenation and acid-base balance data were obtained at birth. RESULTS: (1)H MRS analysis showed the presence of a lactate peak in the brain of the most severely affected IUGR fetus, with abnormal umbilical artery Doppler and fetal heart rate tracing. This finding was consistent with the low oxygen content and high lactic acid concentration observed in umbilical blood obtained at delivery. CONCLUSION: (1)H MRS allows the noninvasive detection of cerebral lactate in IUGR fetuses. Lactate detected by (1)H MRS may represent a possible marker of in utero cerebral injury or underperfusion.

Comparing two dinoprostone agents for cervical ripening and induction of labor: a randomized trial.

OBJECTIVE: To compare dinoprostone gel and insert in achieving successful vaginal delivery in nulliparous and multiparous women. STUDY DESIGN: 220 nulliparous and 100 multiparous with a Bishop score < or =7 were randomized to receive dinoprostone either gel or insert for cervical ripening. The main outcome measures were the rate and latency of vaginal delivery. RESULTS: In nulliparous women no significant differences were found between the gel and insert groups in the rate of vaginal delivery (85.6% vs. 80.7%) delivery < or =12 (36.8% vs. 32.9%) and < or =24h (85.3% vs. 93.4%) regardless of the preinduction Bishop score. Nulliparous with Bishop score < or =4 treated with the insert had a decreased risk (p<0.05) of post partum hemorrhage (4.8%) when compared with nulliparous treated with gel (16.7%). On the contrary, in multiparous the time to delivery interval was significantly shorter in the gel treated group (9.9+/-4.9h vs. 13.1+/-5h; p<0.001) with more patients delivering vaginally < or =12h (75% vs. 37.5%, p<0.001), regardless of the preinduction Bishop score. CONCLUSION: Both dinoprostone gel and insert are efficient in achieving cervical ripening and successful labor in nulliparous and multiparous. In multiparous, however, the gel significantly reduces the time to vaginal delivery with more patients delivering vaginally < or =12h, regardless of the Bishop score.

Human fetal growth and organ development: 50 years of discoveries.

Knowledge about human fetal growth and organ development has greatly developed in the last 50 years. Anatomists and physiologists had already described some crucial aspects, for example, the circulation of blood during intrauterine life through the fetal heart, the liver as well as the placenta. However, only in the last century physiologic studies were performed in animal models. In the human fetus, the introduction of ultrasound and Doppler velocimetry has provided data about the growth and development of the fetus and of the circulation through the different fetal districts. Moreover, in the last 2 decades we have learned about fetal oxygenation and fetal nutrient supply caused by the availability of fetal blood samples obtained under relatively steady state conditions. These studies, together with studies using stable isotope methodologies, have clarified some aspects of the supply of the major nutrients for the fetus such as glucose, amino acids, and fatty acids. At the same time, the relevance of placental function has been recognized as a major determinant of fetal diseases leading to intrauterine growth restriction. More recently, the availability of new tools such as 3-dimensional ultrasound and magnetic resonance imaging, have made possible the evaluation of the growth and development of fetal organs. This knowledge in the healthy fetus will improve the ability of clinicians to recognize abnormal phenotypes of the different fetal organs, thus allowing to stage fetal diseases.

Elevated maternal levels of the long pentraxin 3 (PTX3) in preeclampsia and intrauterine growth restriction.

OBJECTIVE: The prototypic long pentraxin pentraxin 3 is a new candidate marker for inflammatory conditions reflecting the involvement of the vascular bed. Endothelial dysfunction is a prominent feature of preeclampsia as a result of excessive maternal systemic inflammation. We investigated pentraxin 3 levels in preeclampsia and intrauterine growth restriction, pregnancy conditions related to altered placentation. STUDY DESIGN: We cross-sectionally studied nonpregnant women (n = 20); normal pregnancies in the first (n = 8), second (n = 10), and third (n = 26) trimester of pregnancy; 20 pregnancies complicated by preeclampsia; and 16 pregnancies complicated by intrauterine growth restriction. Maternal plasma samples were analyzed and pentraxin 3 determined by enzyme-linked immunosorbent assay. Pattern and site of placental expression of pentraxin 3 were studied by immunohistochemistry. RESULTS: In normal pregnancies pentraxin 3 concentrations were significantly higher than nonpregnant women and did not change among the 3 trimesters. Significantly higher levels of pentraxin 3 were found in preeclampsia (median values 13.8 versus 2.2 ng/mL; P < .001), compared with normal pregnancies. Intrauterine growth restriction pregnancies showed intermediate levels between normal and preeclamptic patients, but this difference was not significant, compared with normal pregnancies (median values 3.9 versus 2.2 ng/mL). No significant difference of pentraxin 3 levels was found between mild and severe preeclampsia. CONCLUSION: Elevated maternal plasma levels of pentraxin 3 in preeclamptic versus normal pregnancies could represent a marker of altered endothelial function, typical of preeclampsia.

