Progesterone supplement in pregnancy: an immunologic therapy?

One of the most interesting functions of the placenta is the regulation of the maternal immune response such that the fetal semi-allograft is tolerated during pregnancy. Trophoblasts are presumed to be essential to this phenomenon because they lie at the maternal-fetal interface, where they are in direct contact with cells of the maternal immune system. Trophoblasts do not express classic major histocompatibility complex (MHC) class II molecules. Surprisingly, cytotrophoblasts express more HLA-G, a MHC class Ib molecule, as they invade the uterus. Progesterone plays an important role in postovulatory regulation of the menstrual cycle. If fertilization occurs, progesterone supports implantation of the ovum and maintains the pregnancy. Progesterone has been named the 'hormone of pregnancy', because in preparing the endometrium for embryo implantation and facilitating endometrial development, it is critical to the very survival of a pregnancy. In addition, this key hormone inhibits the rejection of T cell-mediated tissue and also decreases myometrial activity and sensitivity throughout pregnancy. The cellular actions of progesterone are mediated through intracellular progesterone receptors (PRs), which are well studied gene regulators, not express classic major histocompatibility complex. The more used paradigm is relative to the alteration of relationship TH1/TH2, but the complexity of the respective distributions of cytokines at the materno-fetal interface, strongly suggest that, as useful as it certainly was for a while, the Th1/Th2 paradigm must now be considered as an oversimplification. Rather, the existing data point to sequential windows and are suggestive of a system where an extreme complexity is allied to very precise timing and tuning. They also suggest that the materno-fetal relationship is not simply maternal tolerance of a foreign tissue, but a series of intricate mutual cytokine interactions governing selective immune regulation and also control of the adhesion and vascularization processes during this dialogue. However, as shifting the immune response toward the Th2 pattern (IL-4, IL-5, IL-6) may benefit the fetus, whereas development of proinflammatory Th1 cells (secreting IL-2, IFN g, TNF a) may be harmful. Now we are working to open comprise the precise behaviour of NK populations, with the hope of obtaining a diagnostic test of the condition of abortion from 'immunological causes'.

Flexible treatment of gestational diabetes modulated on ultrasound evaluation of intrauterine growth: a controlled randomized clinical trial.

OBJECTIVES: In order to prevent abnormalities of fetal growth still characterizing pregnancies complicated by Gestational Diabetes (GDM), in the present study we evaluated a therapeutic strategy for GDM based on ultrasound (US) measurement of fetal insulin-sensitive tissues. METHODS: All GDM women diagnosed before 28th week immediately started diet and self-monitoring of blood glucose; after 2 weeks they were randomized to conventional (C) or modified (M) management. In C the glycemic target (GT) was fixed at 90 fasting/120 post-prandial mg/dl; in M GT varied, according to US measurement of the Abdominal Circumference (AC) centile performed every 2 weeks: 80/100 if AC > or =75th, 100/140 if AC<75th. Therapy was tailored to mean fasting (FG) and postprandial glycemia (PPG). RESULTS: Globally, 229 women completed the study, 78 in C, 151 in M. Use of insulin was 16.7% in C, 30.4% in M (total groups), significantly more frequent in M than in C (59.7% vs 15.4%) when considering only women with AC > or =75th c. Mean metabolic data were similar in the 2 groups, but in M a tightly-optimized subgroup, resulting from the lowering of GT due to AC > or =75th, coexisted with a less-controlled one, whose higher GT was justified by AC<75th. Pregnancy outcome was better in M, with lower (p<0.05*) rate of LGA* (7.9% vs 17.9%), SGA (6.0% vs 9.0%) and Macrosomia* (3.3% vs 11.5%). CONCLUSIONS: Our data show the value of a flexible US-based approach to the treatment of GDM. This model does not necessarily involve a generalized aggressive treatment, allowing to concentrate therapeutical efforts on a small subgroup of women showing indirect US evidence of fetal hyperinsulinization. Such a selective approach allowed to obtain a near-normalization of fetal growth, with clear advantages on global pregnancy outcome.

