Current Practice in Obstetrics and Gynecology—2 Pankaj Desai
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SECTION 1
1OBSTETRICS2

Sense and Nonsense of Hormonal Support in First Trimester of Pregnancy1

Prakash Bhatt
 
PREAMBLE
  1. Hormonal support for patients of first-trimester abortion has been an extremely controversial field of the subject of recurrent spontaneous abortion. I plan to confine my presentation to only two hormones1 progesterone2 human chorionic gonadotropins. Let me add that the word “chorionic” need to be replaced because it creates the impression that the hormone has its origin from chorionic tissue. We now know that this crucial chemical is present long before actual chorionic tissue develops.
    The unconventional hormonal support in the form of thyroid hormones in subclinical hypothyroidism or use of dopamine agonists in patients of hyperprolactinemia or hormone for ovulation induction in patients of dysovulatory function or luteal phase defects form a different discussion in their own merits.
  2. The scientific fraternity had viewed hormonal support for its strictly endocrine function only. It is comparatively recently that we have started thinking about immunomodulatory events—perhaps mediated by these hormones acting as paracrine and autocrine chemical messengers—that play a crucial role in “acceptance of fetal allograft” with its sphere of influence at chorio-decidual/fetomaternal interface and even pre implantation/post-fertilization period.
    4
    The immuno modulatory role of hormones, chiefly progesterone and human chorionic gonadotropins has been the center of interest and controversy.
  3. Complete description of immunological events responsible for acceptance or non rejection is out of scope of present article. For the detailed description of these events, I will refer the interested readers to an excellent article by Gavin P Sacks, Chris WG Redman and Ian L. Sergent, published in “Progress in Obstetrics and Gynecology.” Volume 15 edited by John Studd. But I will present various hypothesis and clinical trials in favor/against this role and their significance in reference to successful pregnancy.
  4. He use/misuse/abuse of hormones for several situations which though clinically look different—Luteal phase defect, recurrent pregnancy wastage, recurrent spontaneous abortions in first trimester, even clinical entity known as threatened abortion—stem from a basic immunomodulatory dysfunction.
 
BACKDROP
 
Embryo-decidual Signal
 
Rescue of the Corpus Luteum
Following ovulation, the corpus luteum (CL) is formed and secretes progesterone, which has a trophic effect on the endometrium. Studies have shown that a variety of signals can rescue the CL. These include hCG in humans, prolactin in rodents, and estrogen in pigs, indicating that the CL rescuing signals are species-specific. When cow and mare uteri are removed, prostaglandin F2α (PGF2α) is not released and the CL persists long-term; therefore, the presence of the conception actually prevents luteolysis.1 But the presence of an embryo is not necessary, and hCG injections, for example, can prolong the life-span of the CL to a certain degree. This contrasts with the uterus, in which a viable embryo must be present in order for the endometrium to become receptive. Thus, recognition of pregnancy and successful implantation take place before the stage when rescue of the CL occurs, strongly suggesting that there is no linkage between tolerance and the CL.
Human chorionic gonadotropin (hCG) is a glycoprotein composed of two dissimilar subunits: α and β. The a subunit is similar to pituitary gonadotropins, while the β-hCG is very similar to luteinizing hormone (LH). hCG and LH bind to the same receptor in the corpus luteum. Therefore, both maternal LH and embryonic hCG can regulate hormone secretion from the corpus luteum. During the luteal phase of menstrual 5cycle, either the corpus luteum undergoes spontaneous regression within about 14 days or, if pregnancy occurs, hCG binds to the LH/hCG receptor and extends its viability. hCG stimulates the corpus luteum to produce a number of different hormones, including estrogens, progestins, relaxins, and inhibin.2,3 These hormones in turn maintain early pregnancy until the placenta can produce sufficient levels of steroids to support the conceptus. Increasing levels of hCG are secreted by the syncytiotrophoblast of the early placenta, and appear in serum. The rapidly increasing serum levels of hCG are sufficient to maintain the corpus luteum until its functional capacity diminishes at about the 7th week of gestation, after which the corpus luteum regresses. The decline in corpus luteum function is coincident with the shift in progesterone production from the corpus luteum to the placenta, which then produces sufficient steroids to maintain the rest of the pregnancy.4
In the human, several sources of evidence demonstrate that hCG is necessary for the maintenance of the corpus luteum. Firstly, the administration of exogenous hCG in the absence of pregnancy has been shown to prolong corpus luteum function, provided that exposure to hCG occurs before the onset of luteal regression, which begins on about the 10th post-ovulatory day. Secondly, ovariectomy or removal of the corpus luteum before the 8th week of pregnancy causes miscarriage, whereas pregnancy continues independently of corpus luteum function after the 9th week of gestation.4
Early pregnancy failure is associated with low serum levels of hCG. Low serum hCG may be due to the death of trophoblast several weeks before expulsion of the conceptus. Robust observational evidence indicates that hCG is critical to early pregnancy and that a lack of hCG is related to miscarriage. Understandably, the attractive theory emerges that there may be a beneficial effect of hCG supplementation in idiopathic recurring pregnancy loss (RPL) and in those women with an “endocrine cause” for their recurring pregnancy loss. Clearer attention to the type of pregnancy loss is needed, as historical studies contain poor descriptive information, which in turn can lead to ascertainment and reporting bias.5
The exogenous administration of hCG is strategically aimed at stimulating progesterone production from the corpus luteum and thereafter the fetoplacental unit. In recurring miscarriage patients, a preconceptual, whole-cycle study of the progesterone profile fails to provide proof that such patients have a suboptimal progesterone rise in the luteal phase. Interestingly, a suboptimal luteal estradiol rise was evident in the oligomenorrheic group.
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DOES THE EMBRYO MATERNAL DIALOGUE START PRIOR TO IMPLANTATION?
As we have seen, the CL initially does not need the conceptus, and can persist for a few weeks before it undergoes spontaneous regression, at menses. Therefore, the embryo-maternal dialogue required for implantation likely does not involve the CL. In humans, for example, implantation take place one week before the CL would undergo regression. If the CL were involved in embryo recognition, it could take place only when there was intimate embryo-maternal contact. But this is clearly not the case, and the search for the elements involved in the early interaction has been long going. First, here, brief rationale of the need for maternal recognition of the embryo shortly after fertilization is presented.
 