Fetal nutrition: a review.

Knowledge of fetal nutrient supply has greatly increased in the last decade due to the availability of fetal blood samples obtained under relatively steady-state conditions. These studies, together with studies utilizing stable isotope methodologies, have clarified some aspects of the supply of the major nutrients for the fetus such as glucose, amino acids and fatty acids. At the same time, the relevance of intrauterine growth has been recognized not only for the well-being of the neonate and child, but also for later health in adulthood. The major determinants of fetal nutrient availability are maternal nutrition and metabolism together with placental function and metabolism. The regulation of the rate of intrauterine growth is the result of complex interactions between genetic inheritance, endocrine environment and availability of nutrients to the fetus.

Placental-fetal interrelationship in IUGR fetuses--a review.

The role of placental function in maintaining an adequate fetal growth has been addressed by many different laboratories. The relationship between maternal and fetal circulation in the placenta is crucial for efficient exchanges of oxygen and nutrients. Moreover, maturational changes are taking place throughout gestation within the placenta in order to increase the transfer capacities while fetal/placental weight ratio is significantly decreasing. In human pregnancies, an impairment in the invasion of fetal trophoblast cells into the maternal decidua has been hypothesized as a cause of placental insufficiency leading to intrauterine growth restriction (IUGR). This condition has been associated with a number of adaptive changes taking place in both placenta and fetus. Adaptive changes can be followed by pathology leading to fetal death and therefore staging of the disease is fundamental for timing of delivery.A classification of the severity of IUGR in human pregnancies has been proposed based upon fetal heart rate (FHR) and Doppler velocimetry of the umbilical artery (pulsatility index or PI). This classification of clinical severity reflects different degrees of placental insufficiency and is associated with significant differences in placental nutrient exchange. Only those IUGR with pathological PI and FHR are associated with increasing degrees of hypoxemia and lacticacidemia. Furthermore, significant differences are observed in the transplacental glucose gradient in the most severe cases and the placental transport of essential amino acids is significantly reduced both in vivo and in vitro. These findings suggest that both placental metabolism and transport are altered in intrauterine growth restriction in humans.

The effect of maternal hypothermic cardiopulmonary bypass on fetal lamb temperature, hemodynamics, oxygenation, and acid-base balance.

OBJECTIVE: To evaluate fetal-maternal temperature relationship and fetal cardiovascular and metabolic response during maternal hypothermic cardiopulmonary bypass in pregnant ewes. METHODS: Cardiopulmonary bypass was instituted in 9 pregnant ewes, reaching 2 different levels of maternal hypothermia: 24 degrees C to 20 degrees C (deep hypothermia) in group A (5 cases) and less than 20 degrees C (very deep hypothermia) in group B (4 cases). Hypothermic levels were maintained for 20 minutes, then the rewarming phase was started. Fetal and maternal temperature, blood pressure, heart rate, electrocardiogram, blood gases, and acid-base balance were evaluated at different levels of hypothermia and during recovery. RESULTS: Fetal survival was related to maternal hypothermia: all group A fetuses survived, while 2 of 4 fetuses of group B in which maternal temperature was lowered below 18 degrees C died in a very deep acidotic and hypoxic status. Maternal temperature was always lower than fetal temperature during cooling; during rewarming the gradient was inverted. The start of cardiopulmonary bypass and cooling was associated with transient fetal tachycardia and hypertension; then, both fetal heart rate and blood pressure progressively decreased. The reduction of fetal heart rate was of 7 beats per minute for each degree of fetal cooling. Deep maternal hypothermia was associated with fetal alkalosis and reduction of Po(2). Very deep hypothermia, in particular below 18 degrees C, caused irreversible fetal acidosis and hypoxia. CONCLUSIONS: Deep maternal hypothermic cardiopulmonary bypass was associated with reversible modifications in fetal cardiovascular parameters, blood gases, and acid-base balance and therefore with fetal survival. On the contrary, fetuses did not survive to a very deep hypothermia below 18 degrees C.

