Biology and Medicine
Editor-in-Chief: Eytan R. Barnea MD, FACOG
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EARLY
PREGNANCY: Biology and Medicine Editor-in-Chief: Eytan R. Barnea MD, FACOG |
| January 2001 Volume V, Number 1 ISSN: 1537-6583 Pages: 004-008 |
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The format of the review is to focus on a small number of selective and relevant articles that according to the editor can make a contribution in advancing early pregnancy investigation. Also included are few reports that have clinical relevance to the practicing clinician treating patients in early pregnancy.
Homocysteine and Folate Levels as Risk Factors for Recurrent Early
Pregnancy Loss
The relationship between recurrent early pregnancy loss and levels of serum folate and
plasma homocysteine concentrations was investigated in a case-control study.1
One hundred and twenty three white women who had recurrent pregnancy losses and did not
take folic acid supplements were recruited for the study. Folate, homocysteine (fasting
and afterload), pyridoxyl 5’-phosphate, and cobalamin concentrations were measured
and compared to 104 healthy controls.
Statistically significant lower median serum folate concentrations were observed in women who had spontaneous losses. Elevated levels of homocysteine (fasting and afterload) were also associated with increased risk for recurrent early pregnancy loss. The relative risk for early recurrent loss was increased with lower serum folate concentrations and higher homocysteine concentrations.
This study shows that Folic acid supplementation might be beneficial in women with histories of early pregnancy loss.
Increased Risk of Early Pregnancy Loss by Profound Suppression of
Luteinizing Hormone during Ovarian Stimulation in Normogonadotrophic Women Undergoing
Assisted Reproduction
The two-cell, two-gonadotrophin theory states that both FSH and LH are required for normal
follicular estradiol biosynthesis. However it is believed that low LH concentrations are
sufficient for follicle growth. This retrospective study examines the impact of LH
concentration in mid follicular phase on the outcome of IVF in normogonadotrophic women
subjected to pituitary suppression with GnRH analogue from the mid-luteal phase, followed
by ovarian stimulation with recombinant FSH.2
The outcome of IVF or ICSI in 200 consecutive couples was analyzed retrospectively. In all cases a standard stimulation protocol with mid-luteal GnRH agonist down regulation and ovarian stimulation with FSH was used. Ovarian response was monitored by ultrasound and serum estradiol. On stimulation day 8, serum concentrations of LH were recorded.
Low concentrations of LH (<0.5 IU/I) were found in 49% (98/200) and concentrations higher than 0.5 IU/I in 51% (102/200) of the women. Positive pregnancy tests per started cycle were similar in both groups 30% and 34% respectively. However the group with low LH concentrations had a significantly higher risk of early pregnancy loss (45%) compared to the group with higher LH concentration (9%).
This study suggest that women with low mid-follicular LH concentrations would benefit form supplementation with exogenous LH during ovarian stimulation, however to prove that a large prospective clinical trial is needed.
Polymorphisms in Biotransformation Enzymens and the Risk for Recurrent
Early Pregnancy Loss
Lifestyle factors such as smoking and consumption of alcohol or coffee have been
associated with recurrent pregnancy loss. Most potentially toxic compounds present in
alcoholic beverages, coffee or cigarettes require activation by phase I enzymes such as
cytochrome P450 to become an ultimate reactive compound. These activated forms may then be
subjected to detoxification by phase II enzymes, especially glutathione S-transferase
(GST). Polymorphisms in the phase II enzymes, GST genes may result in impaired
detoxification. In the placenta and deciduas GSTP1-1 is by far the most important isoform
present. The presence of a less functional GSTP1b allele is associated with impaired
detoxification.
The frequency of polymorphic variant of those enzymes was studied in 187 women with recurrent pregnancy loss and in 109 controls.3 The glutathione S-transferase P1b-1b genotype was found significantly more often in women with recurrent early pregnancy loss than in controls (12% versus 5%), in particular in those who consumed coffee or smoked cigarettes.
This study suggests that the presence of the GSTP1b-1b genotype which is associated with impaired detoxification, might cause an imbalance between phase I and II enzymes, and therefore induce the development of recurrent early pregnancy loss, in particular in combination with the consumption of coffee or smoking cigarettes.
