Early transvaginal embryo aspiration: a safer method for selective reduction in high order multiple gestations.

Assisted reproduction technologies and ovulation induction for treatment of infertility continue to cause high order multiple gestations. Increased perinatal morbidity and mortality, as well as maternal morbidity, may complicate these pregnancies. Selective fetal reduction, an acceptable therapeutic approach in these cases, is usually performed at or after the ninth week of gestation, with KCl injected in the vicinity of the fetal heart, and is associated with a total pregnancy loss rate of 11.7%. We report our experience with 90 women who underwent early (mean 7.5 weeks gestation, range 7. 0-8.0 weeks) transvaginal selective embryo aspiration. The mean number of viable embryos before and after reduction was 3.5 and 2.1 respectively. Six (6.7%) pregnancies were lost before 24 gestational weeks. One miscarriage occurred at the tenth gestational week. The other five pregnancies were aborted at 17.3-21.6 weeks gestation. Additional interventions were performed in three of these pregnancies: genetic amniocentesis in two cases and cervical suture in one case. In the subset of 39 patients with>/=4 embryos, only one (2.6%) pregnancy loss was recorded. This loss rate is significantly lower (P < 0.05) than the 15.3% loss rate in patients with >/=4 fetuses calculated from other work. Four (4.4%) other pregnancies were complicated by premature delivery (25-28 weeks gestation). Mean gestational age of delivered pregnancies in our series was 35.7 weeks. In conclusion, early transvaginal embryo aspiration is a simple and relatively safe method for multiple pregnancy reduction. The overall pregnancy loss rate associated with early embryo aspiration is similar to that of procedures performed at later gestational age, but is significantly lower when the initial number of embryos is four or greater.     

Anti-phosphatidylserine/prothrombin antibodies are not frequently found in patients with unexplained recurrent miscarriages

OBJECTIVE: To determine whether the presence of anti-phosphatidylserine/ prothrombin antibodies (anti-PS/PT) can be a major factor in otherwise unexplained recurrent miscarriages. PATIENTS AND METHODS: Eighty-one consecutive patients with history of 2 or more recurrent miscarriages were studied. Patients with history of overt thrombotic events were not included. Patients were examined for plausible causes of miscarriages, and titer of IgG, IgM and IgA anti-PS/PT were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: Thirty-five patients had one or more plausible causes of recurrent miscarriages, including 12 positive for well-established anti-phospholipid antibodies, such as anti-beta2-glycoprotein I. None of the patients included in this study was found to be positive for anti-PS/PT. CONCLUSION: Detection of anti-PS/PT in addition to other anti-phospholipid antibodies does not seem to aid in the evaluation of patients with unexplained recurrent miscarriages.     

825例重度子痫前期患者的分娩时机与围产儿结局分析

目的探讨重度子痫前期孕妇的分娩时机及新生儿的结局。方法对825例重度子痫前期的患者,根据病情进一步治疗,期待治疗和终止妊娠,分析不同治疗方法的预后。结果孕周〉32周的新生儿和围产儿病死率低于32周前终止妊娠者,（P〈0.01）结论孕周已近34周的重度子痫前期患者,经促胎肺治疗后即可终止妊娠。而孕32周之前的重度子痫前期患者,在严密监测下尽量延长孕周,以增加胎儿的成熟度并不增加母亲并发症。     

Massive immunoglobulin treatment in women with four or more recurrent spontaneous primary abortions of unexplained aetiology

The aim of this trial was to investigate the efficacy of massive i.v. immunoglobulin (MIVIg) treatment for women with a history of recurrent spontaneous abortion (RSA) due to unexplained aetiology. The study included nine women (11 pregnancies) with a history of four or more consecutive RSA with unexplained aetiology and no live births. The mean number of fetal losses was 4.5 (range 4-6 abortions). Over the course of 5 days, immunoglobulin (20 g/day) was infused i.v. at gestational weeks 4-7. No additional infusions were carried out. Two pregnancies out of the 11 conceptions resulted in missed abortions at gestational weeks 6 and 7 respectively. Mosaicism (46XX/ 48XX, +16, +20), and tetraploidy (92XXXX) were found by chromosome analyses of the two aborti. Eight out of the other nine pregnancies resulted in full term deliveries of healthy neonates. One pregnancy developed intrauterine growth retardation and fetal distress, resulting in a premature delivery (30 gestational weeks) by Caesarean section. Thus, excluding the two abortions with chromosome aberrations, the MIVIg treatment was effective in all nine pregnancies of RSA women with unexplained aetiology. This MIVIg treatment (100 g administered in early gestation) may be a beneficial alternative to previous IVIg infusion methods, and should be further evaluated in a multicentric, placebo-controlled study, employing a larger number of homogeneous patients who fall into a high risk category of first trimester abortions.      

