Pregnancy in patients with rheumatic disease: anti-inflammatory cytokines increase in pregnancy and decrease post partum.

OBJECTIVE: To investigate changes in the levels of circulating cytokines with a focus on the Th1/Th2 balance during and after pregnancy in patients with rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), and ankylosing spondylitis (AS). METHODS: Plasma and serum samples of 34 pregnant patients, 19 with RA, 6 with JIA, and 9 with AS, and of 30 healthy pregnant women, 20 non-pregnant patients, and 10 non-pregnant healthy women were analysed for levels of interferon gamma (IFNgamma), interleukin (IL) 1beta, IL10, IL1 receptor antagonist (IL1Ra), soluble tumour necrosis factor receptor (sTNFR), and soluble CD30 (sCD30) by ELISA. Clinical assessment and blood sampling in pregnant women was done once in each trimester and 6, 12, and 24 weeks post partum. Disease activity in the patients was evaluated by validated clinical instruments and correlated with circulating levels of cytokines. RESULTS: Low levels of IL10 were found sporadically, whereas IFNgamma and IL1beta were below detection level in the samples tested. Significantly higher concentrations of sTNFR and IL1Ra were measured in pregnant than in non-pregnant subjects. An increase of IL1Ra from the second to the third trimester correlated with improvement of disease activity in patients with RA and AS. Compared with non-pregnant patients and the other pregnant women, patients with RA showed markedly raised levels of sCD30 during pregnancy. CONCLUSIONS: IFNgamma and IL10, markers of a Th1 and Th2 response, respectively, were either low or undetectable in the cohorts analysed. The increase of cytokine inhibitors IL1Ra and sTNFR was related to pregnancy and was independent of an underlying disease. These anti-inflammatory mediators seem to affect disease activity.

[Hypertension and pregnancy]. / Hypertonie und Schwangerschaft.

5-10% of all pregnancies are complicated by high blood pressure; in 70% of cases there are no signs until 20 weeks of gestation; 30% are seen in women with preexisting hypertension. Pre-eclampsia (proteinuric hypertension) is one of the most severe diseases in pregnancy. Maternal mortality and morbidity are high. The outcome of pregnancies with preexisting (mainly essential) hypertension is much worse than that of acute hypertension and depends on duration and severity of the disease. Often chronic hypertension develops from acute hypertension in pregnancy. This article describes the various types of hypertension in pregnancy, diagnosis, complications and management strategies.

Pregnancy-associated recurrent hemolytic uremic syndrome with fetal thrombotic vasculopathy in the placenta.

A case report of hemolytic uremic syndrome with placental involvement in 2 of 3 consecutive pregnancies highlights the impact on the fetal placental compartment and the importance of diligent antenatal care in subsequent pregnancies.

The relationship between cervical dilatation, interleukin-6 and interleukin-8 during term labor.

BACKGROUND: To determine interleukin-6 and interleukin-8 levels in amniotic fluid, retroplacental blood and maternal serum and relate these values with cervical dilatation in term labor. METHODS: Prospective study. n=78 healthy women undergoing term cesarean section, divided into four groups: controls, n=42, (elective cesarean section; no contractions, membrane rupture or cervical dilatation); latent labor, n=12, (latent phase labor; cervix <2 cm dilated); established labor, n=12, (active labor, cervix 2-5 cm); advanced labor, n=12, (active labor, cervix >5 cm). Interleukin-6 and interleukin-8 were determined by ELISA (pg/ml), placenta and placental bed biopsy examined histopathologically, and amniotic fluid also microbiologically. Results were expressed as median and ranges or mean and standard deviations, as appropriate. For statistical analysis, Mann-Whitney U-tests or Kruskal-Wallis tests were used as applicable (Statview 4.5). Power and linear regression analyses were performed. p<0.05 was considered significant, p<0.001 highly significant. RESULTS: Compared with controls, IL-6 and IL-8 increased significantly with cervical dilatation in all compartments tested for almost all labor groups (p<0.05 to p<0.0001). Significant changes were also seen between latent and advanced labor groups in some compartments (p<0.05), but not between established and advanced labor groups. Intrauterine infection was excluded in any of the patients clinically and on histopathological or microbiological analysis of placentae and amniotic fluid. CONCLUSIONS: In term labor without intraamniotic infection, interleukin-6 and interleukin-8 at the fetomaternal interface and in maternal serum rise significantly with cervical dilatation. These cytokines could be used as markers of active labor if vaginal examination is not applicable.

