Mental health of mothers and fathers of twins conceived via assisted reproduction treatment: a 1-year prospective study.

BACKGROUND: Although twin deliveries after assisted reproduction treatment (ART) are common, the mental health of the parents has scarcely been addressed. Therefore, we evaluated the psychological well-being of ART and spontaneously conceiving parents of twins and singletons. Furthermore, the impact of parity and children's health-related factors on mental health was evaluated. METHODS: We conducted a prospective longitudinal questionnaire study among ART parents of 91 pairs of twins and of 367 singletons and on control parents of 20 pairs of twins and of 379 singletons in the 2nd trimester of pregnancy (T1), and when the children were 2 months (T2) and 1-year old (T3). Symptoms of depression and anxiety, sleeping difficulties and social dysfunction were addressed via a questionnaire. The effects of parity and child-related factors were assessed at T2. RESULTS: At T1, ART mothers of twins showed fewer symptoms of depression than control mothers of twins (P < 0.05). At T2, both ART and control mothers of twins had more symptoms of depression and anxiety than all mothers of singletons (F = 5.20, P < 0.05 and F = 3.93, P < 0.05, respectively). At T3, both ART and control mothers of twins continued to report more symptoms of depression than the mothers of singletons (F = 10.01, P < 0.01), but a difference in anxiety symptoms was seen only in the control group. All fathers had similar mental health at T1. At T2, ART and control fathers of twins reported more symptoms of depression (F = 4.15, P < 0.05) and social dysfunction than fathers of singletons. At T3, both ART and control fathers of twins had more symptoms of depression (F = 4.29, P < 0.05) and anxiety (F = 5.40, P < 0.05) than fathers of singletons. Control fathers of twins had more sleeping difficulties than fathers of singletons (F = 6.66, P < 0.01). Parity did not differently affect parental mental health at T2 in the study groups. Prematurity did not affect maternal mental health, but it had a negative impact on control fathers' social dysfunction (F = 3.34, P < 0.05). CONCLUSIONS: Twin parenthood, but not ART, has a negative impact on the mental health of mothers and fathers during the transition to parenthood. ART parents' mental health was not affected by parity or children's health-related factors.

Infertility treatment and marital relationships: a 1-year prospective study among successfully treated ART couples and their controls.

BACKGROUND: Evidence about the effects of infertility and assisted reproduction technique (ART) on marital relationships is discrepant. Here, we examined the impact of ART on marital relationships. The roles of life stressors, infertility and treatment characteristics in predicting marital relations were also evaluated. SUBJECTS: 367 couples with singleton IVF/ICSI pregnancies. CONTROLS: 379 couples with spontaneous singleton pregnancies. Women and men were assessed when the child was 2 months (T2) and 12 months old (T3). They further reported stressful life events at T2 and depression in pregnancy. RESULTS: No between-group differences were found in marital satisfaction and dyadic cohesion. Dyadic consensus deteriorated from T2 to T3 only among control women. Sexual affection was low among control men at T2 and stressful life events decreased it further. Depression during pregnancy predicted deteriorated marital relations only in control couples. Several unsuccessful treatment attempts were associated with good dyadic consensus and cohesion among ART women. Spontaneous abortions and multiple parity predicted poor marital satisfaction in ART women, whereas long duration of infertility and multiple parity predicted poor marital relations in ART men. CONCLUSIONS: Successful ART does not constitute a risk for marital adjustment. The shared stress of infertility may even stabilize marital relationships.

Fear of childbirth and pregnancy-related anxiety in women conceiving with assisted reproduction.

OBJECTIVE: To compare the prevalence and predictors of severe fear of childbirth and pregnancy-related anxiety in groups of assisted reproduction treatment (ART) and spontaneously conceiving women with singleton pregnancies. METHODS: The ART group (n = 367, nulliparous 260) represented a cohort from five Finnish infertility clinics in 1999. The control group (n = 379, nulliparous 135) was enrolled in this study by consecutive sampling the same year. Fear of childbirth was assessed by means of the revised version of the Fear-of-Childbirth Questionnaire and pregnancy-related anxiety by means of the Pregnancy Anxiety Scale at gestational week 20 +/- 3.2 (mean+/-standard deviation). RESULTS: The frequency of severe fear of childbirth and anxiety (classified as total scores in the 90th percentile or higher in the revised Fear of Childbirth Questionnaire and Pregnancy Anxiety Scale) did not differ between the groups. Nulliparity was associated with more frequent severe anxiety only in the controls. In nulliparous participants, a partnership of more than 5 years decreased the risk of severe fear of childbirth (odds ratio 0.3, 95% confidence interval 0.2-0.7). In the nulliparous ART group, a long duration of infertility (7 or more years) increased the risk of severe fear of childbirth (odds ratio 4.4, 95% confidence interval 1.2-16.9). CONCLUSION: Women conceiving after ART do not experience severe fear of childbirth or pregnancy-related axiety more often than spontaneously conceiving controls. However, a long duration of infertility is an independent risk factor regarding severe fear of childbirth. LEVEL OF EVIDENCE: II-2.

