Shun-ichiro Izumi

Prevalence and heterogeneity of antiphosphatidylethanolamine antibodies in patients with recurrent early pregnancy losses.

OBJECTIVE To describe the prevalence of antiphospholipid antibodies to both anionic and zwitterionic phospholipids in women with early recurrent pregnancy losses (RPLs). DESIGN Retrospective data analysis. SETTING Tokai University Hospital, Kanagawa, Japan. PATIENT(S) One hundred thirty-nine patients with unexplained early RPLs. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Enzyme-linked immunosorbent assays were used to measure autoantibodies to phosphatidylethanolamine, cardiolipin, and phosphatidylserine. RESULT(S) Twenty-eight (20.1%), 17 (12.2%), and 2 (1.4%) patients of the 139 total patients were positive for immunoglobulin (Ig) G, IgM, and IgA antiphosphatidylethanolamine antibodies, respectively. Because 3 patients had two isotypes, 44 (31.7%) of the patients were positive for antiphosphatidylethanolamine antibodies. Six patients (4.3%) and 1 patient (0.7%) were positive for IgG and IgM antiphosphatidylserine antibodies, respectively. Seven patients (5%) were positive for beta2-glycoprotein I-independent anticardiolipin IgG, and 1 patient was positive for beta2-glycoprotein I-dependent anticardiolipin IgG. Two patients (1.4%) had lupus anticoagulant. CONCLUSION(S) Our data show a statistically stronger association between RPLs and antiphosphatidylethanolamine antibodies than between RPLs and antibodies to anionic phospholipids for early gestational losses. Our data suggest that antiphosphatidylethanolamine antibodies may be a risk factor in patients with early RPLs.

Anti-annexin V antibodies in patients with early pregnancy loss or implantation failures.

OBJECTIVE To describe the prevalence of annexin V antibodies (aANX) in women with early recurrent pregnancy losses (RPLs) or recurrent IVF-ET failure. DESIGN Retrospective data analysis. SETTING Tokai University Hospital, Kanagawa, Japan. PATIENT(S) Two hundred thirty-eight patients with RPLs, 48 patients with recurrent IVF-ET failure and 179 nonpregnant and 120 pregnant control group women. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) ELISA was used to measure autoantibodies to annexin V. RESULT(S) An ELISA system developed for aANX revealed a dose-dependent relationship between annexin V and aANX. The positive/negative cutoff was set at 7 multiples of the median based on the 99th percentile of normal nonpregnant control group patients. Patients with RPLs (5.5%) or recurrent IVF-ET failure (8.3%) had a significantly increased incidence of aANX (IgG) compared with normal nonpregnant (1.1%) or pregnant control group women (0), whereas the prevalence of aANX between both patient groups or between both control groups was not statistically different. Specificity was confirmed by absorption studies using annexin V and by immunoblots. CONCLUSION(S) Our data show that aANX are associated with both RPLs and IVF-ET failure. We propose that anti-annexin V antibodies should be considered a risk factor for these reproductive failures.

Individualized High-Dose Cabergoline Therapy for Hyperprolactinemic Infertility in Women with Micro- and Macroprolactinomas

CONTEXT Cabergoline is effective for hyperprolactinemic hypogonadism. However, the rate of cabergoline-induced pregnancy in women with prolactinoma remains unknown. Also unknown is whether cabergoline can control tumor growth and thereby achieve successful pregnancy in patients with macroprolactinomas. METHODS Eighty-five women with macroprolactinomas (n = 29) or microprolactinomas (n = 56) received prospective, high-dose cabergoline therapy for infertility based on individual prolactin suppression and/or tumor shrinkage. The patients included 31 bromocriptine-resistant, 32 bromocriptine-intolerant, and 22 previously untreated women. Conception was withheld until three regular cycles returned in women with microadenoma and until tumors shrank below 1.0 cm in height in women with macroadenoma. Cabergoline was withdrawn at the fourth gestational week. RESULTS Cabergoline normalized hyperprolactinemia and recovered the ovulatory cycle in all patients. All adenomas contracted, and 11 macroadenomas and 29 microadenomas disappeared. Eighty patients (94%) conceived 95 pregnancies, two of which were cabergoline-free second pregnancies. The dose of cabergoline at the first pregnancy was 0.25-9 mg/wk overall and 2-9 mg/wk in the resistant patients. Of the 93 pregnancies achieved on cabergoline, 86 resulted in 83 single live births, one stillbirth, and two abortions; the remaining seven were ongoing. All babies were born healthy, without any malformations. No mothers experienced impaired vision or headache suggestive of abnormal tumor reexpansion throughout pregnancy. CONCLUSION Cabergoline achieved a high pregnancy rate with uneventful outcomes in infertile women with prolactinoma, independent of tumor size and bromocriptine resistance or intolerance. Cabergoline monotherapy could substitute for the conventional combination therapy of pregestational surgery or irradiation plus bromocriptine in macroprolactinomas.

Increased natural Killer-Cell activity is associated with infertile women

PROBLEM: An increase in natural killer (NK)‐cell activity has been observed in women with unexplained recurrent miscarriages. Because of the many similarities between infertility and early pregnancy loss patients, we investigated whether infertile women had raised NK‐cell activity.
 METHOD OF STUDY: We tested 94 infertile women who, in spite of treatment, were unable to conceive for 6 or more months. NK‐cell activity was measured by using a chromium‐51 release cytotoxicity assay, with K562 human myeloid leukemia cells as targets.
 RESULTS: NK‐cell activity of the infertile group (mean±SD; 40.2%±14.7) was significantly higher than the control group (31.5%±11.9, P<0.0001). The increased NK‐cell activity was not associated with age, infertile duration, depression scores, treated hyperprolactinemia, or treated endometriosis.
 CONCLUSIONS: In certain patients, elevated NK‐cell activity may be considered an independent risk factor for infertility.