Complement Activation and Pregnancy Failure

Pregnancy represents a physiologic condition where maternal immune system tolerates the semi-allogenic fetus. The fetal tissues are directly exposed to the maternal blood with potential attacks from maternal immune system, including the activation of complement cascade. Small amounts, of both early and late components, of complement are physiologically found in the placenta, maybe in relation to the vascular remodeling process. A significant increase of complement activation was associated with different pathologic pregnancy outcomes, namely pre-eclampsia, recurrent spontaneous abortions, intra-uterine growth retardation, and anti-phospholipid syndrome (APS). In some, but not in all, mice models of APS, complement activation plays a major role in pregnancy loss, with a massive accumulation of C3 in the placenta, while C3 deficient mice didn't show fetal resorption. Basing on these findings, anti-phospholipid antibodies and complement activation (via C3a, C5a, and MAC) may cooperate in triggering a local inflammatory process, eventually leading to placental thrombosis, hypoxia, and neutrophil infiltration. However, histological analysis of human placenta tissues from APS women shows small rather than widespread inflammation. In a similar manner, complement activation can be detected in human APS placentas but without any relationship with pregnancy outcome and therapy. Further studies are necessary to investigate whether complement activation and inflammatory processes found in animal models are really taking place in APS.     

Maternal phenylketonuria collaborative study (MPKUCS) offspring: Facial anomalies,malformations, and early neurological sequelae

Maternal phenylketonuria (PKU) in untreated women has resulted in offspring with microcephaly, mental retardation, congenital heart disease (CHD), and intrauterine growth retardation. The Maternal Phenylketonuria Collaborative Study (MPKUCS) was designed to determine the effect of dietary control of blood phenylalanine (Phe) during pregnancy in preventing damage to the fetus associated with untreated Maternal PKU. A cohort of offspring from MPKUS pregnancies was ascertained and examined to evaluate malformations, including CHD, craniofacial abnormalities, microcephaly, intrauterine and postnatal growth retardation, other major and minor defects, and early abnormal neurological signs. For analysis, the women were grouped according to their mean Phe levels in μmol/liter, ≤360, 361–600, 601–900, or >900, during critical gestational weeks of 0–8 (N = 203) and 8–12 (N = 190), and average for Phe exposure throughout pregnancy (N = 183). Frequencies of congenital abnormalities increased with increasing maternal Phe levels. Significant relationships included average Phe 0–8 weeks and CHD (P = 0.001); average Phe 8–12 weeks and brain, fetal, and postnatal growth retardation (P < 0.0005 for all), wide nasal bridge (P < 0.0005), and anteverted nares (P = 0.001); and average Phe exposure during the entire pregnancy and neurological signs (P < 0.0005). Although 14% of infants had CHD, none of the CHD occurred at 120–360 μmol/liter and only one (3%) at 361–600 μmol/liter. At levels of 120–360 μmol/liter, there were three infants (6%) with microcephaly, two (4%) with postnatal growth, and none with intrauterine growth retardation, in contrast to 85%, 51%, and 26%, respectively, with Phe above 900 μmol/liter. These data support the concept that women with PKU should begin a low-phenylalanine diet to achieve Phe levels of <360 μmol/liter prior to conception and should maintain this throughout pregnancy. Am. J. Med. Genet. 69:89–95, 1997. © 1997 Wiley-Liss, Inc.     