Impact of infertility characteristics and treatment modalities on singleton pregnancies after assisted reproduction.

Obstetric and neonatal outcomes of assisted reproduction and control singletons were evaluated after taking into account treatment characteristics and infertility background. The elective single embryo transfer (eSET) group (n = 45) was compared with the compulsory single embryo transfer (cSET; n = 52), double embryo transfer (DET; n = 227) and control (n = 304) groups. Infertility-related prognostic factors for neonatal outcomes were also analysed. Data were collected with structured questionnaires at gestational week 20 and 8 weeks after delivery. Spontaneous onset of delivery was more typical of the eSET group than of cSET and DET groups (68.9 versus 52.0%, P = 0.02). Mean (+/-SD) gestation at birth (39.3 +/- 1.6 weeks) and mean birth weight (3,470 +/- 505 g) of eSET singletons were comparable with other assisted reproduction groups, but gestational duration was lower than in the eSET group than in the control group (39.9 +/- 1.4; P < 0.05). However, numbers of preterm births and low birth weight infants were similar between groups. History of induced abortion increased risk of preterm birth (OR 4.5 and 95% CI 1.2-17.1) in assisted reproduction singletons. A small though clinically unimportant difference in gestational age at birth and birth weight between assisted reproduction and control singletons was found regardless of the number of embryos transferred.

The impact of successful assisted reproduction treatment on female and male mental health during transition to parenthood: a prospective controlled study.

BACKGROUND: The dynamics of mental health during the transition to parenthood have not been a focus of research. Our prospective longitudinal study was designed to reveal whether there are differences in mental health during the transition to parenthood between parents undergoing treatment with assisted reproduction techniques (ART) and those who conceive spontaneously. STUDY GROUP: 367 couples with a singleton ART pregnancy using their own gametes. CONTROL GROUP: 379 couples with a spontaneous singleton pregnancy. Men and women separately filled in questionnaires including the General Health Questionnaire: at the 18th-20th week of pregnancy, 2 months postpartum and 1 year postpartum (T3). The effect of social and child-related factors on mental health was examined. RESULTS: ART women had fewer depressive symptoms during pregnancy than controls, but at T3 their depressive symptoms were at the same level as seen in controls. Anxiety symptoms increased among control but not among ART women across the transition. ART men reported generally fewer mental health symptoms than their controls. Social and child-related stressors had negative impacts on mental health changes among control couples, whereas no impact was found among ART couples. CONCLUSIONS: Successful ART did not predict mental health problems during the transition to parenthood. Moreover, ART couples' mental health was remarkably resistant to social and child-related stress during the transition to parenthood.

Luteal phase start of low-dose FSH priming of follicles results in an efficient recovery, maturation and fertilization of immature human oocytes.