[Two-stage delivery after spontaneous rupture of fetal membranes and delayed abortion of the first twin in conservative management]. / Zweizeitige Geburt nach spontanem Blasensprung und Spätabort des ersten Mehrlings bei konservativem Management.

INTRODUCTION: 1-2% of all twin pregnancies are complicated by premature contractions, leading to premature rupture of membranes before 26 weeks of pregnancy. In this situation, a decision is required to either actively induce premature delivery or to initiate expectant management. Maternal and fetal risks regarding perinatal mortality and morbidity and the benefits of pregnancy prolongation have to be weighted against each other. CASE REPORT: We present delayed deliveries of two I-Parae with dichorionic twin pregnancies, achieved by in vitro fertilisation. In both cases, spontaneous membrane rupture and miscarriage of the leading fetus occurred prior to 20 gestational weeks. As signs of infection were missing initially, we adopted a conservative, expectant management. In both cases, the pregnancies could be prolonged to more than 30 weeks' gestation. DISCUSSION: In the absence of additional risk factors, expectant, conservative management of multiple pregnancies after loss of one fetus can lead to pregnancy prolongation of 91 and 96 days, respectively. The gained gestational age of the remaining fetus and the healthy mother-child pairs are discussed under perinatal, economical and psychological aspects.

Rescue by birth: defective placental maturation and late fetal mortality.

OBJECTIVE: To estimate the incidence and lethality of placental maturation defect, and to determine the impact of the pattern of placental dysfunction on the risk of recurrent stillbirth or maternal disease in later life. METHODS: Questionnaire and archival analysis of fetal deaths from placental dysfunction at 32-42 weeks (1975-1995 in Zurich), classified as chronic (parenchyma loss) or acute (maturation defect of the terminal chorionic villi). Population survey of 17,415 consecutive unselected singleton placentas (1994-1998 in Berlin). RESULTS: Of the 71 stillbirths, 34 were due to parenchyma loss and 37 to maturation defect. Parenchyma loss predominated in the first pregnancy (73.5% compared with 43.2%; P <.05). The risks of recurrent stillbirth and subsequent childlessness did not differ between the two groups. Eleven percent of mothers whose placenta had maturation defect had diabetes in the index pregnancy; none of the other women in the group developed diabetes over the 5-20-year observation period. In the population survey, incidence of maturation defect was 5.7%, and was associated with fetal death in 2.3% of cases. Normal placentas were associated with fetal death in 0.033%. CONCLUSION: Placental maturation defect can be a cause of fetal hypoxia. Although the risk of stillbirth is 70-fold that of a normal placenta, few affected fetuses actually die. The risk of recurrent stillbirth is tenfold above baseline and occurs mostly after 35 weeks' gestation.

Feto-maternal interface of human placenta inhibits angiogenesis in the chick chorioallantoic membrane (CAM) assay.