UNIQUE PHENOMENA REQUIRE UNIQUE SIGNALS
In order for a semi-or totally foreign embryo or even a cross-species transfer to implant and lead to successful progeny, unique embryo derived signals must be present, due to the absence of a host-versus-graft or graft-versus-host reaction. Moreover, the maternal system must accommodate and nurture the conceptus until delivery, and any immune tolerance is therefore conditional because rejection may take place at any moment until delivery. In addition, such a unique phenomenon would have to be pregnancy specific; for tolerance to be successful, the embryo must be viable and the maternal system receptive. The signal must be present early in embryo development, must be potent, and must have specific sites of action both on the maternal immune system and on the endometrium. The signal must also be universally mammalian, because the same early phenomenon takes place in all mammals (and any diversity only occurs at the implantation phase).
What properties would such a signal have? It would modulate the maternal immune system without suppressing it. This is essential, because during pregnancy the mother is exposed to pathogens and her ability to maintain an effective immune system to combat disease is essential for survival—both for her and for the embryo. Therefore, the signal would have to allow maternal immunity to function unimpeded, allowing it to fight bacteria, viruses, and parasites, while maintaining the tolerance towards the embryo. The tolerance that this signal creates must not be excessive; otherwise the mother's ability to reject a defective embryo or seriously infected fetus would be inhibited. Of course, most defective 7embryos are rejected early, and, in case of infection, premature labor frequently ensues. An additional role of this signal would be to prime the endometrium, and make the uterine environment hospitable to the embryo. Finally, it is clear that as the embryo-maternal interaction becomes intimate, the dynamics change, and there are complex events that take place that could be labeled as a maintenance of tolerance rather than the initiation of tolerance.
 
WHICH CURRENTLY KNOWN COMPOUND COULD BE THE UNIVERSAL TOLERANCE BIOMARKER?
This chemical signal—which will be a wonder drug to solve several issues in several areas of medicine, has been ascribed to several known agents uptil now. “Growth Factor Impurity of commercially available urinary hCG”, hCG itself and several more compounds have been the targeted molecules. The main diagnostic marker of human pregnancy is hCG, but it does not reflect pregnancy viability, it cannot be detected early in embryo culture media, and its persistence in the circulation after pregnancy has terminated, greatly limits its clinical use. hCG has an important role in the maintenance of the corpus luteum following implantation, and it has been shown to be involved in altering the biochemical behavior and morphology of endometrial cell types, by acting on a specific binding site (CG/LH-R). A local immunological role has also been ascribed to hCG.6 However, hCG is not pregnancy-specific, is unique to humans, and significantly, is also found in various cancers. It appears that most of the effect of hCG in supporting pregnancy is at implantation and beyond. Various agents like platelet activating factor,7 early pregnancy factor,8 HLA-G9 have been considered. However, it was this immunological face of hCG which attracted the scientific community to a great extent for years together. hCG was perhaps, is the strongest contender.
 
