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2 Why the Above Enlisted Causes Cannot Be the Real Cause of Recurrent Miscarriage

2 Why the Above Enlisted Causes Cannot Be the Real Cause of Recurrent Miscarriage

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5.2



Why the Above Enlisted Causes Cannot Be the Real Cause of Recurrent Miscarriage



69



Table 5.1 Pregnancy outcomes during the third to seventh pregnancies of 100 untreated patients

after two miscarriages

Preceding no. of miscarriages

2

3

4

5

6

Total



No. of patients



Birth N (%)



100

33

15

8

5



67 (67 %)

18 (55 %)

7 (45 %)

3 (35 %)

2 (30 %)

97 (97 %)



Miscarriage N (%)

33 (33 %)

15 (45 %)

8 (55 %)

5 (65 %)

3 (70 %)

63



after seven or more miscarriages). Altogether, in 100 patients with two previous

abortions, 97 will give birth over five consecutive pregnancies. Out of the pregnancies following two abortions, 40 % will end in miscarriage and out of those

giving birth, 40 % will have preterm birth (Table 5.1).

Based on epidemiological data, merely 3 % of patients fail to give birth without treatment between their third and seventh pregnancies. Therefore, up to 3 %

of patients with RM may have a permanent cause underlying pregnancy loss,

which would lead to the abortion of all further pregnancies. This observation

seriously calls into question – or rather excludes – the actual role of immunological factors, thrombophilia, subseptated or septated uterine cavity, etc. in

RM, as the spontaneous cessation of these causes can hardly be expected. The

failure of treatments based on these presumed causal factors also seems to support this conclusion.

We certainly do not present these results in order to advocate neglecting therapeutic interventions, but solely because of the logical conclusions they imply

with regards to the cause of RM. A majority of patients do not get as far as seven

abortions. Some of them “surpass” the reproductive age in time, which is further

facilitated by the fact that in 15 % of patients, miscarriage is followed by a minimum 2-year infertile period and a significant proportion of them give up trying.

2. According to the observations of several authors (Coulam 1991; Jaslow et al.

2010), the prevalence of the above listed causal or risk factors – immunological

causes, thrombophilia, anatomical conditions and other causes of unexplained

origin (in about 50 % of patients) – is approximately identical after three, four or

five abortions without treatment. ASRM modified the definition of RM in 2008

(two or more abortions instead of three or more) because the occurrence rates of

the causal factors investigated until now are the same after the second and the

third or further abortions. Therefore, there is no point waiting until the third

abortion to perform medical examinations.

This observation also means that the chance of losing the following pregnancies is almost the same whether these causes are present or not. If the prevalence

of miscarriage was higher with any of these causal factors after, for example, two

abortions, then this cause would have to occur more frequently during the following pregnancies compared to the other factors and so on. However, based on



70



5



Recurrent Miscarriage and Folliculo-Luteal Function



the cited results, this is not the case. These observations make the actual role of

earlier suspected causal factors in RM deeply questionable. For instance, it is

difficult to interpret the fact that in the case of immunological causes, abortion

occurs in approximately 33 % in pregnancies after two miscarriages, similarly to

congenital thrombophilia and idiopathic origin, and after three miscarriages,

abortion occurs in 45 % of cases whether any causal factors are present or not. If

abortion is due to some immunological cause or congenital thrombophilia, why

would it occur depending on the number of miscarriages in the anamnesis, and

why would these conditions fail to cause abortion in each following pregnancies? If, for example, a congenital or acquired cause (septated uterus, thrombophilia or immunological conditions) already led to abortion twice, why does it

cause miscarriage again only in approximately 33 % of third pregnancies and in

approximately 45 % of the fourth pregnancies, when the change of this “cause”

is ruled out, or in case of immunological reasons, it may have worsened?

Moreover, the mechanisms through which the frequently occurring, mainly

numerical chromosomal abnormalities are generated (in 50 % of the abortions) –

which are present in almost the same rate in various particular causes – remain

unknown.

3. Congenital uterine malformation (septated uterus, bicornuate uterus) occurs in

approximately 4 % of women with obstetric histories without complications

(95 % of women) and in approximately 8 % of women with habitual abortion

(5 % women). Based on the above, 50 out of 1000 women will have recurrent

miscarriage, and we expect that four (8 %) have the above-mentioned anomalies,

while out of the remaining 950 couples, we expect 38 cases (4 %). Thus, the

question arises: why only every 10th woman with uterine alterations will develop

recurrent miscarriage? It seems likely that a causal factor other than, for example, a septum in the uterine cavity is necessary for recurrent miscarriage to

develop. The situation is the same with APS (antiphospholipid syndrome) as its

prevalence in the total obstetric patient population is 3–5 % and 5–15 % in

women with habitual abortion. If we also consider that 85 % of these women will

give birth without any treatment in their third or fourth pregnancy (out of 100

patients, 67 will give birth after two abortions, and after three abortions, 55 % of

the remaining 33, that is, 18; thus 15 will be childless), then only a small fraction

of the affected patients will fail to have a child after the fourth pregnancy

(Table 5.1).

The fact that the prevalence of another abortion and the occurrence of numerical CAs both depend on the number of abortions in the anamnesis, either in the

presence or absence of any presumed causes and independently of them, implies

the substantial role of a yet unrecognised cause (or causes).