The Effect of Thrombophylaxis on Pregnancy Outcome in Patients with
Recurrent Pregnancy Loss Associated with Factor V Leiden Mutation
Prevalence of Factor V leiden mutation has been found to be 2% to 6% in different
populations. Factor V leiden mutation has been found to be a significant risk for
thrombotic complications and is also associated with recurrent pregnancy loss. Twelve
women were found to have factor V leiden mutation out of fifty-six consecutive women
studied who had a history of two or more unexplained pregnancy losses.4 During
the study period seven of these women with factor V leiden mutation conceived and were
place on thrombophylaxis regimen. Starting early first trimester subcutaneous low
molecular weight heparin and oral low dose aspirin were given until delivery. Low
molecular weight heparin was continued six weeks following delivery.
Two women with factor V leiden had missed abortions early in the first trimester and five women completed their pregnancies and delivered healthy infants. The five pregnancies that progressed to term had normal fetal growth, normal Doppler flow studies. Thrombocytopenia and/or bleeding disorders were not encountered in any of the women.
In women with recurrent pregnancy loss associated with factor V leiden mutation thrombophylaxis with low molecular weight heparin and aspirin seems to be effective in reducing the risk of recurrent loss and allowing for a good neonatal outcome. A larger prospective study is needed to further justify this recommendation.
Early Detection of Preeclampsia by Determination of Platelet Aggregability
Preeclampsia is a leading cause of maternal and fetal morbidity and mortality in late
pregnancy. The exact pathophysiology of preeclampsia is still unknown and early diagnosis
is lacking. This study was designed to evaluate whether corrected whole blood platelet
aggregability is a suitable marker for early detection of preeclampsia.5 A
total of 71 pregnant women were studied. Twenty-five enrolled in the study before 25 weeks
gestation and 46 after. Out of the twenty-five women enrolled in the study early in the
pregnancy ten developed preeclampsia and all showed significantly higher collagen induced
platelet aggregation compared to control. The sensitivity and specificity of the collagen
induced whole blood platelet aggregometry was 100% for both in women enrolled before 25
weeks gestation and 81.5% and 47.4% respectively after 25 weeks gestation.
This study shows that platelet activation takes place early in preeclampsia and allows identification of pregnancies at risk for developing preeclampsia. Early detection of preeclampsia may be achieved by measuring collagen induced whole blood platelet aggregation with correction for the influence of hematocrit and platelet count.
The Optimum Time for Exogenous Human Chorionic Gonadotropin to Rescue the
Corpus Luteum
The optimal dosage, timing and frequency of hCG administration following in vitro
fertilization are unknown. In this study, hCG injections mimicking an early pregnancy
signal were administered and the response of the corpus luteum was monitored.6
Fourteen subjects were recruited and given exogenous hCG, 250, 500, 1000 and 2000 IU
intramuscularly on consecutive days starting on luteal day 4 (Group A; n = 5), luteal day
8 (Group B; n = 5), and luteal day 12 (Group C; n = 4). Corpus luteum response was
measured using salivary progesterone. All subjects acted as their own controls in a
preceding normal menstrual cycle.
Group B showed the highest mean peak progesterone concentration and the total amount of salivary progesterone secreted was significantly higher than in the control cycles. This study shows that the optimal time for administration of hCG to "rescue" the corpus luteum is around the midluteal phase in normally cycling women, coincident with the time of implantation.
Nausea and Vomiting in Early Pregnancy: Its Role in Placental Development
The etiology of morning sickness, which is experienced in early pregnancy by up to 70% of
pregnant women, has been linked to increased levels of thyroxine and placental hCG.
Morning sickness has been associated with decreased risk of miscarriage, preterm birth,
low birth weight, and perinatal death. Based on data from the literature a functional role
for morning sickness in stimulating early placental growth is postulated.7
Nausea and vomiting during early pregnancy induces a reduction in maternal energy intake causing lower levels of anabolic hormones, insulin, and insulin growth factor-1 (IGF-1). The lower levels of these anabolic hormones decreases anabolic maternal synthesis and fat deposition, favoring nutrients to be used more for the developing placenta. There is also data in the literature that suggests that women who are underweight will experience less severe symptoms of morning sickness compared to women with a normal pre-pregnancy body mass index. It is postulated that in women that are underweight the increase in energy intake will result in elevated insulin levels leading to impaired placental development and therefore reduced production of placental hCG and thyroxine and less nausea and vomiting.
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References