The rapidly growing chorionic villi of the human placenta characteristically show constant blood vessel growth and differentiation. In contrast, the underlying decidua reveals tissue remodeling without apparent angiogenesis. Using the chick chorioallantoic membrane (CAM) assay, we found marked inhibition of angiogenesis by the feto-maternal interface tissue derived from nine human placentas obtained minutes after delivery. Inhibition was prevented by the addition of monensin, which blocks the release of synthesized cell products, and was markedly reduced by drying or freezing the tissue before the assay. Histology, combined with statistical analysis of the constituent cell types, correlated inhibition of angiogenesis with the number of fetally-derived extravillous trophoblasts in the feto-maternal interface tissue. Electron microscopy revealed endothelial cell damage in preexisting small (but not large) CAM vessels. We conclude that decidual tissue inhibited angiogenesis by releasing a water soluble factor which was under apparent constant production by vaible trophoblast on the CAM. The extravillous trophoblast population resembles tumor cells in its migratory and invasive properties but, in contrast to tumor induced angiogenesis, it is angiostatic, perhaps to counteract angiogenic proteins leaking from the intervillous space which could be detrimental to the maternal organism if active.

Fetal varicella syndrome: disruption of neural development and persistent inflammation of non-neural tissues.

Primary varicella zoster virus (VZV) infection during pregnancy is rare. If it occurs between the 8th and 20th week of gestation, fetal varicella syndrome results in 1-2% of the fetuses. We report about a varicella infection that affected a pregnant mother in the 12th week of gestation. At 33 weeks, a premature girl was born with destruction of neurons in spinal cord, spinal ganglia and plexus myentericus, and secondary developmental disturbance including mummification of one arm and segmental intestinal atresia. The brain did not show any abnormalities. However, VZV DNA could be detected by PCR in tissues from the brain and spinal ganglia. Chronic necrotizing inflammation was found in the placenta, fetal membranes, and one ovary. These locations showed nuclear inclusions which by in-situ-hybridization were proven to be VZV derived. This case demonstrates that in the fetal age, 'neurotropism' of VZV signifies severe destruction but not necessarily persistent inflammation of neural tissue. However, due to the inefficient fetal immune system, inflammation can go on for weeks, preferentially in non-neural tissues.

Aberrant positioning of trophoblast and lymphocytes in the feto-maternal interface with pre-eclampsia.

Pregnancy represents the growth of an allograft where fetal trophoblast cells evade immune rejection and invade maternal tissue. There should be a balance between fetal trophoblast and maternal immune-responsive cells and alterations in the proportion of these cells may relate to pregnancy disorders. To test this, the decidual tissue of placental bed biopsies was examined and trophoblast cells and lymphocytes were quantified morphometrically; spiral arteries were classified as unchanged, transformed or affected by acute atherosis. Normal pregnancy (n=19) was characterized by the transformation of about one half of all spiral arteries within the placental bed. We found that 40% of all lymphocytes were CD56+ uterine NK cells and 60%, CD3+ T-lymphocytes; about 30% of these were CD8+ T cells. Intrauterine growth retardation in the context of preeclampsia (n=15) was accompanied by reduced trophoblast numbers within smaller and more tortuous arteries and an increase in the proportion of CD56+ uterine NK cells and CD8+ T lymphocytes in the decidua (70% of all CD3+ cells). In the case of pre-eclampsia without fetal growth retardation (n=14) no increase in CD56+ uterine NK cells was seen, while CD8+ T lymphocytes were significantly increased compared with the normal level (50% of all CD3+ cells). Fetal growth retardation is associated with poor transformation of spiral arteries and characterized by an increase of uterine NK cells. Symptoms of pre-eclampsia are independently associated with an increase in the cytotoxic T subset of decidual lymphocytes. Pre-eclampsia and related fetal growth retardation are seemingly caused by an enhancement of the maternal cytotoxic defence against the fetal allograft.

Role of duplex color Doppler ultrasound, computed tomography, and MR angiography in the diagnosis of septic puerperal ovarian vein thrombosis.