Preimplantation Factor (PIF)
Over the past several years, team of Barnea's et al10 studies has focused in identifying and documenting the role of PIF in mammalian pregnancy. PIF is only found in pregnancy, is similar in all mammals, and is found very early, shortly after fertilization—all for which suggest that PIF is the factor initiating maternal recognition of pregnancy.
Earlier work had shown that viable human and rabbit human embryo culture media contain unidentified immune modulatory compounds.11,12 8They developed a novel bioassay and reported that viable human and mouse embryo conditioned culture media, and human and porcine pregnancy serum, contain immune modulatory compounds that increase rosette formation between donor lymphocyte and platelets in the presence of CD2MAb due to PIF, a low molecular weight peptides.13–19
The presence of PIF activity in maternal sera 4 days after embryo transfer was followed in 27/38 (71%) live births, while only three pregnancies occurred from 114 embryo transfer (3%) with non-detectable PIF activity, due to delayed implantation. In Human pregnancy, detection of PIF activity in maternal sera predicted viable pregnancy after IVF with excellent sensitivity, specificity, and positive and negative predictive values (88%, 95%, 94% and 90% respectively) in 65 patients beginning 4 days after embryo transfer. In retrospective study, the presence of PIF was found to be highly specific (100%) for pregnancy.13 The accuracy of the PIF assay in predicting successful and nonviable pregnancies has been confirmed in another study.14 Furthermore, the premature disappearance of PIF activity led to embryonic demise, approximately 3 weeks prior to decline in hCG levels.
Synthetic PIF was shown to have a potent dose and time dependent effect by mostly affecting mitogen-activated human immune cells. This was shown by blocking peripheral blood monocular cell (PBMC) proliferation, modulating the secretion of both Th1 and Th2 cytokines, favoring the letter.
One aspect of the activity of PIF namely its immunomodulatory properties, is a necessity in pregnancy. Moreover, the effect is cross-species, since the peptide originally derived from the mouse is effective on human cells.
The second characteristic of PIF, in order for it to be relevant to the very early stages of embryo development, is its ability to interact with the endometrium. Their data show that PIF has a clear effect on human endometrial cells, increasing receptivity molecules. It is pertinent to find out whether PIF can be detected in the early stage of pregnancy and is capable of exerting its effects in low concentrations at the relevant time. In addition, they measured PIF concentrations in both viable single human (4-8 cells) and mouse embryo culture media (Barnea, Roussev, and Coulam, unpublished work). These data demonstrated the link between the presence of the peptide in peripheral blood in sufficient amounts to explain its observed biological effects.
9
 