Immunotherapy in Spring-Time Hay Fever

In a study of the efficacy of two different treatment schedules for perennial immunotherapy, 47 adult patients with spring-time hay fever due to allergy against birch and other deciduous trees were randomly assigned to three treatment groups: one group received birch, alder and hazel allergen in Allpyral, another group received the same Allpyral mixture and in addition all relevant tree pollens in aqueous extract and a control group received no injections. For determination of antibody titres the radioallergosorbent test (RAST) and the ammonium sulphate precipitation (ASP) technique were used. Cellular responsiveness was studied by measuring birch pollen (BP) induced leucocyte histamine release in peripheral blood. The clinical and immunological response was similar in the two treated groups. Treated patients had less symptoms and a lower consumption of antihistamine tablets during the pollen season than the control group. Non-IgE BP antibodies and IgE antibodies recorded with the ASP technique increased after immunotherapy while RAST values did not change significantly. A decrease of RAST values from postseasonal values during the first year to preseasonal values in the following year was seen in all patient groups but was less pronounced in treated than in untreated patients. The decrease was more pronounced in patients with high RAST values of postseasonal sera than in patients with low RAST values. Cellular reactivity increased slightly during the first phase of therapy but returned to the pre-treatment level later. Clinical improvement was positively correlated to the percentage increase of non-IgE antibody titre and to the pre-treatment non-IgE/IgE antibody ratio. Patients with high preseasonal RAST titres or high cellular sensitivity tended to have more severe symptoms during the pollen season. It is concluded that a mixture of birch, alder and hazel is sufficient for immunotherapy in spring-term hay fever. It is obvious that changes of a single immunological variable do not account for the therapeutic results in immunotherapy.     

Immunology: Defective maternal--fetal interaction in a murine autoimmune model

Anti-cardiolipin antibodies (ACA) are associated with recurrentfetal loss, but their role in this pathological condition isunknown. We recently developed an experimental mouse model ofthe anti-phospholipid syndrome, in which immunization of femalemice with a monoclonal anti-cardiolipin antibody resulted insubstantial failure of pregnancy. We observed that pre-implantationembryos derived from ACA-injected mothers exhibited morphologicalabnormalities and failed to implant in vitro. In the presentstudy, we designed embryo transfer experiments to determinewhether defective embryonic development originated as a maternaldefect, an embryonic defect or both. Embryos (3.5 day old),taken from ACA- and control-immunized mothers were transferredinto either an ACA-or a control-treated uterine environment(day 2.5 pseudo-pregnant females). On day 14 of gestation theincidence of pregnancy, the average number of fetuses per femaleand fetal resorptions were assessed. The ACA-treated uterineenvironment was found to be non-supportive for the developmentand implantation of normal embryos. Moreover, embryos derivedfrom ACA-immunized mothers, even after their removal from theACA-environment and transfer to a normal uterus, remained deficientThese results demonstrate that both the maternal and the embryoniccompartments were defective, as a result of previous exposureto the ACA.     

Heterotopic Caesarean scar pregnancy combined with intrauterine pregnancy successfully treated with embryo aspiration for selective embryo reduction: case report

Ectopic pregnancy situated in a Caesarean section scar is a rare but potentially life-threatening event. Because of its rarity, there are no universal treatment guidelines to manage this condition. We report a case of IVF-induced triplet heterotopic pregnancy of early gestational age that included one Caesarean scar pregnancy diagnosed as early as 6 weeks gestation. Treatment with embryo aspiration under vaginal ultrasonography for selective embryo reduction was given and the concurrent intrauterine twin pregnancy was preserved successfully.     