In this prospective study we investigated whether the maturation and fertilization of immature oocytes can be improved by administration of recombinant follicle stimulating hormone (rFSH) starting in the late luteal phase in two groups of women: group 1 (n = 6) women with regular menstrual cycles; and group 2 (n = 6) women with irregular cycles and polycystic ovaries (PCO) on ultrasound examination. Low-dose (37.5 IU) rFSH was commenced 11 days after LH surge during a spontaneous menstrual cycle and on the ninth day of progesterone administration in an irregular cycle. Recombinant FSH was continued until the leading follicle was approximately 10 mm in diameter. The oocytes were retrieved after withdrawing rFSH for 2-5 days. In total, 136 oocytes were recovered (group 1, 67 oocytes; group 2, 69 oocytes). Nine of the oocytes from PCO women were atretic at retrieval. Oocytes complete with cumulus cells were cultured for 44 h in complex tissue culture medium supplemented with gonadotrophins and fetal calf serum. After maturation, the cumulus cells were removed and metaphase II oocytes were injected with spermatozoa. Respectively, the oocyte maturation and fertilization rates were 64 and 72% in group 1, and 78 and 57% in group 2 (not significant). After fertilization, the zygotes (group 1, n = 22; group 2, n = 11) and cleavage stage embryos (group 1, n = 9; group 2, n = 15) were frozen in propanediol. All women except one (11/12) had approximately five zygotes or cleaved embryos frozen. The viability of in-vitro matured frozen-thawed embryos was generally poorer than that (81%) seen after conventional intracytoplasmic sperm injection, with 61% survival in group 1 and 23% in group 2. Fifteen embryo transfers resulted in one miscarriage at 6 weeks gestation. The late luteal start of low-dose rFSH yielded a good number of immature oocytes in women with both regular and irregular cycles. Two out of three of these oocytes matured and fertilized. However, cryosurvival of the zygotes and cleaved embryos was unsatisfactory and thus cryopreservation of in-vitro matured embryos may not be an optimal procedure.

VEGF, its receptors and the tie receptors in recurrent miscarriage.

The aetiology of recurrent miscarriage (at least three consecutive miscarriages) usually remains unsolved. The vascular endothelial growth factor (VEGF) family of proteins, together with their receptors and the Tie (tyrosine kinase with immunoglobulin and epidermal growth factor homology domains) receptors, are crucial for embryonic development. Therefore, we used immunohistochemistry to analyse the expression of VEGF, the VEGF receptors (VEGFR)-1, -2, and -3, and the Tie-1 and Tie-2 receptors in placental and decidual tissue of women with a history of recurrent miscarriage and missed abortion (MA; n = 12) or blighted ovum (BO; n = 6), and from normal early terminated pregnancies (n = 12). Compared with controls, the MA and BO groups showed: (i) diminished placental trophoblastic VEGF immunoreactivity; (ii) weaker VEGFR-1 and -2 immunoreactivity in decidual vascular endothelium; (iii) reduced placental trophoblastic Tie-1 receptor immunoreactivity; and (iv) reduced decidual vascular endothelial Tie-1 and -2 receptor immunoreactivity. The absence of VEGFR-3 immunoreactivity in decidual vascular endothelium was also noted in all study groups. Interestingly, placental villi from the BO group presented blood vessel-like structures negative for von Willebrand factor, but positive for VEGF, VEGFR-1, -2, -3, Tie-1 and Tie-2 receptor. We conclude that the expression of these antigens may be altered in recurrent miscarriages.

Comparison of two recombinant follicle-stimulating hormone preparations in in-vitro fertilization: a randomized clinical study.

A randomized comparison of two recombinant human follicle-stimulating hormone (recFSH) preparations (Gonal-F and Puregon) in ovarian stimulation for in-vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) was carried out at the Infertility Clinic of the Family Federation of Finland. A total of 348 women (aged 22-43 years) suffering from infertility due to miscellaneous causes was recruited. Of these, 344 underwent stimulation using equal starting doses (150 IU/day: Gonal-F n = 164, Puregon n = 158 or 300 IU/day: Gonal-F n = 8, Puregon n = 14) after down-regulation with intranasal buserelin from the mid-luteal phase. Similar clinical pregnancy rates were achieved with both preparations; 33.5% per cycle and 37.4% per embryo transfer (24.5% one-embryo and 75.5% two-embryo transfers, n = 147) with Gonal-F (150 IU/day) and 32.9% per cycle and 36.4% per embryo transfer (30.1% one-embryo and 69.9% two-embryo transfers, n = 145) with Puregon (150 IU/day). The ongoing cumulative pregnancy rates after frozen-thawed embryo transfer were 35.4% with Gonal-F and 37.7% with Puregon. Six cycles were cancelled because of a low response (three in each group). Similar numbers of oocytes were obtained in both groups; 13.0 with 150 IU/day and 6.1 with 300 IU/day Gonal-F, and 12.4 with 150 IU/day and 7.1 with 300 IU/day Puregon. The fertilization and cleavage rates and the incidence of moderate or severe ovarian hyperstimulation syndrome (Gonal-F, 2.0% and Puregon, 0.7%) were also similar. Gonal-F and Puregon were equally and highly effective in stimulation for IVF and ICSI.