ENDOCRINE MODULATION OF DECIDUAL IMMUNITY
 
Progesterone and Immunomodulation
There is increasing evidence that progesterone is a key modulator in the immune response required to achieve a successful pregnancy outcome. The complexities of the adaptation between the maternal immune system and the semi-allograft of the fetoplacental unit are not clearly understood.
The transformation of endometrium to decidua affects all cell types present in the uterine mucosa. These morphologic and functional changes facilitate implantation, but they also help control trophoblast migration and prevent over invasion in maternal tissue. Attention focuses on the interaction between the extravillous trophoblast and the leukocyte populations infiltrating the uterine mucosa. Most of these cells are large granular lymphocytes (LGLs) and macrophages; few T and B cells are present. The LGL population is unusual, staining strongly for natural killer (NK) cell marker CD56, but the cells do not express the CD16 and CD3 NK markers. NK cells with this distinct phenotype are found in high numbers, primarily in the progesterone-primed endometrium of the uterus. The number of CD56 cells is low in the proliferative-phase endometrium, increases in the midluteal phase, and peaks in the late secretory phase, suggesting that recruitment of LGLs is under hormonal control.
Progesterone is essential because LGLs are not found before menarche, after menopause, or in conditions associated with unopposed estrogen (e.g. endometrial hyperplasia, carcinoma). In women who have undergone oophorectomy, LGLs appear only after treatment with both estrogen and progesterone. The increase in the number of NK cells at the implantation site in the first trimester suggests their role in pregnancy maintenance. They preferentially kill target cells with little or no HLA expression. The extravillous trophoblast (which expresses modified forms of 1 HLA) is resistant to lysis by decidual NK cells under most circumstances, allowing the invasion needed for normal placentation. These CD56 cells probably differentiate in utero from precursor cells because serum levels are negligible.
The only cytokine that has been able to induce proliferation of these cells is IL-2. IL-2 also transforms NK cells into lymphokine-activated killer (LAK) cells, which can lyse first-trimester trophoblast cells in vitro. As expected, IL-2 has not been found in vivo at uterine implantation sites; otherwise, stimulation of decidual NK cells would cause widespread destruction of the trophoblast. Trophoblast HLA expression 10is increased by interferon, a phenomenon that may offer protection from LAK cell lysis. Therefore, an equilibrium exists between the level of HLA expression on the trophoblast and the amount of lymphokine activation of NK cells, leading to the concept of fine regulation of trophoblast invasion.
In pregnant women, a 34 kDa protein has been identified that can block natural killer (NK) cell-mediated lysis of K562 tumor cells.20,21 Because the expression of this protein by CD8+ T Lymphocytes (γ/δ T cells) requires progesterone exposure for expression, it was called the progesterone-induced blocking factor (PIBF).22 PIBF may induce a shift from Th1 to Th2 cytokines.21,23
These data support the following hypothesis as to one way the fetus escapes immune rejection by NK cells:
The fetal semi-allograft induces PgR γ/δ T cells following trophoblast invasion. The interaction with high concentration of progesterone causes the expression of PIBF by γ/δ T cells with induced PgR. The PIBF is only made at the maternal fetal interface, because that is where there is an adequate progesterone concentration. PgR are made in γ /δ T cells throughout the body, but the progesterone level is insufficient to cause PIBF expression by γ/δ T cells that are not situated at the maternal fetal interface. The PIBF inhibits NK-cell cytologic activity at least partially by inhibiting the release of perforin from storage granules of NK cells.24 PIBF also inhibits Th1 cytokines and favors Th2 cytokines thus inhibiting cellular immune response and promoting humoral responses. The suppression of the cellular immune system is limited to the maternal fetal interface, and this constitutes selective immune tolerance.
The cellular T cell system, in particular the Th1 cells, modulates this immune response, releasing either Th1 cytokines (e.g. tumor necrosis factor α, TNF-α) that induce cytotoxic and inflammatory reactions, or Th2 cytokines (interleukin-10, IL-10) associated with B-cell production.25 Serum cytokine profiles demonstrate a shift towards Th2 in normal pregnancy, whereas in recurrent miscarriage sufferers, the Th1 response predominates.26
The difficulty in determining the role of progesterone in preventing recurrent pregnancy loss is due to difficulty in determining who has progesterone deficiency and in establishing the diagnosis. Also, the question arises as to whether the problem starts in the luteal phase or whether a need for more progesterone can arise after the pregnancy is more advanced. Are some women more prone to have ovulatory dysfunction or corpus luteum of pregnancy dysfunction—but not in every 11cycle—leading to a higher frequency of miscarriage in any given pregnancy but possibly without causing recurrent miscarriages?
It is hypothesized27 that there may be a spectrum of progesterone deficiency with effects of ranging from prevention of embryonic implantation, through successful implantation but with early loss leading to a chemical pregnancy only, through sufficient progression to allow ultrasound evidence of at least a gestational sac with either a non viable fetal pole or an empty sac (so-called blighted ovum), through fetal viability but death before the end of the first trimester, through second trimester loss, and finally preterm delivery.
It is known that estradiol (E2) induces PgR in the human endometrium.28,29 Women with regular menses who do exhibit a rise in progesterone during the luteal phase may actually not generate a sufficient peak serum E2 level to induce adequate PgR in the endometrium. J Check27 performed a study (unpublished) on fertile women seeking contraception, and found that the great majority attained an average follicle diameter of minimum 18 mm and a serum E2 level of 200 pg/ml or more. Let us now examine the clinical evidences in favor or against hormonal support of either progesterone or hCG or both.
 
