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EARLY PREGNANCY: Biology and Medicine Editor-in-Chief: Eytan R. Barnea MD, FACOG

The format of the review is now to focus on a small number of selective and relevant articles that can make a contribution in advancing early pregnancy investigation. Also included are some reports, which have clinical relevance for the practicing clinician treating patients in early pregnancy.

Vitamin B12 deficiency, Infertility and Recurrent Fetal Loss
The relationship of infertility and recurrent early fetal loss in patients who were vitamin B12 deficient was investigated in a small group of patients. Fourteen patients with 15 episodes of vitamins B12 deficiency were studied. Vitamin B12 levels less than 175pg/ml were considered subnormal. In 11 of the 15 episodes levels of less than 100 pg/ml were seen.

In 11 of 15 episodes, recurrent early fetal loss was a prominent feature. Two of these patients had never had a full-term delivery. One case had seven spontaneous abortions before the finding of vitamin B12 deficiency. Treatment with vitamin B12 resulted in the patient’s first full-term delivery within nine months and two more full-term deliveries afterwards. In six cases patients with vitamin B12 deficiency spontaneous abortions were followed by a period of infertility greater than one year.

Vitamin B12 is a co-factor in the methylation pathway converting homocysteine to methionine, and a deficiency will lead to raise homocysteine levels. Hepercoagulability due to elevated homocysteine levels may lead to fetal loss. A prolong deficiency may result in infertility by interfering with ovulation or leading to implantation defects.

HLA-G Expression in Trophoblast Cells Circulating in Maternal Peripheral Blood during Early Pregnancy
During early pregnancy fetal cells circulate in the maternal blood. The purpose of this study was to evaluate the use of trophoblast cells in maternal peripheral blood during early pregnancy and to demonstrate their use for clinical diagnosis.

Twenty-two women were recruited at the prenatal diagnostic center to participate in this study. 25 to 30 ml heparinized blood samples were taken at 8 to 14 weeks gestation. After an enrichment step with density gradient centrifugation, immunocytochemical identification and deoxyribonucleic acid fluorescence in situ hybridization was carried. A specific HLA-G antibody was used together with X and Y chromosome specific probes. Fetal sex was correctly identified in 17 of the 21 euploid pregnancies. In one pregnancy complicated by trisomy 21 male fetal trisomic cells were identified in the sample.

The procedure described needs to be improved and tested on a large series. However the concept that trophoblast cells circulating in maternal blood early in pregnancy can be used for screening for numeric chromosomal abnormalities was demonstrated.

Plasma Volume Expansion in Early Pregnancy
Inadequate plasma volume expansion in pregnancy has been linked with fetal growth restriction and preeclampsia. The objective of this prospective study was to determine the timing of the onset of plasma volume expansion through the menstrual cycle into pregnancy and to examine if reduced plasma volume before conception contributes to infertility.

Twenty-one subjects were studied during 38 menstrual cycles to establish baseline menstrual cycle data. Ten subjects conceived within 1 year of menstrual cycle data. Plasma volume changes beginning with menses and continuing into pregnancy were examined in these ten women.

Plasma volume expansion can be identified after the sixth menstrual week. By 12 menstrual week, plasma volume has expanded by about 14%± 12% over follicular phase measurements. No association between plasma volume and infertility was found, however the study lacked sufficient power for this conclusion.

In vitro Fertilization and Embryo Transfer during Natural Cycles
Ovarian stimulation has been widely used in In Vitro Fertilization (IVF) programs. Concerns about risks of ovarian stimulation such as hyperstimulation syndrome, multiple fetal pregnancies, decreased endometrial receptivity and increased cost has renewed interest in IVF undertaken without ovarian stimulation.

Results of a prospective clinical study including women under 40 with a single cause of infertility and regular ovulatory cycles were presented. Other inclusion criteria were normal semen analysis and serum FSH level on day 2 of <10 IU/L.

Thirty-two cycles were started in 19 patients who satisfied the inclusion criteria. Egg collection was performed in 12 cycles. Four pregnancies resulted from embryo transfer (ET) in eight cycles. Pregnancy rates were 12.5% per cycle initiated, 33.3% per retrieval cycle and 50% per transfer.

Natural cycle IVF provides a simple low-cost with less side effect alternative for patients with tubal or unexplained infertility.

Factor XII Deficiency in Women with Recurrent Miscarriage
Patients with recurrent venous thromboses have been found to increase rates of factor XII deficiency. The aim of this study was to determine the prevalence of factor XII deficiency in women with a history of recurrent miscarriage.

A total of 241 consecutive Japanese women with a history of two or more recurrent miscarriage were assessed for the etiology by conventional screening methods. After excluding other causes for recurrent miscarriage seven women were found to have reduced Factor XII activity and APTT prolongation. Of these seven patients, six had experience early pregnancy losses while one patient had repeated mid-trimester fetal losses. None of these patients had antiphospholipid antibody syndrome (APS).

In 241 women with a history of recurrent miscarriage, the prevalence of Factor XII deficiency was 2.9%. Factor XII deficiency may have an impact on embryo development and a cause for early fetal loss due to thromboembolus in syncitiotrophoblasts of the uterine spiral artery.

Polycystic Ovaries and Recurrent Miscarriage a Reappraisal
The aim of this study was to determine if women with polycystic ovaries (PCO) and history of recurrent pregnancy loss are also at risk for adverse pregnancy outcome. Other aims were to determine the prevalence of PCO among women with recurrent miscarriage and the biochemical profile of women with recurrent miscarriage and PCO.

The prevalence of PCO was established among 2199 consecutive women with a history of recurrent pregnancy loss. A diagnosis of PCO was made if the ovarian volume was enlarged (>9ml), there were ³ 10 cysts of 2-8 mm in diameter in one plane and there was increased density of the stroma.

The prevalence of PCO was 40.7% (895/2199). There was not a statistically significant difference in the overall live birth among women with PCO (60.9%; 142/233) compared to women with normal ovaries (58.5%; 148/253). There was also no difference in the mean gestation at delivery or the mean birth weight between the two groups. Neither an elevated serum luteinizing hormone concentration (>10) nor an elevated serum testosterone concentration (>3nmol/l) was associated with increased pregnancy loss.

This study did not find a specific endocrine abnormality that can distinguish between women with PCO into those with good or poor prognosis.

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References:

1. Bennett M.: Vitamin B12, Deficiency, Infertility, and Recurrent Fetal Loss. J. Rep Med Vol 46, No 3., 2001

2. Van Wijk I., Griffioen S., et al.: HLA-G Expression in Trophoblast Cells Circulating in Maternal Peripheral Blood during Early Pregnancy. Am J Obstet Gynecol, Vol 184, No 5., 2001

3. Bernstein I. R., Ziegler W., Badger G.: Plasma Volume Expansion in Early Pregnancy. Obstet Gynecol Vol. 97, No. 5, Part 1, May 2001

4. Yu Ng E. H., Chi Chui D. K., et al.: In Vitro Fertilization and Embryo Transfer during Natural Cycles. The Journal of Repro Med 95, March 2001

5. Yamaada H., Kato E.: Factor XII Deficiency in Women with Recurrent Miscarriage. Gynecol Obstet Invest 49:80-83, 2001

6. Rai R., Backos M., et al.: Polycystic Ovaries and Recurrent Miscarriage a Reapraisal. Hum Reprod, 15 (3):612-5, March 2000