Different antiphospholipid antibody specificities are found in association with early repeated pregnancy loss versus recurrent IVF-failure Patients

PROBLEM: Patients having in vitro fertilization and embryo transfer (IVF‐ET) failures show an increased incidence of antiphospholipid (aPL) antibodies; but controversy exists whether aPL can induce IVF‐failure. This study was designed to compare aPL specificities between recurrent IVF‐failure patients versus repeated early pregnancy loss (RPL) patients.
 METHOD OF STUDY: Anticardiolipin (aCL), lupus anticoagulant (LA), antiphosphatidylserine (aPS), antiphosphatidylethanolamine (aPE), and antinuclear antibodies (ANA) were measured in 74 recurrent IVF‐ET failure patients and compared with 273 early RPL patients (<10 weeks).
 RESULTS: An increased incidence of IgG‐aPE and ANA was observed for both groups in comparison with controls. Patients with recurrent IVF‐ET failure showed a significantly higher prevalence of IgG‐aPS (P=0.02) and IgG‐aCL (P=0.02) when compared with early RPL patients or controls.
 CONCLUSIONS: IgG‐aPS and IgG‐aCL may be responsible for some IVF‐failures. Additional studies are needed to clarify the pathogenic role of IgG‐aPS and IgG‐aCL on IVF‐ET failure.

Effect of psychiatric group intervention on natural-killer cell activity and pregnancy rate

We investigated the effects of psychiatric group intervention on the emotions, natural-killer (NK) cell activity and pregnancy rate in Japanese infertile women by a randomized study. Thirty-seven women completed a 5-session intervention program and were compared with 37 controls. Psychological discomfort and NK-cell activity (47.7% to 34.1%, P<.0001) significantly decreased after the intervention, whereas no significant changes were observed in controls. According to a 1-year follow-up of both groups, the pregnancy rate in the intervention group was significantly higher than that of controls (37.8% vs. 13.5%, P=.03). Psychological group intervention was therefore effective in Japanese infertile women.

Dietary intake estimations of polybrominated diphenyl ethers (PBDEs) based on a total diet study in Osaka, Japan

This study presents the results of a total diet study performed for estimating the dietary intake of polybrominated diphenyl ethers (PBDEs) in Osaka, Japan. The concentrations of 36 PBDEs were measured in samples from 14 food groups (Groups I–XIV). PBDEs were detected only in Groups IV (oils and fats), V (legumes and their products), X (fish, shellfish, and their products), and XI (meat and eggs) at concentrations of 1.8, 0.03, 0.48, and 0.01 ng g−1, respectively. For an average person, the lower bound dietary intakes of penta- and deca-formulations were estimated to be 46 and 21 ng day−1, respectively. A high proportion of the decabrominated congener (DeBDE-209) was observed in Group IV. To confirm the presence of DeBDE-209 in vegetable oils, an additional analysis was performed using 18 vegetable oil samples. Of these, seven contained ng g−1 levels of DeBDE-209.

Stiffness of systemic arteries in appropriate- and small-for-gestational-age newborn infants.

OBJECTIVE. The purpose of this work was to study the stiffness of systemic arteries in appropriate and small for gestational age newborn infants. The distance between diametrically opposite points of the arterial lumen was measured with a phase locked loop echo tracking system coupled to a B-mode ultrasonic imager. PATIENTS AND METHODS. A cross-sectional study of 51 appropriate for gestation age infants including 22 preterm infants was done to obtain normal data. We also studied 47 small for gestational age infants, who were identified antenatally by an umbilical artery Doppler flow waveform pulsatility index >95th percentile. The stiffness index of the common carotid artery and abdominal aorta was calculated from the relationship between systemic blood pressure and arterial diameter during the cardiac cycle. RESULTS. In the appropriate for gestation age group, the systolic and diastolic diameters of the common carotid artery and abdominal aorta, as well as the stiffness index, increased with the gestational age at birth. In the small for gestational age group, the arterial diameters and blood pressure were also within the reference range. Using the arterial stiffness index values from the appropriate for gestation age group, the small for gestational age group was divided into 3 subgroups: 18 infants with normal stiffness index values for both arteries, 19 infants with a high stiffness index of the abdominal aorta, and 10 infants with a high stiffness index for both arteries. The clinical outcome was significantly worse in the latter 2 subgroups compared with the normal infants and was also worse in the infants with a high stiffness index for both arteries compared with the high abdominal aorta subgroup. CONCLUSION. The antenatal increase of afterload caused by a high placental vascular resistance was associated with a decrease of aortic distensibility in the compromised small for gestational age infants, suggesting that the structure of the aortic wall was altered. In the most profoundly compromised small for gestational age infants, the high stiffness index of both the common carotid artery and abdominal aorta may indicate more extensive arterial damage.

Anti-annexin A5 Antibodies in Reproductive Failures in Relation to Antiphospholipid Antibodies and Phosphatidylserine

Problem: The presence of IgG anti‐annexin A5 (IgGαA5) and/or antiphospholipid antibodies (aPL) are risk factors associated with recurrent spontaneous abortion. Problems are whether IgA anti‐annexin A5 (IgAαA5) is pathogenic, and how IgGαA5 works.

Preconception Peripheral Natural Killer Cell Activity as a Predictor of Pregnancy Outcome in Patients with Unexplained Infertility

Problem:  Preconception high peripheral natural killer (NK) cell activity in women with recurrent spontaneous abortion can predict subsequent miscarriages. We have examined prospectively, for the first time, the pregnancy rate in patients with unexplained infertility by measuring the peripheral NK activity.