Evidence for and Against
A recent study has reported that the administration of intramuscular progesterone injections to recurrent miscarriage patients restored levels of soluble TNF receptors to values seen in women with no such history.30 However, the treatment only commenced at 8 weeks of gestation, included women up to 40 years of age, and further more, showed that in some of the cases no response in terms of receptor levels was seen in pregnancies that then went on to miscarry. PIBF appears to be the main modulator of the actions of progesterone, with significantly lower expression in recurrent miscarriage patients compared with those with a healthy pregnancy.31
Conversely, Check et al32 treated women in the first trimester aggressively with progesterone, but found no differences in PIBF expressions by lymphocytes. However Th1 and Th2 cytokines were not measured in this study, and could not be correlated either with PIBF levels or with any given response to progesterone supplementation in specific patients. Murine experiments have shown a poor correlation between Th1/Th2 cytokine ratios and abortion rates, implicating environmental selective pressures in eliminating “genetically weaker” 12embryos in early pregnancy.33 While some rodent data are enticing, PIBF data in human pregnancy are scanty, the mechanisms underlying immune-mediated pregnancy loss remain incompletely elucidated.34
J Check et al27 evaluated 100 women with a minimum of 1 year's infertility with an out of phase late luteal phase endometrium, and found that 42 did not achieve a mature follicle. They were randomized into three treatment regimens. Only 3 of 12 (25%) conceived within 6 months following exclusive treatment with luteal phase progesterone (but there were no miscarriage), versus 7 of 10 women (70%) with follicle maturing drugs (but 4 of these 7 (57.1%) miscarried), versus 14 of 20 (70%) conceiving with the combination of follicle maturing drugs and progesterone (with only 1 miscarriage (7.1%).35 These data suggest that women not producing mature follicles before egg release need more than luteal phase support to achieve pregnancies, but follicle-maturing drugs may not fully correct the luteal phase, so that progesterone supplementation is needed to inhibit miscarriage.35 These data are consistent with another prospective study where 50 women conceiving after follicle maturing drugs who were given progesterone supplementation in the luteal phase had miscarriage rate of 6 percent, versus 28 percent in controls not given progesterone.36
There were 58 women in the infertility study with LPD who did attain a mature follicle.35 They were randomized into a group receiving only progesterone supplementation in the luteal phase and a group receiving only follicle maturing drugs. Of the women taking only progesterone, 24 (77.4%) conceived within 6 months of therapy and 1 (4.2%) miscarried.35 In comparison only 3 of 27 (11.1%) conceived with clomiphene citrate or human menopausal gonadotropin and 2 (66.7%) miscarried. Interestingly, 25 women failing to have successful pregnancies with follicle-stimulating drugs were treated exclusively with progesterone supplementation during the next 6 months, and 16 (64%) conceived, with only 1 (6.2%) miscarriage.35 These data show that, at least in infertile women with apparent luteal phase defects, progesterone therapy can reduce the risk of miscarriage.
But what about the group of women who can conceive without help but then miscarry? A study was performed where women seeking help because of previous miscarriage32 without delivery were offered progesterone therapy starting in the luteal phase and continued through the first trimester, but were warned about the possible risk of birth defects. Of the 100 progesterone treated women, 10 (10%) had a first 13trimester miscarriage, compared with of 24 (41.6%) who elected not to be treated with progesterone.37
In order to clear the cob web of variable results and conflicting claims of various studies, Shazia Malik and Lesley Regan have proposed that these trials should meet certain minimum criteria to be considered reliable enough to draw evidence based conclusions. The study criteria for recurrent pregnancy loss treatments have been soundly identified.38 Unfortunately, very few trials have satisfied majority of these criteria.
In a more recent trial,39 a significant reduction in the miscarriage rate was observed in women receiving dydrogesterone (10 mg orally) in early pregnancy compared with those who remained untreated (p <0.05). In this trial, women with an average of 3.3 previous unexplained recurrent abortions were randomized to receive either no treatment (n = 30), dydrogesterone (n = 48), or human chorionic gonadotropin (hCG; 5000 IU intramuscularly every 4 days; n = 36) from as soon as pregnancy was confirmed until the 12th week of gestation. This trial does not, however, conform to the standards cited in Table 1.1.
However the numbers of studies examining the efficacy of progesterone supplementation in early pregnancy remains small and they do not fulfill the criteria required for meaningful results. In addition, the diversity of biological and pharmacological properties does not allow extrapolation of results across studies. Although there are no obvious adverse effects to mother or fetus, a low level of risk may as yet be unidentified. The observed frequency of another miscarriage after three is over 50 percent, and the wish to prescribe an apparently safe and well-tolerated treatment is appealing, especially in light of the emerging scientific understanding of early pregnancy failure.
Table 1.1   Study criteria for recurrent pregnancy loss treatments 38
  • Scientifically sound rationale
  • Power calculation ensuring sufficient numbers under reasonable assumptions (e.g. 60%
success without and 80% success with treatment)
  • Exclusions of patients with less than three unexplained clinical pregnancy losses
  • Exclusions of patients with presumed causes for prior pregnancy losses
  • Prospective study design
  • Prestratification of participants by age and number of prior loses (both of which are independent risk factor for subsequent loss)
  • Effective randomization after prestratification
  • Placebo-controlled
  • Double-blinded
  • No concomitant therapy
  • Karyotype of subsequent losses
  • Follow-up to ensure safety
14
As yet, however the evidence for “tender loving care” shows a similar improvement in outcomes. The need “to do something” for a group of unfortunate patients often seems to over-ride the use of an evidence based therapy. While treatment does not appear to do harm, the evidence for the use of progesterone supplementation in recurrent pregnancy loss is contentious at best, dated and poor at worst.
The recommendations from the American College of Obstetricians and Gynecologists40 conclude that it has not been shown conclusively that progesterone treatment or corpus luteum support influence outcome in women with RPL, and that luteal phase progesterone support is of unproven efficacy.
Having gone through several conflicting results, let us turn to “Mother” of all evidence based searches, i.e. Cochrane Data Base:41 Progestogen for preventing miscarriage.
 