Pregnancy: Intrauterine sonographic assessments of embryonal liver length

Our purpose was to evaluate embryonal liver length measurementusing intrauterine sonography with a specially developed 20MHz flexible catheter-based high-resolution real-time miniature(2.4 mm outer diameter) ultrasound transducer in early first-trimesterpregnancy. A total of 36 women about to undergo therapeuticabortion at 7–9.9 weeks gestational age and one abnormalpregnancy with fetal hydrops at 9 weeks were studied. The normalrange of embryonal liver length for each day of pregnancy wasdetermined. A relationship between embryonal liver length andcrown-rump length measurements is described. A linear relationshipwas found between the menstrual age and embryonal liver length(R² = 93.3%), and a normal range of embryonal liver length forestimating the growth of the embryonal liver during early firsttrimester pregnancy was generated. A nonnogram of menstrualage as predicted by embryonal liver length was also generated.Embryonal liver length was curvilinearly correlated with crown-rumplength (R² = 92.3%). Embryonal liver length value (6.4 mm) ina case of fetal hydrops at 9 weeks was above the normal range.These results may provide an additional measurement for theestimation of gestational age in the early first trimester ofpregnancy. In this limited series one embryonal liver enlargementwas demonstrated and, thus, there is a potential for its usein the detection of embryonal congestive heart failure. Thevalue and potential applications of this new embryonal parameterare discussed.     

Heterogeneity of binding reactivity to different phospholipids of antibodies from patients with systemic lupus erythematosus (SLE) and with syphilis.

The binding specificities were investigated of anti-phospholipid antibodies derived from sera from 55 patients with SLE and related diseases, and from 33 patients with syphilis. Antibodies from both these groups of patients bind strongly to cardiolipin in solid-phase immunoassays, but only antiphospholipid antibodies from patients with autoimmune diseases are associated with thrombotic complications and recurrent spontaneous abortions. IgG anti-phospholipid antibodies from both groups of patients cross-reacted with a range of negatively charged phospholipids, but binding to neutral phospholipids was largely restricted to sera from patients with syphilis. A monoclonal IgM lambda anti-cardiolipin antibody, derived from a patient with autoimmunity, was used to inhibit binding of anti-phospholipid antibodies to cardiolipin and to phosphatidic acid. This antibody inhibited the binding of autoimmune sera to cardiolipin more strongly than sera from syphilis patients, but the converse pattern of inhibition of binding to phosphatidic acid was observed. The VDRL titre correlated with anti-phospholipid antibody activity in sera from syphilis patients, but not from those with autoimmunity. Lupus anti-coagulant activity correlated weakly with IgG antibody levels to each of the negatively charged phospholipids among the patients with autoimmunity. Lupus anticoagulant activity did not correlate uniquely with any anti-phospholipid antibody specificity. These results provide further documentation of the great heterogeneity of anti-phospholipid antibodies associated with autoimmune disease and syphilis.     

Transvaginal injection of potassium chloride and methotrexate for the treatment of tubal pregnancy with a live fetus.

A case of ectopic pregnancy with a gestational sac in the right tube of 25 mm diameter and beating fetal heart was treated conservatively by transvaginal, ultrasonically guided injection of potassium chloride and methotrexate. Serum levels of beta-human chorionic gonadotrophin returned to normal in 42 days and the tubal mass collapsed gradually and resolved in 7 weeks.     

Sonographic measurement of the fetal pancreas in women with gestational diabetes

IntroductionMaternal glycemic state is positively correlated with fetal insulin secretion. Randomized control studies have shown that treatment during pregnancy inhibits to some degree this glycemic effect. Our study aimed to assess fetal pancreas size in a population of treated mothers with gestational diabetes.Material and methodsA cross-sectional, prospective observational study was conducted. Pregnant women at 19–36 weeks of gestation with pre-gestational diabetes receiving insulin therapy or with gestational diabetes receiving either insulin or oral hypoglycemic therapy were recruited. The fetal pancreas circumference was measured and compared to the normal reference range. The Z score of the difference between measured and normal predicted mean pancreas circumference, the regression analysis throughout pregnancy, and the correlation between estimated fetal weight centile and pancreas circumference were calculated.ResultsNinety-one women who had gestational diabetes and thirty-four women who had pre-gestational diabetes were included in the study. For both groups, fetal pancreas circumference correlated significantly with abdominal circumference, estimated fetal weight and gestational age. The mean Z score between the predicted pancreas circumference in the group of women diagnosed with gestational diabetes and the predicted pancreas circumference in a normal population peaked at around 24 weeks of gestation (1.1) and decreased gradually afterward to a value of zero at 37 weeks. The mean Z score between the predicted pancreas circumference in the group of women with pre-gestational diabetes and the predicted pancreas circumference in a normal population constantly decreased with duration of pregnancy. It was positive until the 25^th week of gestation and then presented negative values towards the term.ConclusionsThe presented preliminary data suggest a possible correlation between glycemic control treatment, pancreas size, and gestational age.     