Surgical treatment of ovarian dermoid cysts: a comparison between laparoscopic and vaginal removal.

BACKGROUND: In the last years transvaginal ultrasonographic diagnosis of ovarian dermoid cyst together with laparoscopic approach have greatly improved the treatment of this benign lesion. Vaginal approach with laparoscopic assistance has been proposed as an alternative to total laparoscopic removal. METHODS: A retrospective comparison between total laparoscopic (56 patients) and direct vaginal removal (30 patients) of ovarian dermoids. RESULTS: There were few, but significant, advantages of vaginal removal, especially regarding operating time, intraperitoneal spillage of dermoid tissue and post-operative outcome. CONCLUSION: Vaginal approach to the removal of dermoid cysts can be considered a safe alternative procedure to laparoscopy.

Human fetal brain chemistry as detected by proton magnetic resonance spectroscopy.

Magnetic resonance spectroscopy represents an invaluable tool for the in vivo study of brain development at the chemistry level. Whereas magnetic resonance spectroscopy has received wide attention in pediatric and adult settings, only a few studies were performed on the human fetal brain. They revealed changes occurring throughout gestation in the levels of the main metabolites detected by proton magnetic resonance spectroscopy (N-acetylaspartate, choline, myo-inositol, creatine, and glutamate), providing a reference for the normal metabolic brain development. Throughout the third trimester of gestation, N-acetylaspartate gradually increases, whereas choline undergoes a slow reduction during the process of myelination. Less clear are the modifications in creatine, myo-inositol, and glutamate levels. Under conditions of fetal distress, the meaning of lactate detection is unclear, and further studies are needed. Another field for investigation involves the possibility of early detection of glutamate levels in fetuses at risk for hypoxic-ischemic encephalopathy, because the role of glutamate excitotoxicity in this context is well-established. Because metabolic modifications may precede functional or morphologic changes in the central nervous system, magnetic resonance spectroscopy may likely serve as a powerful, noninvasive tool for the early diagnosis and prognosis of different pathologic conditions.

Attitudes and knowledge regarding influenza vaccination among hospital health workers caring for women and children.

This cross-sectional study of 340 obstetrics/gynecology, 123 neonatology, and 244 pediatric health care workers (HCWs) was designed to evaluate compliance with recommendations concerning the use of influenza vaccine during pregnancy and among pediatric subjects. The results clearly show that only a marginal number of the HCWs in all three fields currently recommend vaccine use for pregnant women and healthy young children. Moreover, all of the HCWs were seriously deficient in terms of their general knowledge of influenza prevention and their own personal vaccination coverage was low. Extensive and sustained efforts to overcome cultural limitations concerning influenza and its prevention are urgently required among HCWs caring for women and children in order to ensure effective compliance with the current recommendations.

Follicular fluid levels of the long pentraxin PTX3.

OBJECTIVE: Pentraxin-3 (PTX3) is a long pentraxin that plays a key role in female fertility as a structural and essential constituent of the cumulus oophorus extracellular matrix. Despite considerable evidence supporting this role of PTX3 in mice, data in humans are scanty. The aim of the present study was (1) to evaluate follicular fluid concentrations of PTX3; (2) to test the hypothesis that levels of the molecule correlate with oocyte characteristics (corona radiata, aspect of the cumulus, nuclear maturity, and fertilization); and (3) to evaluate the possibility that peripheral concentration of PTX3 may be of clinical help in monitoring ovarian hyperstimulation. METHODS: ELISA was used to determine PTX3 concentration. Levels of PTX3 were tested in 96 follicles. RESULTS: The mean +/- SD and the median (interquartile range) were 17.9 +/- 18.3 and 12.1 (6.5-23.6) ng/mL, respectively. Levels of the molecule did not appear to be normally distributed. At the day of ovum pick-up, levels of PTX3 were 6.3-fold higher in follicular fluid than in peripheral blood (95% CI, 3.6-9.0). No statistically significant difference emerged linking follicular fluid concentration of PTX3 and oocyte quality. In a series of ten women, plasma concentration of PTX3 did not vary during ovarian hyperstimulation, resulting in levels of 1.0 +/- 0.5 at the 3rd day of the menstrual cycle and 1.0 +/- 0.6 ng/mL at the day of oocyte retrieval. CONCLUSIONS: Results from the present study support the following conclusions: (1) elevated levels of soluble PTX3 can be found in follicular fluid; (2) follicular fluid concentration of PTX3 cannot by used as a marker of oocyte quality; and (3) plasma concentration of the molecule is not influenced by ovarian hyperstimulation.