BACKGROUND: Septic puerperal ovarian vein thrombosis (SPOVT) is one of the underlying etiologies of puerperal fever. A correct diagnosis of this condition is important because adequate treatment requires additional administration of anticoagulants. The purpose of this study was to evaluate the role of duplex color Doppler ultrasound (CDUS), computed tomography (CT), and magnetic resonance angiography (MRA) in the detection of SPOVT. METHODS: Twenty-six patients with puerperal fever suspected to be due to SPOVT and unresponsive to broad antibiotic treatment for at least 48 h were included in a prospective study using CDUS, CT, and MR imaging including MRA. Examinations were analyzed and then correlated to a standard of reference gathered from surgical and clinical follow-up data and from results of imaging. RESULTS: SPOVT was present in nine patients (right side n = 8, bilateral n = 1). CDUS was inconclusive due to gaseous distention of the bowel or obesity in 13 of 26 cases. After counting inconclusive findings as wrong results for statistical purposes, sensitivity, specificity, and accuracy for CDUS were 55.6%, 41.2%, and 46.2%, respectively. CT had a sensitivity of 77.8% with a specificity of 62.5%; accuracy was 68.0%. MRA rendered conclusive results in all evaluated patients, resulting in a sensitivity and specificity of 100%. CONCLUSION: MRA is recommended in all patients with inconclusive CDUS findings and persistent suspicion for SPOVT. CT has the advantage of more rapid access and lower cost and thus will probably remain a sufficiently accurate alternative. Septic puerperal ovarian vein thrombosis (SPOVT)-Computed tomography-Magnetic resonance angiography-Ultrasound.

Primäre Kaiserschnittentbindung mit und ohne antiretrovirale Prophylaxe und Prävention der materno-fetalen Transmission von HIV-1.

BACKGROUND: Studies of caesarean section and the rate of perinatal transmission of HIV-1 (RPT) have reported conflicting results if AZT was not administered simultaneously. METHODS: To investigate the probable sources of error, 387 singleton pregnancies of HIV-1-infected mothers were enrolled in a prospective, observational study. To avoid contamination of the fetal mouth with maternal blood at caesarean section, the uterus was opened under careful preparation of the fetal membranes, maintaining their integrity as long as possible. To 105 pregnant women AZT was administered at various gestational ages (median 29th week), depending on the stage of the disease of the mother or obstetrical complications. The majority of newborns received AZT for 10 days I.V. RESULTS: Group 1: For those, for whom vaginal delivery was intended (n=163, RPT=20.2%), this could be realized in 82% of the cases only. There was no significant difference in the RPT (23%-19,5%) between emergency caesarean section and vaginal delivery (odds ratio [OR]=1,25; 95% CI 0,41-3,44). Risk factors of fetal HIV infection (p≤0.05) were delivery <37th week, rupture of membranes (ROM) ≥4 h, labor ≥5 h before delivery, CD4 ≤400 cells/µl, p24 antigenemia, and viral load. Group 2: If an elective caesarean section (n=119) was intended, the RPT (4,2%) was reduced compared to group 1 (OR=0.17; 95% CI 0.04-0,52; p=0.0002); however, in 16% emergency sections had to be performed because labor or ROM occurred before the planned date of elective caesarean section without difference in the RPT (4-5%) (OR 1,35; 95% CI 0,03-14,51). Significant risks (p≤0.05) of fetal infection were preterm labor and viral load. Group 3: If an elec- tive caesarean section under AZT (n=105) was intended, the RPT (1,3%) was significantly different to group 1 (OR=0,08; 95% CI 0.1-0.31; p=0.00003), but not to group 2 (OR=0.44; 95% CI 0.04-2.79). However, an elective caesarean section was feasible only in 74% without significant differences in the RPT (1,3-4%) (OR=2,96; 95% CI 0,04- 235,42). Except for the viral load (p=0.04), no risk factor was associated with fetal infection. CONCLUSIONS: Elective and emergency caesarean section, performed early in parturition under surgical care to avoid contamination, significantly decreases the risk of fetal transmission, irrespec-tive of low CD4 cell counts, p24 antigenemia, viral load and ROM, but not preterm labor. Simultaneous administration of AZT in gestation and to the newborn further reduces the risk of peripartal infections and obviously provides additional safety at caesarean sections.