Risk of congenital complete heart block in newborns of mothers with anti-Ro/SSA antibodies detected by counterimmunoelectrophoresis: a prospective study of 100 women.

OBJECTIVE: To assess the true prevalence of congenital complete heart block (CCHB) in infants of anti-Ro/SSA-positive women known to have connective tissue disease (CTD) and, secondarily, to evaluate the prevalence of other electrocardiographic abnormalities in these newborns at birth. METHODS: A prospective study was conducted in 4 referral hospitals. One hundred anti-Ro/SSAA-positive mothers were followed up before they became pregnant and during the index pregnancy. Counterimmunoelectrophoresis and immunoblotting were used to test for antibodies to extractable nuclear antigens. RESULTS: Of the 100 women with anti-Ro/SSA antibodies, 2 had infants who developed CCHB in utero (2%). The CCHB was detected at 22 weeks and 20 weeks, respectively. One of the 2 mothers had primary Sjögren's syndrome (SS), and the other had undifferentiated CTD (UCTD). No case of CCHB occurred among the infants of 53 mothers with systemic lupus erythematosus (SLE). No fetal death occurred due to CCHB. In 2 centers, electrocardiography was recorded in 24 unselected newborns, and 4 were found to have sinus bradycardia. CONCLUSION: The prevalence of CCHB in newborns of prospectively followed up women already known to be anti-Ro/SSA positive and with known CTD was 2%. This finding is useful with regard to preconception counseling of these women. The risk of delivering an infant with CCHB may be higher in mothers with primary SS or UCTD than in those with SLE. Additional electrocardiographic abnormalities such as sinus bradycardia and prolongation of the QT interval may be present in their children.

[Neonatal lupus: clinical features and risk of congenital cardiac heart block in newborns from mothers with anti Ro/SSA antibodies] / Lupus neonatale: manifestazioni cliniche e rischio di blocco cardiaco congenito in neonati da madri con anticorpi antiRo/SS-A.

OBJECTIVE: To assess the prevalence of Congenital Heart Block (CHB) in newborns from anti Ro/SS-A antibodies positive mothers affected by connective tissue diseases (CTD) and to evaluate the prevalence of other manifestations of Neonatal Lupus (NL) and the electrocardiographic abnormalities. METHODS: A prospective study was conducted on 100 anti Ro/SS-A positive mothers that were followed before and during their 118 pregnancies (4 twin pregnancies and 18 second pregnancies). Counterimmunoelectroforesis (CIE) and immunoblot (IB) were used to test antibodies to extractable nuclear antigens (ENA). RESULTS: Only 2 cases of CHB (1.8%) were found among the 112 living newborns. In one case the mother with primary Sjögren's Syndrome (pSS) was anti Ro 60 and 52kD positive while in the other case the mother affected by undifferentiated connective tissue disease (UCTD) was anti Ro 60kD and anti La positive. No fetal death was due to CHB. There were no cutaneous rashes at birth while mild hepatic enzyme alterations were observed in 21 (68%) of the 31 tested newborns. In 22 healthy newborns an ECG have been registered and in 4 cases (18.2%) sinus bradycardia was found. During the follow up 7 suckling showed Cutaneous Neonatal Lupus. Moreover a six month girl developed Kawasaki Syndrome. CONCLUSIONS: The risk of delivering a child with CHB is 1.8% in anti Ro/SS-A positive mothers with CTD. This finding is extremely important in the preconceptional counseling of anti-Ro/SS-A positive women. Furthermore mild electrocardiographic abnormalities may be found in their healthy newborns.

[Clinical course of pre- and post-natal isolated congenital atrioventricular block diagnosed in utero]. / Evoluzione pre e postnatale del blocco atrioventricolare congenito isolato diagnosticato in utero.