Lack of association between serum antibodies to Chlamydia trachomatis and a history of recurrent pregnancy loss.

OBJECTIVE: To study the relation between recurrent pregnancy loss (RPL) and infection with Chlamydia trachomatis, and to compare the prevalence of antibodies to C. trachomatis in women with primary and secondary RPL. DESIGN: Prospective comparative study. SETTING: University hospital and university student health center. PATIENT(S): Seventy patients with RPL were selected from women attending an RPL outpatient clinic; 40 normal parous women and 94 asymptomatic sexually active women served as controls. INTERVENTION(S): Blood samples were collected during the clinical examinations for RPL. MAIN OUTCOME MEASURE(S): Serum immunoglobulin (Ig) G and IgA antibodies were detected by two independent methods, a recombinant ELISA specific to the genus Chlamydia and microimmunofluorescence testing specific to the species C. trachomatis. RESULT(S): There was no statistically significant difference in the frequencies of IgG or IgA between the women with RPL and the controls. The antibody frequencies were similar in the women with primary and secondary RPL. CONCLUSION(S): The presence of serum antibodies to C. trachomatis is not associated with RPL. Women with primary and secondary RPL do not differ with respect to the prevalence of antichlamydial antibodies. Thus, women with RPL do not benefit from screening for chlamydial IgG or IgA antibodies.

Screening for coeliac disease in women with a history of recurrent miscarriage or infertility.

Because subclinical coeliac disease may decrease fertility or complicate pregnancy, we screened women with recurrent miscarriage of unknown aetiology (n = 63), unexplained infertility (n = 47) and infertility with a known cause (n = 82), for anti-endomysium antibodies in serum to find undiagnosed coeliac disease. One woman (1-6%) with recurrent miscarriage, another woman (2.1%) with unexplained infertility and one woman (2.0%) in the control group (n = 51), were considered to have coeliac disease. We could not demonstrate a higher frequency of coeliac disease in women with infertility or recurrent miscarriage, but suggest that undiagnosed coeliac disease is common in women.

Fertilization, embryo quality, and cryosurvival in in vitro fertilization and intracytoplasmic sperm injection cycles.

PURPOSE: Our purpose was to investigate the influence of semen quality on fertilization, embryo morphology, cleavage, and cryosurvival in conventional in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) programs. METHODS: A retrospective analysis of 513 couples undergoing IVF and 255 couples undergoing ICSI was done. RESULTS: Semen quality influenced fertilization in IVF and abnormal fertilization in IVF and ICSI, but no effects on the development, morphology, implantation capacity, or cryosurvival of embryos were found. Fertilization, embryo quality, and cryosurvival rates were similar after IVF and ICSI. The fertilization rate of mature oocytes in IVF was lower when cytoplasmic immaturity in the oocyte population was frequent. The speed of development of embryos was 2 hr faster after ICSI than after IVF. Two-cell-stage embryos survived best after cryopreservation with propanediol and sucrose on day 2. CONCLUSIONS: After fertilization, semen parameters had no effect on the quality or cryosurvival of embryos in either IVF or ICSI.

Genetic variant of luteinizing hormone in women with a history of recurrent miscarriage.

Because the biological and clinical significance of a genetic variant of luteinizing hormone (LH) is unclear, we therefore evaluated the occurrence of variant LH in women with a history of recurrent spontaneous abortion (RSA) and related it to specific LH concentrations, luteal function and pregnancy outcome. Of the 85 RSA women, 30 (35.3%) had variant LH (28 heterozygous and two homozygous), and 55 women (64.7%) a normal wild-type LH ratio. These frequencies are similar to those reported from the general Finnish population. No significant differences were observed in specific LH concentrations based on LH status (7.2+/-1.4 IU/l, mean +/- SEM, variant LH, versus 8.5+/-1.6 IU/l, wild-type LH). Variant LH was twice as common in women with body mass index (BMI) > 25 kg/m2 (9/15, 60.0%) than in those with BMI < or =25 kg/m2 (21/70, 30.0%, P < 0.05). The presence of variant LH was not associated with any clear effect on endocrine variables such as endometrial maturation or mid-luteal phase oestradiol and progesterone concentrations. During follow-up, 23 women with variant LH (76.7 %) and 41 with wild-type LH (74.5%) became pregnant: 14 miscarried (21.9%, six with variant LH and eight with wild-type LH) and two had ectopic pregnancies, whereas 48 (75.0%) succeeded (17 with variant LH and 31 with wild-type LH). LH concentrations before pregnancy were similar in women with a successful outcome (8.0+/-1.3 IU/l) or with a miscarriage also in that pregnancy (7.4+/-1.4 IU/l). In conclusion, variant LH is common in RSA women who are relatively overweight (BMI > 25 kg/m2) but its presence is not reflected in endometrial maturation and miscarriage rates.