Main Results
Fifteen trials (2118 women) are included. The meta-analysis of all women, regardless of gravidity and number of previous miscarriages, showed no statistically significant difference in the risk of miscarriage between progestogen and placebo or no treatment groups (Peto odds ratio (Peto OR) 0.98; 95 percent confidence interval (CI) 0.78 to 1.24) and no statistically significant difference in the incidence of adverse effect in either mother or baby.
In a subgroup analysis of three trials involving women who had recurrent miscarriages (three or more consecutive miscarriages), progestogen treatment showed a statistically significant decrease in miscarriage rate compared to placebo or no treatment (Peto OR 0.38; 95% CI 0.20 to 0.70). No statistically significant differences were found between the route of administration of progestogen (oral, intramuscular, vaginal) versus placebo or no treatment.
This review of fifteen trials (2118 women) found no evidence that progestogens can prevent miscarriage in general. There was evidence, however, that women who have suffered three or more miscarriages may benefit from progestogen during pregnancy but more trials are needed and are under way, particularly where potential adverse effects on the baby are measured.
15
 
Progestogen for Treating Threatened Miscarriage
Threatened miscarriage is when a mother might be losing her baby at less than 23 weeks' gestation. The signs are vaginal bleeding, with or without abdominal pain, while the cervix is closed. Once the cervix begins to open, miscarriage and pregnancy loss are inevitable. Miscarriage is common, happening in about 15 to 20 percent of pregnancies, and it can cause emotional problems in terms of depression, sleep disturbances, anger, etc. Miscarriage can also be associated with excessive bleeding and shock, and in low-income countries sometimes causes maternal death, though this is very rare in high-income countries. Progestogen is an essential hormone for establishing and maintaining pregnancy, and so is therefore thought to be a possible treatment for threatened miscarriage. The review of trials located just two studies, involving 84 women, that met the entry criteria but they were still poor quality studies. Hence, there is insufficient evidence to assess if progestogen is an effective treatment for threatened miscarriage. Any future studies should not only look at the possible impact on miscarriage and pregnancy, but also need to check there are no adverse effects on the baby.
 
Authors' Conclusions
There is no evidence to support the routine use of progestogen to prevent miscarriage in early to mid-pregnancy. However, there seems to be evidence of benefit in women with a history of recurrent miscarriage. Treatment for these women may be warranted given the reduced rates of miscarriage in the treatment group and the finding of no statistically significant difference between treatment and control groups in rates of adverse effects suffered by either mother or baby in the available evidence. Larger trials are currently underway to inform treatment for this group of women.
 
Discussion
The aim of this review was to assess the effectiveness of progestogens to prevent miscarriage. Although there has been much speculation that progestogens may reduce the miscarriage rate, the results of this meta-analysis show no statistically significant difference between women receiving progestogen and those receiving only placebo or no treatment, when no provision is made for obstetric history. Subgroup analysis by method of administration (oral, intramuscular or vaginal) also showed 16no statistically significant difference between progestogen and placebo groups.
However, when provision was made for obstetric history, by way of a subgroup analysis only including women who had suffered three or more consecutive miscarriages directly prior to the studied pregnancy, a statistically significant difference was found in favor of the progestogen group. This finding should be approached with caution, however, as numbers are small. Two trials are currently underway to further evaluate therapy in this subgroup of women. The meta-analysis showed no statistically significant difference in the number of fetal abnormalities (including virilization and hypospadias) in babies whose mothers had been given progestogens whilst in vitro, nor in intrauterine death/still birth or neonatal death.
There has been much discussion as to whether progestogen may prevent preterm birth (Keirse 1990). There was no statistically significant difference in our meta-analysis between the number of preterm births in the progestogen and placebo groups. However, it is important to note that this systematic review only assesses progestogen given in early pregnancy to prevent miscarriage, rather than trials assessing progestogen given in the second or third trimester to try to prevent preterm delivery. No studies reported adverse maternal effects.
 