Early invasive diagnostic techniques in pregnant women who are infected with the HIV: a multicenter case series.

OBJECTIVE: Studies that mostly were conducted before the widespread use of combination antiretroviral treatments have reported that antenatal invasive procedures markedly increase the risk of human immunodeficiency virus vertical transmission. We aimed to evaluate the vertical transmission rate and other maternal and neonatal complications among women who were infected with human immunodeficiency virus who underwent antenatal invasive procedures during the second trimester of pregnancy and who were delivered after the advent of antiretroviral regimens. STUDY DESIGN: We conducted a multicenter case series of women who were infected with human immunodeficiency virus who underwent amniocentesis or chorionic villus sampling or cordocentesis during the second trimester of pregnancy and who were delivered after January 1, 1997. RESULTS: Sixty-three of 775 recruited women (8.1%) had performed early invasive diagnostic techniques . This rate has improved progressively from 4% in 1997 to 14%. Two of 60 viable infants (3.3%; 95% CI, 0.6%-10.1%) were infected with the human immunodeficiency virus. This rate did not differ significantly from the transmission rate that was observed in women who did not undergo antenatal invasive techniques (1.7%; P = .30). CONCLUSION: The current risk of human immunodeficiency virus vertical transmission that is associated with early invasive diagnostic techniques is lower than previously reported.

Maternal and fetal amino acid concentrations in normal pregnancies and in pregnancies with gestational diabetes mellitus.

OBJECTIVE: This study was undertaken to compare amino acid concentrations in normal pregnancies and pregnancies with gestational diabetes (GDM), a condition associated with altered fetal growth. STUDY DESIGN: Maternal and fetal amino acids were evaluated by high-performance liquid chromatograph at the time of delivery in 16 normal and 17 GDM pregnancies. Fetal weights were not different, but placental weights were significantly higher and fetal/placental weight ratios were significantly lower in GDM compared with normal. RESULTS: Ornithine was significantly increased in GDM mothers. In umbilical vein and artery of GDM significant increases were observed for valine, methionine, phenylalanine, isoleucine, leucine, ornithine, glutamate, proline, and alanine, whereas glutamine was significantly decreased. CONCLUSION: Placental amino acid exchange is altered in GDM pregnancies. Moreover, the changes observed for glutamine and glutamate in the umbilical samples suggest that in GDM the fetal hepatic production of glutamate is increased, likely as a consequence of the endocrine changes in the fetal compartment.

Cardiac autonomic modulation in normal, high-risk, and in vitro fertilization pregnancies during the first trimester.

OBJECTIVES: The purpose of this study was to test the adaptation of autonomic modulation of heart rate in high-risk or in vitro fertilization (IVF) pregnancies during the first trimester. STUDY DESIGN: Thirty-three pregnant women were studied between 6.0 and 12.5 weeks of gestation and were divided into three groups: normal (n=17), high-risk (n=7), and IVF pregnancies (n=9), together with 9 nonpregnant women of comparable age. All subjects underwent a short-term continuous electrocardiographic recording to measure short-term heart rate variability (HRV). RESULTS: Average values of mean R-R interval, total power, and low-frequency (LF) component were similar in nonpregnant and normally pregnant women. The high-frequency (HF) component was only slightly increased in normal pregnant women but no difference was observed in LF/HF ratio. High-risk and IVF pregnancies were characterized by a significant increase in LF component in comparison to normal pregnancies. In pregnancies that had obstetric complications, signs of abnormal autonomic modulation of the sinus node were particularly evident. CONCLUSION: Short-term analysis of HRV in high-risk and IVF pregnancies was significantly different from that observed in normal pregnancies. These differences were more significant in those pregnancies later complicated by an adverse outcome, suggesting an early origin of these pathologic conditions.

Genetics of endometriosis: a role for the progesterone receptor gene polymorphism PROGINS?