Comparison of buserelin and nafarelin in IVF cycles and in subsequent frozen-thawed embryo transfer cycles.

OBJECTIVE: To compare two gonadotropin-releasing hormone agonists for down-regulation prior to superovulation in in vitro fertilization/embryo transfer treatment. METHODS: Infertility patients (n=181) were randomized to receive buserelin (1200 microg/day, n=90) or nafarelin (800 microg/day, n=91) intranasally starting in the luteal phase. Serum levels of LH, estradiol and progesterone were measured during the treatment. The cycles were compared with regard to number of oocytes, fertilization and implantation rates and achieved pregnancies. RESULTS: Serum LH was lower after two weeks on buserelin: 1.8 (1.3-2.4) IU/L (median, with lower and upper quartile in parenthesis), than after nafarelin: 2.6 (1.8-4.0) IU/L, (p=0.0001). No other differences in serum hormone levels could be detected. More oocytes were recovered in the buserelin group: 13.0 (8.0-19.0) vs 11.0 (6.8-15.0), (p=0.046), but the fertilization rate was higher in the nafarelin group (49.9%, vs 45.1%, p=0.023). Implantation rate was higher in the nafarelin group (26.28% vs 15.5%, p=0.030), but there were an equal number of deliveries in both groups (20.9% vs 15.6% per started stimulation, p=0.420). In the subsequent frozen-thawed embryo transfer cycles the implantation rate was 21.1% (nafarelin group) and 10.6% (buserelin group, p=0.067), the pregnancy rate/ET was 31.7% and 17.0% (p=0.107) and the delivery rate was 22.0% and 10.6% (p=0.148), respectively. CONCLUSIONS: Differences exist in IVF-cycles down-regulated with buserelin or nafarelin which might affect embryo quality and treatment outcome.

Low-dose aspirin in prevention of miscarriage in women with unexplained or autoimmune related recurrent miscarriage: effect on prostacyclin and thromboxane A2 production.

Early pregnancies in women with a history of recurrent spontaneous abortion (RSA) are accompanied by a deficiency in vasodilatory and anti-aggregatory prostacyclin (PGI2) and/or overproduction of its endogenous antagonist thromboxane A2 (TXA2). We evaluated the effect of a low-dose aspirin (LDA) on PGI2 and TXA2 production and on pregnancy outcome in RSA women with and without detectable anticardiolipin antibodies (ACA). Of 82 RSA women studied, 66 became pregnant, and of them, 33 (six with elevated and 27 with normal ACA concentrations) were randomized to receive LDA (50 mg/day) and 33 (six with elevated and 27 with normal ACA concentrations) to receive placebo (PLA) from a mean of 6.6 days after the missed period to delivery. Treatment with LDA inhibited platelet TXA2 production similarly in RSA women with and without detectable ACA and with continuing pregnancies (7.0 +/- 0.7 ng/ml, LDA group versus 254.5 +/- 37.8 ng/ml, PLA group, mean +/- SEM, P < 0.0001) or miscarrying pregnancies (13.8 +/- 3.8 ng/ml compared with 233.6 +/- 59.8 ng/ml, P < 0.0001 respectively). Furthermore, LDA decreased urinary excretion of the TXA2 metabolite (2,3-dinor-TXB2) both in pregnancies which went to term (6.1 +/- 0.6 ng/mmol creatinine, LDA group versus 19.3 +/- 3.0 ng/mmol creatinine, PLA group, P < 0.0001) or again ended in miscarriage (4.7 +/- 0.8 ng/mmol creatinine versus 17.3 +/- 4.4 ng/mmol creatinine, P < 0.0001 respectively), but did not affect the excretion of the prostacyclin metabolite (2,3-dinor-6-keto-PGF1alpha). Early pregnancy ultrasound examination revealed a living fetus in 58 women. Of these, seven in the LDA group (23.3%, four with elevated and three with normal ACA concentrations) and five in the PLA group (17.9%, two with elevated and three with normal ACA concentrations; not significant) experienced a miscarriage. All infants were healthy, and the frequency of growth retardation was similar in both groups (13.0%). One woman in the LDA group (4.3%) and three women receiving PLA (13.0%) developed pre-eclampsia (not significant). Therefore, although treatment with LDA caused a desirable biochemical effect, it did not improve pregnancy outcome in RSA women with or without detectable ACA.