Seven cases of Wiedmann-Beckwith syndrome, including the first reported case of mosaic paternal isodisomy along the whole chromosome 11.

Genomic imprinting of chromosome arm 11p is involved in the Wiedemann-Beckwith syndrome (WBS). About 20% of patients with sporadic WBS have paternal uniparental disomy (UPD) of 11p. Mitotic recombination at the 11p region has been suggested to be responsible for the somatic mosaicism in these patients. Our current study concerning sporadic WBS patients demonstrated six patients with mosaic isodisomy restricted to part of 11p and one patient with mosaic paternal uniparental disomy for the whole chromosome 11. Apparently the clinical findings for this patient did not differ from data reported for other WBS patients. This case makes it unlikely that the proximal short arm and the long arm of chromosome 11 contain imprinted genes with a phenotype recognizable prenatally or in infancy, and gives some support to the hypothesis that non-mosaic UPD-11 is prenatally lethal.

Fetuses from preeclamptic mothers show reduced hepatic erythropoiesis.

The fetal liver is the main hematopoietic organ during intrauterine life. Morphometrical studies were performed on liver sections to detect changes occurring with intrauterine growth retardation and preeclampsia. Compared with the controls (n = 10), fetuses from preeclamptic mothers showed a severe reduction of erythroid cells by 60% on average (n = 18). Closer examination revealed that the erythroid cells at early stages of differentiation were more affected (80% reduction) than at later stages (55%). Seven out of 18 fetuses from preeclamptic mothers did not show growth retardation but exhibited severely reduced hepatic erythropoiesis. We suggest that the prime factor for impaired red blood cell production is preeclampsia itself rather than intrauterine growth retardation. Regulation of erythropoiesis in utero might depend on the interaction of many hematopoietic growth factors, and preeclampsia might alter the balance. To test this notion, we quantitated erythropoietin in fetal blood and various cytokines in the amniotic fluid. An elevation of erythropoietin and interleukin (IL)-3 levels was seen in babies born under the conditions of preeclampsia, whereas the concentrations of granulocyte/macrophage-colony-stimulating factor (CSF), granulocyte-CSF, and IL-1 beta were reduced, and the levels of IL-6 and IL-8 remained constant. With preeclampsia, a discrepancy between elevation of erythrocyte numbers in peripheral blood and depression of hematopoiesis at the main production site, the fetal liver, is seen. Concomitantly, there is elevation of some but reduction of other hematopoietic cytokines. We envision that during the course of preeclampsia quantitation of hematopoietic growth factors might allow to predict the deterioration of in utero life conditions.

Reference resistance indices of the umbilical, fetal middle cerebral and uterine arteries at 24-42 weeks of gestation.

The objective of this cross-sectional study was to construct new reference ranges for Doppler flow velocity waveform resistance indices for the fetal umbilical artery, middle cerebral artery, placental and non-placental uterine arteries and the placentocerebral ratio in a large and minimally selected population attending a single clinic. Study design and data analysis adhered to a number of stringent and validated methodological recommendations derived both from the recent literature and from a review of earlier publications in this field. The final database comprised initial routine Doppler velocimetry at 24-42 weeks' gestation in 1675 pregnancies. Separate regression models were fitted to estimate the mean and standard deviation at each gestational age for each vessel. New charts, centile tables and regression equations are presented for the resistance indices of the fetal umbilical artery, middle cerebral artery, placental and non-placental uterine arteries and the mean of both uterine arteries and for the placentocerebral ratio.

Lethal multiple pterygium syndrome: suggestion for a consistent pathological workup and review of reported cases.

We report on 2 brothers with lethal multiple pterygium syndrome (LMPS) born to non-consanguineous parents as late spontaneous abortions. Both fetuses presented with massive nuchal edema, and facial anomalies including cleft palate and broad ribs. Apparently, several subgroups of LMPS exist. Differentiation is difficult, as there is no consistent agreement on a workup protocol for autopsies. We compared the findings in the literature on cases with LMPS, and we suggest a standardized workup as an initial step for more efficient differentiation between various subgroups.