The effects of IgG purified from women with SLE and associated pregnancy loss on rat embryos in culture

PROBLEM: Recurrent fetal loss occurs in approximately 1% of women. Autoimmune causes have been suggested as a factor in some of these cases. High rates of intrauterine fetal growth retardation and increased incidence of prematurity is associated with systemic lupus erythematosus (SLE) and the anti-phospholipid syndrome (APS). Autoantibodies from sera of SLE/APS patients affect reproductive outcome in pregnant mice, as was studied in vivo, where injection of immunoglobulin (Ig)G purified from patients with APS to mice caused fetal resorptions and growth retardation. METHODS: In order to investigate the direct effect of IgG purified from women with SLE or APS on the growth and viability of embryos, we cultured 11.5-day old-rat embryos in their yolk sacs in the presence of IgG purified from SLE and APS patients. RESULTS: IgG purified from SLE and recurrent pregnancy loss (RPL) patients affected directly the embryo and yolk sac reducing their growth. The purified IgG positive for anti-cardiolipin/anti-DNA antibodies reduced yolk sac and embryonic growth more than sera negative for these antibodies. CONCLUSION: Various antiphospholipid antibodies affect differently the growth and development of the embryo and the placenta.     

Pregnancy outcome in recurrent spontaneous abortion associated with antiphospholipid antibodies: a comparative study of intravenous immunoglobulin versus prednisone plus low-dose aspirin

PROBLEM: To compare the use of intravenous immunoglobulins (IVIG) with prednisone plus low-dose aspirin (LDA) in treating pregnant women with a history of recurrent fetal loss having the antiphospholipid antibody (aPL), in terms of live-birth rate and maternal and perinatal morbidity. METHOD: A prospective, two-centers trial study included 82 recurrent aborters with aPL syndrome. Twenty-nine were treated with prednisone and LDA in one center, 53 received IVIG in the other center. Maternal and fetal outcomes and pregnancy complications were compared between groups. RESULTS: Live-birth rates were equivalent between groups (78 vs 76%). Mean birth weight was higher in the IVIG group than in the prednisone plus LDA group. In the prednisone- plus LDA-treated patients, gestational hypertension and gestational diabetes were found significantly more often than in the IVIG-treated group (14 vs 5% and 14 vs 5%, respectively). CONCLUSION: In patients with aPL syndrome, IVIG treatment improved pregnancy outcome, with significantly lower pregnancy complication rates, when compared with prednisone plus LDA therapy.     

Is there a human fetal gallbladder contractility during pregnancy?

The purpose of this study was to evaluate whether human fetal gallbladder contractility exists in the second half of pregnancy. Ultrasound examinations were performed on 54 normal pregnant women from 20 to 40 weeks of gestation. Fetal gallbladder volume was monitored every 30 min from 08:00 to 18:00 h in each patient. Maximum gallbladder volume was related linearly with gestational age between 20 and 32-35 weeks of gestation, after which a plateau was observed. Minimum gallbladder volume was unchanged throughout gestation. Functional capacity (maximum volume - minimum volume) of the fetal gallbladder increased linearly with advancing gestation until 32-35 weeks gestation, and thereafter was constant. Contractility rate [(maximum volume - minimum volume/maximum volume)x100] increased curvilinearly with advancing gestation (R(2) = 30.7%, P < 0.0001). The daily change in fetal gallbladder volume showed a typical sinusoidal pattern, and the contractility cycle of gallbladder volume was unchanged during pregnancy (3.1 +/- 0.6 h). These results suggest that there is an apparent gallbladder contractility in human fetuses in utero, and that maternal meals seem not to affect the volume of the fetal gallbladder. Further study is needed to clarify the physiological role of fetal gallbladder contractility during pregnancy.     