Deficient syncytiotrophoblast tumour necrosis factor-alpha characterizes failing first trimester pregnancies in a subgroup of recurrent miscarriage patients.

Pregnancy failure in mice has been associated with increased placental concentrations of the pro-inflammatory cytokine tumour necrosis factor-alpha (TNF-alpha). To investigate the role of uterine TNF-alpha in human first trimester miscarriage, we have collected human decidual and trophoblast tissue from women (i) undergoing surgical termination of pregnancy (n = 27), (ii) undergoing a sporadic miscarriage (n = 20) and (iii) with a history of recurrent pregnancy loss [>3 consecutive pregnancy losses (n = 26)] undergoing a further miscarriage. Formalin fixed tissues were examined for TNF-alpha mRNA (in-situ hybridization) and protein (immunohistochemistry). In decidua from all three groups, TNF-alpha protein and mRNA were co-localized to the decidual stroma, the luminal surface of some maternal vessels and to the glandular epithelium. Chorionic villi from the normal pregnancy and the sporadic miscarriage group exhibited co-localized TNF-alpha protein and mRNA in the syncytiotrophoblast and cytotrophoblast. In the recurrent miscarriage group, however, 63.6% of the biopsies showed positive immunostaining in only the cytotrophoblast, compared with 4.0% of women undergoing surgical termination of pregnancy and 0.0% of women with a sporadic failed pregnancy (P < 0.001). TNF-alpha mRNA was also localized exclusively to this layer. This may be a secondary effect caused by a different mechanism of pregnancy loss unique to this subgroup.

The immunolocalization of bcl-2 at the maternal-fetal interface in healthy and failing pregnancies.

Programmed cell death by apoptosis occurs in both fetal and maternal tissues during early pregnancy. To investigate a role for apoptosis at the maternal-fetal interface, we have immunolocalized the bcl-2 protein in formalin-fixed decidual and placental tissue collected from women undergoing surgical termination of pregnancy (n = 22), from women undergoing a sporadic miscarriage (n = 16) and from women with a history of recurrent pregnancy loss (more than three consecutive pregnancy losses; n = 22) undergoing a further miscarriage. In all three groups, bcl-2+ cells were found in aggregates and dispersed in the stroma, and immunoreactivity was observed in glandular epithelium. Double immunostaining revealed that a majority of stromal bcl-2+ cells were CD56+ large granular lymphocytes. A computerized image analysis revealed no significant differences in percentage area of bcl-2 or CD56+ immunostaining. Significantly more biopsies from the surgical termination group (4/10) had > 20% positive immunostaining for CD56 compared with 0% in the other two groups combined (0/20; P < 0.05). Bcl-2 immunoreactivity was observed in the villi syncytiotrophoblast, and staining intensity was consistently greater in the surgical termination group. The possible roles of bcl-2 at the maternal-fetal interface are discussed.

Antibodies to beta 2-glycoprotein I and prothrombin in habitual abortion.