We evaluated the pre- and postnatal outcome of isolated atrioventricular (AV) block detected during fetal life in order to identify factors that may affect the natural history of this lesion and to assess prenatal therapy. Over the past eight years, we consecutively evaluated 10 fetuses with complete AV block. The mean gestational age at diagnosis was 25.3 weeks and the mean heart rate was 57 bpm; two fetuses were hydropic. During pregnancy, one fetus suddenly died, while 6 out of 9 fetuses had a mean reduction in heart rate of 17.8 bpm; 4 patients had heart rate < 50 bpm. Five fetuses developed heart failure, which was severe in 2 cases and mild in 3. The mean gestational age at delivery was 31 weeks. Dexamethasone was administered to the mothers during pregnancy in 4 cases without modification of AV block and/or of heart rate, but in 3 out of 4 fetuses the general condition remained stable in spite of the reduction in heart rate in two of them. Sympathomimetic drugs were employed in 3 cases with an increase in fetal heart rate, but maternal discomfort appeared in two cases. Three newborns died during the first week of life, two of hydrops and one of persistent pulmonary hypertension. Cardiac pacing was performed in 6/9 patients within the first 8 months of life and in 3 within the first 2 days. In conclusion, morbidity and mortality are high when AV block is detected during fetal life. Negative prognostic factors are hydrops and a heart rate < 50 bpm. Pre-term delivery to enable cardiac pacing is probably the therapy of choice if gestational age is > 27-28 weeks. Sympathomimetic drugs are effective but are poorly tolerated by the mothers. Dexamethasone has no effect on AV block and/or heart rate, but may improve clinical tolerance of conduction disturbance.

Fetal blood sampling immediately before and within 24 hours of death in monochorionic twin pregnancies complicated by single intrauterine death.

OBJECTIVE: Our goal was to investigate the mechanisms that play a role in intrauterine death in monochorionic twins and that contribute to the high perinatal mortality and morbidity in the survivors. STUDY DESIGN: In 8 monochorionic twin pregnancies complicated by the intrauterine death of a single twin, we took samples from 5 twin fetuses immediately before death and from 4 of their cotwins and also from 4 surviving fetuses within 24 hours after death of the cotwin. RESULTS: Four of the 5 fetuses sampled who subsequently died were acidemic and 3 were hypoxemic. None of these fetuses or their cotwins were anemic at that time. All 4 survivors sampled within 24 hours of the death of each cotwin had low hematocrits. CONCLUSION: Fetal anemia, probably the consequence of acute blood loss just before the time of death of the cotwin, may play a role in the high mortality and morbidity found in the surviving twin. It is unlikely that immediate delivery of the surviving twin after death could affect the outcome.

Should we treat minor degrees of glucose intolerance in pregnancy?

We examined the pregnancy outcome of 112 women classified as minor degrees of glucose intolerance (MDGI) in pregnancy in a screening program based on Carpenter and Coustan's criteria. The MDGI group comprised 49 women with abnormal oral glucose challenge test (OGCT) followed by normal OGTT (group A), and 63 with "borderline" OGTT (1 abnormal value, group B). No treatment was offered to 88 MDGI women, while 26 received dietary advice and metabolic monitoring. A control group was constituted from 112 age- and BMI-matched negative screenees. Similar rates of cesarean sections and macrosomia, but higher rate of large for gestational age (LGA) babies (25.9% vs 14.3%) were found in MDGI, without difference between groups A and B. When comparing treated and untreated MDGI, lower LGA incidence (11.5% vs 30.2%) and no macrosomia were found in the former. In conclusion, untreated MDGI may present excessive fetal growth, which can be normalized by dietary treatment and metabolic monitoring.

[Prenatal diagnosis of anatomo-pathologic aspects of 2 cases of sirenomelia]. / Diagnosi prenatale e quadro anatomopatologico di 2 casi di sirenomelia.

The antenatal echographic diagnostic aspects and anatomopathological features of two foetuses suffering from sirenomelia, or caudal pole regression syndrome, are examined. Conduction of the two cases is compared. In the first case, observed at the 22nd week, antenatal diagnosis of sirenomelia led to the therapeutic interruption of pregnancy. The second case, seen close to term, closed with the birth of an already dead sirenomelic foetus.