OBJECTIVE: Endometriosis is a steroid-dependent disease with a particular genetic background, but the locations of possible genomic aberrations are still poorly clarified. We have investigated the potential association between endometriosis and the PROGINS 306 base pair insertion polymorphism in intron G of the progesterone receptor (PR) gene, which has been reported previously to segregate with this disease. DESIGN: In a case-control study, we examined the PROGINS polymorphism of the progesterone receptor gene in 131 Italian women affected by endometriosis diagnosed according to published criteria for the definition of the definite disease. Control subjects were represented by 127 Italian women without laparoscopic evidence of the disease. MEASUREMENTS: Peripheral blood samples, DNA extraction and polymerase chain reaction (PCR) were used to genotype women for the presence of the PROGINS polymorphism. RESULTS: We found a statistically significant difference in the distribution of PROGINS genotypes between patients with and without endometriosis. The frequency of the PROGINS allele T2 was 17.2% and 11%, respectively, in affected women and in controls [odds ratio (OR) = 1.7, 95% confidence interval (CI) 1.0-2.8]. This association was stronger in patients with more severe forms of endometriosis, such as an infiltrating disease or a disease characterized by severe pelvic adhesions (OR 2.4, 95% CI 1.2-4.8; and OR 2.7, 95% CI 1.4-5.3, respectively). Combination of the results from an earlier study and the current data indicates that carrying the allele variant T2 is associated with a twofold increase in the risk of developing endometriosis (OR 2.0, 95% CI 1.3-2.9). CONCLUSIONS: Our results further support the idea that the PROGINS polymorphism of the progesterone receptor may be associated with an increased risk of endometriosis.

Intrauterine growth restriction is associated with changes in polyunsaturated fatty acid fetal-maternal relationships.

Fetuses with intrauterine growth restriction (IUGR) are at increased risk of death and disease during neonatal, pediatric, and adult life. Postnatal deficits in essential fatty acids have been associated with the neural and vascular complications of premature neonates. We studied whether fetal-maternal fatty acid relationships are already impaired in utero in IUGR fetuses. Fetal (F) and maternal (M) fatty acid profiles were determined in utero in 11 normal [appropriate for gestational age (AGA)] and in 10 IUGR fetuses by fetal blood sampling (FBS) between 19 and 39 wk. Total plasma fatty acid concentrations were significantly higher in M than in F of both AGA (M: 2.03 +/- 0.53 mg/mL; F: 0.64 +/- 0.29 mg/mL; p < 0.001) and IUGR (M: 2.16 +/- 0.59 mg/mL; F: 0.73 +/- 0.17 mg/mL; p < 0.001). The F/M ratio was significantly higher for linoleic acid (AGA: 0.36 +/- 0.09; IUGR: 0.52 +/- 0.12; p < 0.01) and significantly lower for the long-chain polyunsaturated fatty acid docosahexaenoic acid (AGA: 1.94 +/- 0.32; IUGR: 1.25 +/- 0.19; p < 0.05) and arachidonic acid (AGA: 2.35 +/- 0.35%; IUGR: 2.04 +/- 0.3%; p < 0.05) in IUGR compared with AGA pregnancies. The differences observed in the relative amounts but not in total plasma concentrations of fatty acid fetal-maternal relationships in pregnancies associated with IUGR could be related to inadequate transplacental supply as well as to a fetal lack of the enzymes necessary for elaboration of these metabolically relevant conditionally essential fatty acids. These differences might have a role in determining the biochemical environment leading to the neural and vascular complications associated with IUGR.

The effect of a maternal infusion of amino acids on umbilical uptake in pregnancies complicated by intrauterine growth restriction.

OBJECTIVE: To establish whether, in human pregnancies complicated by intrauterine growth restriction (IUGR), the maternal intravenous infusion of amino acids can increase fetal amino acid concentrations and umbilical uptake. STUDY DESIGN: Before elective cesarean delivery, a solution of amino acids was infused into a maternal vein in 8 patients with pregnancies complicated by IUGR (experimental group). At cesarean delivery, maternal, umbilical venous, and arterial blood samples were obtained. Ten comparable IUGR pregnancies were compared with those in the experimental group. RESULTS: In the experimental group, all maternal amino acid concentrations were increased significantly. In the umbilical vein, valine, methionine, isoleucine, leucine, phenylalanine, arginine, serine, glycine, and proline concentrations were elevated. Umbilical venoarterial differences of amino acid per mole of oxygen for leucine, isoleucine, methionine, arginine, glycine, serine, and proline were elevated but not for lysine, histidine, threonine, valine, and phenylalanine. CONCLUSION: In pregnancies complicated by IUGR, increasing the maternal concentration of amino acids leads to an increased umbilical uptake of some of the amino acids to the fetus. There was no evidence of a change in the uptake of 3 essential amino acids: lysine, histidine, and threonine.