Authors' Conclusions
 
Implications for Practice
There is no evidence to support the routine use of progestogen to prevent miscarriage in early to mid-pregnancy.
 
Implications for Research
A finding of a significantly reduced miscarriage rate in women with a history of recurrent miscarriage (three or more consecutive miscarriages) deserves further study.
 
hCG Support
There have been two small studies,42,43 triggering larger trials which were meta analyzed and meta analysis42–45 suggested a reduced risk of miscarriage in women with past history of recurrent miscarriage. The problems with all of these trials are the methods of recruitment and timing of intervention. Most studies require the presence of an ultrasound-17proven fetal heart rate, even though, once this is present, it is unlikely that hormonal support will be beneficial, since successful implantation has occurred. In humans hCG supplementation has not shown any benefit after 8 weeks' gestation. Also by this time, the levels of endogenous hCG are so high that it is unlikely that any exogenous therapy will increase them. If an earlier recruitment is used, trialists worry that they will include those who will inevitably miscarry. A recent medium-sized study, using early recruitment, demonstrated a significant benefit from both an oral and progestin and less so, hCG, in recurrent miscarriage.46 Therefore, all the early work and recent trial suggest a potential benefit of hormonal support in a targeted population. The problem is what that target group is. Studies suggest that up to 30 percent of women may benefit from therapy,46 and these would be those with a history of early loss47 and/or oligomenorrhes.48 James Walker et al49 support the use of hCG in the treatment of recurrent miscarriage in an appropriately assessed population.
 
THREATENED MISCARRIAGE
Recent evidence is available from a randomized controlled trial in which hCG supplementation has been used to treat threatened miscarriage and prevent pregnancy loss in 183 women.50 The study designed was robust, based on a prospective double blind, placebo-controlled trial. Compared with placebo, the author clearly demonstrated no benefit from the use of hCG in early pregnancy, with similar miscarriage rates in both treatment groups (11% vs 12%, risk ration (RR) 1.1, 95% confidence interval (CI) 0.63-1.6).
 
PREGNANCY FOLLOWING OVULATION INDUCTION
Single-centre non-randomized observational studies have reported improved pregnancy outcome when hCG has been used in very early pregnancy.51 However, in the absence of a prospective randomized controlled trial design, there are clear concerns regarding selection and ascertainment bias that are inherent in all studies of this nature. The authors have focused on the possibility of ‘luteal dysfunction’ as a primary cause, but fail to define or measure this entity prior or conception.
 
RECURRING MISCARRIAGE
In the absence of evidence based practice, several authors have examined the role of hCG supplementation during early pregnancy in differing 18clinical scenarios. A well recognized review has suggested that hCG is not recommended in women with recurring miscarriage, as it is of no proven value, but the same author states that an exception to this rule applies when oligomenorrhea is present prior to conception.52 A Cochrane review of 200553 suggested that evidence for the use of hCG treatment in the prevention of recurrent miscarriage remains inconclusive and that there was insufficient support for its routine use in clinical practice.
A double blind, placebo controlled trial53 examining hCG supplementation has been reported with cases of idiopathic recurring miscarriage. Eighty one patients were recruited before 6 weeks' gestation, proven by ulrasonography, following their referral. All patients were given supportive therapy, which consisted of review and a reassurance, ultrasound scan fortnightly between 6 and 14 weeks in their pregnancy. Patient characteristics showed little difference in the age of number of previous miscarriages between each group of patients in the trial. Unsuccessful pregnancies (total = 15) included ectopic pregnancy (2) and first trimester (12) and second trimester (1) miscarriage, and there were no third trimester intrauterine deaths. In the regular menstrual cycle group, hCG had no beneficial effect on the success rate above that obtained by reassurance and placebo injections (86% vs. 86%). The high success rate in the placebo group (86%) reflects the reported benefits of studies of supportive therapy. In the subgroup of patients with oligomenorrhea, there was a statistically significant advantage conferred by hCG. Of 13 patients treated with hCG, 11 had a favorable outcome (85%). However, of 10 patients treated with placebo, only 4 had a favorable outcome (40%). A two tailed Fisher exact test was used to give a p-value of 0.039. hCG elevated the success rate of the oligomenorrheic group to that established in the regular menstrual cycle group (85% × vs 86%). However number of patients in the subgroup are too small to derive authentic conclusion.
 