Diaphragmatic defects, limb deficiencies, and ossification defects of the skull: a distinctive malformation syndrome.

We report on prenatal and postnatal findings in 4 consecutive fetuses with a pattern of severe congenital anomalies who were born to a healthy nonconsanguineous couple. The spectrum of malformations includes diaphragmatic defects, hypoplastic lungs, omphalocele, limb deficiencies, syndactyly of toes, and ossification defects of the skull. This specific spectrum of anomalies is not fully compatible with that of any established syndrome. No prenatal exposure to any possible teratogen was found. Family history is suggestive for autosomal recessive inheritance, even though germ-line mosaicism in one of the parents cannot completely be excluded.

Cytokine production and visualized effects in the feto-maternal unit. Quantitative and topographic data on cytokines during intrauterine disease.

BACKGROUND: A large array of cytokines show high activity in amniotic fluid. Attempts have been made to quantify the concentrations or to track rising levels for diagnostic purposes when examining disturbances of the feto-maternal unit. However, the kinetics of cytokine production in the amniotic fluid are not well understood, and there is lack of knowledge about concomitant levels in fetal and maternal blood. EXPERIMENTAL DESIGN: The presence of cytokines in fetal and placental cells was demonstrated by immunohistochemistry using mAb. Cytokines were quantified by enzymimmunoassay in amniotic fluid and fetal and maternal blood. This was done with regard to two disease states that quite frequently complicate the course of pregnancy, namely chorioamnionitis and intrauterine growth retardation. The cytokines examined were G-CSF, GM-CSF, TNF-alpha, IL-1, IL-6, and IL-8. RESULTS: In chorioamnionitis, all cytokines, except GM-CSF, were elevated about 100 times in the amniotic fluid. An accompanying increase in maternal and fetal blood was only found for IL-6 and G-CSF; IL-8 was elevated in fetal blood only. Intrauterine growth retardation was characterized by elevated levels of TNF-alpha in the amniotic fluid, whereas G-CSF, GM-CSF, and IL-1 beta were significantly reduced. Immunohistochemistry showed that under normal conditions the cytokines are to be found in a characteristic distribution in certain cell types in the fetus, the placenta, and the placental bed. With rising concentrations, more cells seemed to be recruited for cytokine production, especially macrophages and decidual cells. In chorioamnionitis, fetal extramedullary granulopoiesis was augmented, and in intrauterine growth retardation, erythropoiesis as well as granulopoiesis were depressed. CONCLUSIONS: Not only inflammatory disease but also intrauterine growth retardation is characterized by a changing cytokine pattern. Alterations in fetal hematopoiesis observed at postmortem examination of perinatal deaths can be correlated to changes in cytokine production within the feto-maternal unit.

Prenatal sonographic diagnosis of autosomal recessive polycystic kidney disease (ARPKD) during the early second trimester.

Autosomal recessive polycystic kidney disease (ARPKD) is a rare hereditary disease with a high neonatal mortality. Currently, prenatal diagnosis is possible only during the second half of pregnancy, when bilaterally enlarged, echogenic kidneys are visible by ultrasound. We describe a case in which a diagnosis of ARPKD was sought in the first half of pregnancy. High-resolution ultrasonography revealed echogenic, normal-sized kidneys at 15 + 4 weeks. Microsatellite DNA analysis of a chorionic villus sample, parental blood, and blood of an affected sibling showed that the fetus had the maternal haplotype and a recombination of the paternal haplotype. Thus, no distinction between homo- and heterozygosity for the ARPKD mutation in the fetus was possible. A further ultrasound examination at 19 + 4 weeks confirmed the previous results, indicating that the fetus was likely to be affected. After termination of the pregnancy, the diagnosis was confirmed on microscopic examination.