OBJECTIVE: To determine the occurrence of antibodies to beta 2-glycoprotein I (beta 2-GP-I) and prothrombin in women with histories of habitual abortions when pregnant and nonpregnant. DESIGN: Antibodies to beta 2-GP-I and prothrombin were measured by ELISA using irradiated polystyrene plates in 43 women with habitual abortions and 22 healthy controls. SETTING: Departments I and II of Obstetrics and Gynecology, University Central Hospital of Helsinki. PATIENT(S): Twenty-two women of the habitual abortion patients had never delivered (primary aborters) and 21 had delivered at least one living child before miscarriage (secondary aborters). INTERVENTION(S): Venous blood samples were collected before and during pregnancy. MAIN OUTCOME MEASURE(S): Immunoglobulin G class antibodies to beta 2-GP-I and prothrombin. RESULT(S): The secondary aborters showed higher levels of antibodies to prothrombin than the primary aborters when both pregnant and nonpregnant and also showed higher levels of antiprothrombin antibodies than the controls when pregnant. No such differences were found in levels of antibodies to beta 2-GP-I. The habitual abortion patients showed a tendency toward higher levels of these autoantibodies when pregnant than when nonpregnant. Gestational diabetes was more common among the antibody-positive habitual abortion patients than among the antibody-negative patients. CONCLUSION(S): Increased levels of antiprothrombin antibodies were associated with secondary abortions. Elevated levels of antibodies to beta 2-GP-I and prothrombin often were found in habitual abortion patients with gestational diabetes.

Prostaglandin and cytokine release by trophoblastic villi.

Trophoblastic villi may have several protective mechanisms against the maternal immune system. They do not display major human leukocyte antigen antigens, and therefore a T cell-mediated response is unlikely. The syncytiotrophoblast provides a seamless coating, and the microvilli on its surface represent a very large surface area which has a high capacity for absorbing antibody. The syncytiotrophoblast also contains inhibitors of complement. Although these mechanisms are essential, they may not be sufficient protection. An additional mechanism by which the trophoblast could control its immediate environment in the decidua or maternal blood may be through the release of prostaglandins (PG) and cytokines. This possibility has been investigated here by measuring PG and several cytokines released from first trimester trophoblastic villi cultured for 24 h. PGE is the main primary prostaglandin with a release of 240 +/- 95 pg/mg/24 h. There was an extensive accompanying production of metabolites (13,14-dihydro-15-keto PGF, 2.4 +/- 0.4 ng/mg/24 h, and 13,14-dihydro-15-keto PGE, 0.61 +/- 0.11 ng/mg/24 h). Cytokines were measured in culture fluid by specific enzyme-linked immunosorbent assays. Interleukin (IL)-2 and IL-10 release were not detectable, but IL-1 beta (5.2 +/- 1.1 pg/mg/24 h) and tumour necrosis factor (TNF) alpha (2.3 +/- 0.5 pg/mg/24 h) were found to be accompanied by much higher concentrations of inhibitors, IL-1 receptor antagonist (200 +/- 44 pg/mg/24 h) and soluble receptors for TNF types I (19.5 +/- 1.6 pg/mg/24 h) and II (19.3 +/- 2.8 pg/mg/24 h). Because PGE can influence the function of many leukocytes by raising intracellular cAMP concentrations, the release of humoral factors from the villous trophoblast might be important in pregnancy maintenance.

Antibodies to oxidized low-density lipoprotein and to cardiolipin in nonpregnant and pregnant women with habitual abortion.

OBJECTIVE: To determine the occurrence of antibodies to oxidized low-density lipoprotein (LDL) in women with a history of habitual abortion before and during pregnancy. DESIGN: Immunoglobulin G class antibodies to malondialdehyde modified LDL were determined by a solid-phase ELISA in 42 habitual aborters before pregnancy, in 39 patients during pregnancy, and in 23 comparable nonpregnant and 22 pregnant control women without a history of abortion. In addition, we assessed the presence of anticardiolipin antibodies by ELISA in the same sera. SETTING: Departments I and II of Obstetrics and Gynecology, University Central Hospital of Helsinki, Helsinki, Finland. RESULTS: Early pregnancy was accompanied by a decrease in the median levels of antibodies to oxidized LDL both in habitual aborters and in the control series. Only one patient exhibited a raised level of antibodies to oxidized LDL before pregnancy but, during pregnancy, nine patients (23%) had elevated levels of antibodies to oxidized LDL, similar to women with a favorable outcome of pregnancy (6/27, 22%) and in women whose current pregnancy also ended in abortion (3/12, 25%). Cardiolipin binding antibodies were detected in three habitual aborters before pregnancy (7%) and in nine women during pregnancy (23%), with a tendency to be more frequent in patients with miscarrying pregnancies than in those with continuing pregnancies (4/12, 33% and 5/27, 19%). Antibodies to oxidized LDL and cardiolipin were simultaneously present in three habitual aborters with continuing pregnancies. CONCLUSIONS: Increased levels of antibodies to oxidized LDL and cardiolipin may be associated with habitual abortion.