OTHER hCG TRIALS AND META-ANALYSIS
The efficacy of hCG in early pregnancy had historically been examined in three trials.43,44,54 Two found hCG to improve pregnancy outcome43,54 and one showed no statistically significant benefit.44 All trials had methodological difficulties. Svigos54 series did not use placebo for the control group and gave no details of randomization procedures. The first Dublin trial43 consisted of only 20 patients and did not report on 19the method of blinding or randomization, and the difference in outcome between the two groups was large so as to seem implausible (100% vs 30% success rate). The second Dublin trial44 stated that some data was lost, as it was controlled by a drug company.
Both versions of the meta-analysis results indicate that hCG may have a beneficial effect upon the risk of miscarriage for all women with a history of recurrent miscarriage. However the overall analysis is greatly influenced by the two earliest studies, both of which had significant methodological weaknesses. The confidence intervals for the later two studies do cross 1, implying that any improvement could have occurred by chance. As a matter of fact, Cochrane Data base has withdrawn the articles and the systematic review, sited above from its list of systematic reviews in 2008 January.
 
Oligomenorrhea and Recurrent Miscarriage
When oligomenorrheic women with recurrent miscarriage are considered independently, hCG does confer a statistically significant reduced risk of miscarriage. However, the Liverpool study is the only trial to differentiate between regular cycles and oligomenorrhea, and the patient numbers 13 in the treatment arm and 10 in the placebo arm) are too small to draw significant conclusions. This observation is underpinned by the Cochrane review.52
Further observational data (1994-2000) from the same unit, based on a quasirandomized patient preference basis, shows continued benefit for women with recurrent miscarriage and oligomenorrhea who receive hCG in early pregnancy. The data fail to show significant improvement, but do indicate that some level of benefit may be present for this specific patient group.
Quenby and Farquharson55 have performed a prospective cohort study investigating the possibility of using elements of the medical history and investigation of women with recurrent miscarriage to predict future pregnancy outcomes.56 They found that oligomenorrhea (infrequent periods more than 35 days apart) was an important risk factor for predicting subsequent miscarriage in this population of women suffering recurrent miscarriage. Further investigation of women with recurrent miscarriage and oligomenorrhea detected a difference in the hormone profile of these women compared with those with regular menstrual cycles. Hasegawa et al57 demonstrated that, in a population of 119 consecutive women with spontaneous first trimester miscarriage, the 20incidence of Oligomenorrhea was overrepresented at 11 percent (compared with 0.9% in the general female population). In the oligomenorrheic women, a normal fetal karyotype was shown in 34 percent, versus 12.5 percent (p < 0.01) in the women with normal menstrual cycles. Further analysis revealed that, for those women with embryonic pregnancy and normal karyotype, the incidence of oligomenorrhea was 57 percent. These results suggest that oligomenorrhea is associated with loss of normal rather than abnormal pregnancies.
 
CONCLUSION
Hormonal therapy is not a panacea for all cases of recurrent miscarriage, but it appears to be beneficial in a particular targeted group. The problem is how to diagnose these women. Certainly, those with a proven cause, such as antiphospholipid syndrome and chromosomal abnormalities, will not benefit. Those with repeated early loss (prior to a positive fetal heartbeat) and those with an irregular cycle would appear to be more likely to benefit. Using these criteria, around 30 percent of cases of recurrent miscarriage could be offered hormonal support, with a success rate of around 85 percent.46 Whether to use a progestogen or hCG is a more difficult argument. However, with the concerns over in utero effects, hCG has the advantage of being more “natural”, with evidence of similar benefits.
At present hCG support should not be offered to those women with recurrent miscarriage unless oligomenorrhea is present. In the latter group too, a large prospective randomized controlled trial of hCG versus placebo in early pregnancy support, with standardized nomenclature and exclusion of abnormal embryonal karyotype is needed. The power calculation demands a recruitment of at least 300 women with Oligomenorrhea
There is no evidence to support the routine use of progestogen to prevent miscarriage in early to mid-pregnancy. However, there seems to be evidence of benefit in women with a history of recurrent miscarriage. Treatment for these women may be warranted given the reduced rates of miscarriage in the treatment group and the finding of no statistically significant difference between treatment and control groups in rates of adverse effects suffered by either mother or baby in the available evidence.
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