Hydatidiform mole coexistent with a twin live fetus: a national collaborative study in Japan

A national collaborative study was conducted in Japan to evaluate the clinical course and the sequelae of patients with hydatidiform mole coexistent with twin live fetus (HMTF). Seventy-two cases of HMTF were diagnosed based on gross appearance and histopathological criteria. In 18 cases, the molar parts were cytogenetically confirmed to be of androgenetic origin (complete mole). The overall incidence of persistent trophoblastic tumour (PTT) in patients with HMTF was 30.6%, and it increased to 50.0% in the 18 patients with proven androgenetic complete mole coexistent with twin live fetus (CHMTF). Among these patients, the mean gestational age at termination of pregnancy or delivery in those who developed PTT (n = 9) and those who did not (n = 9) were 20.6 and 19.4 weeks respectively. The incidence of severe maternal complications was significantly higher in patients who subsequently developed PTT (P < 0.05). The rate of subsequent development of PTT in patients with CHMTF was found to be considerably higher than in a previous study of patients with single complete mole (50 and 12.5% respectively). However, since the risk of malignancy is unchanged with advancement of gestational age, continued pregnancy may be allowed in patients with HMTF provided that severe maternal complications are controlled and fetal karyotype and development are normal.     

IgG class anti-cardiolipin antibody as a possible marker for evaluating fetal risk in patients with systemic lupus erythematosus

To identify the correlation between incidence of anti-phospholipid antibodies and fetal prognosis in pregnant SLE patients, we measured the amount of anti-cardiolipin antibody in their sera, using solid-phase enzyme immunoassay (EIA) methods. Findings in the group having poor obstetric results (fetal loss group) and in those with a history of full-term births (live birth group) were compared with regard to other anti-phospholipid antibodies. The incidence of IgG class anti-cardiolipin antibody was 60% in the fetal loss group and 19% in the live birth group, (P less than 0.05). The incidence of the other anti-phospholipid antibodies, including lupus anticoagulant and biological false-positive serological test for syphilis (BFP-STS), did not differ significantly between the two groups. Therefore, the presence of IgG class anti-cardiolipin antibody may prove to be a useful marker for evaluating fetal risk in SLE patients.     

A Clinical Trial for the Treatment of Antiphospholipid Antibody-Associated Recurrent Pregnancy Loss With Lower Dose Heparin and Aspirin

This study was conducted to determine if lower dose heparin (LD Heparin) combined with aspirin is as efficacious as higher dose heparin (HD Heparin) for the treatment of the antiphospholipid antibody syndrome in women seeking pregnancy. The method of the study was a prospective, single center trial including 50 patients who were consecutively assigned to treatment. Each patient had at least three consecutive, spontaneous pregnancy losses, positive antiphospholipid antibodies on two occasions, and a complete evaluation. Data were compared using Fisher's exact test. Viable infants were delivered from 20/25 (80%) women treated with higher dose heparin vs. 19/25 (76%) of women treated with lower dose heparin. There were no significant differences between groups with respect to gestational age at the time of delivery (37.2 ± 3.4 versus 37.7 ± 1.6 weeks), maternal complications, or fetal complications. A lower dose of heparin plus aspirin was as effective as higher dose heparin for the treatment of antiphospholipid antibody-associated recurrent pregnancy loss.     

Reduction of multifetal pregnancies to twins does not increase obstetric or perinatal risks.

Selective reduction in cases of multiple fetuses is used more often nowadays due to the increased number of multiple pregnancies resulting from assisted reproduction. In this retrospective study, we investigated whether twin pregnancies derived from fetal reduction carry a higher obstetric and perinatal risk compared to standard twin pregnancies. We found that the rate of miscarriage was 10.6% in the reduction group (n = 158) compared to 9.5% in the controls (n = 135). Mean gestational age at delivery was 35.7 weeks in the reduction group versus 35.1 weeks in the control group. Mean neonatal weight at birth was 2.260 g (800-3.750 g) in the reduction group compared to 2.240 g (540-3.360 g) in controls. Perinatal mortality rate was 49.3 per thousand after reduction and 42.0 per thousand in the control group. There was no statistically significant difference in any of the above parameters. Therefore, multifetal pregnancy reduction to twins does not appear to increase obstetric or perinatal risks.