According to the presented data and the conclusions drawn, RM can only

have a cause (or causes) in most patients (approximately 97 %) that might be

permanent or temporary, but that has a serious chance to cease in each pregnancy. Our hypothesis is that this common cause is the folliculo-luteal insufficiency that leads to abortion, preterm birth, IUGR, mature birth and temporary



5.3



The Crucial Role of Folliculo-Luteal Function in Recurrent Miscarriage



71



or permanent infertility via the different levels of inadequate placentation. The

significantly lower average luteal P levels measured in women with recurrent

miscarriage compared to pregnancies resulting in mature, singular and eutrophic

newborns (13.6 and 29.8 ng/ml) also support this view (Chap. 2).



5.3



The Crucial Role of Folliculo-Luteal Function

in Recurrent Miscarriage



Encouraged by our preliminary studies and our positive therapeutic results (Siklósi

1991, 1992), we performed a randomised, placebo-controlled trial to investigate the

role of FLI in RM (Siklósi et al. 2012). The circumstances of implantation and placentation are determined by the characteristics of the endometrium (thickness, blood

supply, secretory transformation, biochemical features, etc.), which are essentially

defined by the follicular E2 and the following P and E2 effect. The final maturation

of the dominant follicle is closely related to the final maturation of the oocyte, the

preovulatory E2 secretion, how granulosa cells are prepared for luteinisation and

luteal P secretion. The corpus luteum is generated through continuation of the maturation process of the developed dominant follicle (Pohler et al. 2012). We assumed

that the disturbance of this process underlies RM. The insufficient E2 then P effect

may cause the formation of an inadequate secretory endometrium and impaired placentation, while the disturbed final maturation of the oocyte – during the meiosis and

the first three mitoses – may lead to an oocyte with inappropriate cytoplasmic and/or

karyotic features, which is incapable of reproduction (Heikinheimo and Gibbons

1998; Handyside 2012; Mantokou et al. 2012). These two closely related factors can

cause euploid or aneuploid abortion, or in case of slight disturbances, more likely late

abortion or preterm birth and IUGR. The great variability of the menstrual cycle can

account for the notable dissimilarities detectable in different cycles of a given patients

with regards to FLF (Chap. 3). Most authors consider the abnormalities of implantation and placentation as the determining cause underlying these complications (Li

et al. 2002; Salker et al. 2010; Matthiesen et al. 2012). Hormonal causes seem to be

the most reasonable in the occurrence of abnormal placentation, although different

authors are seeking immunological or other causes (e.g. thrombophilia) in its development as they consider the mere presence of ovulatory cycles or P values over

10 ng/ml as physiological. As our results showed a physiological luteal P substantially higher (21 ng/ml in case of birth) than the usually accepted value (≥10 ng/ml),

we primarily searched for the causes of placental abnormalities in the different levels

of folliculo-luteal insufficiency.



5.3.1



Patients and Methods



We performed our studies on patients of the Endocrine Unit of the 2nd Department

of Obstetrics and Gynaecology, Semmelweis University. We obtained the informed

consent of the patients before entering them into the study. We considered patients



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5



Recurrent Miscarriage and Folliculo-Luteal Function



who had had three or more spontaneous clinical abortions before the 24th week of

pregnancy – confirmed in their anamnesis – to have recurrent miscarriage (foetal

weight <500 g and/or foetal length <300 mm, Berry et al. 1995; Christiansen et al.

2005). This was in order to ensure that our results are comparable with those of other

researchers (as then the usual criteria of RM was three or more abortions). As the aim

of our study was to investigate the effect of FLF normalisation generally in recurrent

miscarriage, we did not apply any selection criteria (immunological, anatomical, etc.

causes) apart from the number of previous clinical abortions (with at least one intact

tuboovarian complex, verified ovulation and normospermia). We enrolled 120

patients in our randomised, placebo-controlled study (Siklósi et al. 2012).



5.3.2



Power Analysis



In our preliminary studies, we achieved a successful birth rate of above 90 % with

physiological FLF after three or more abortions, while it failed to reach 60 % in

untreated patients. Therefore, we calculated a minimum 30 % difference regarding

birth rates between the treated and the placebo group when determining the patient

population size. To get a significance level of 0.01 with 99 % power (α) during a

two-sampled t-test with a difference of 30 %, 90 patients are needed. We factored in

a 10–15 % drop out rate and 10–15 % infertility rate per year (especially in the placebo group). Therefore, we started our research with 120 patients.



5.3.3



Treatment Protocol



We randomised patients by numbers generated by a computer. We used clomiphene

citrate (CC) (Clostilbegyt, EGIS) for the normalisation of FLF in the treatment

group, together with the regular control of luteal P and E2. We applied CC treatment

between the 5th and 9th day of the cycle, with an initial dose of 5 × 100 mg if the

progesterone level was below 15 ng/ml, and 5 × 50 mg if the P value was over 15 ng/

ml, and increased the dosage by 5 × 50 mg per cycle until we reached the physiological average (21.0 ng/ml), or the physiological minimum (17 ng/ml). We recommended that patients use traditional contraceptive methods until the achievement of

the physiological value. We advised patients to try to get pregnant only after the

physiological value was achieved, along with the continued application of the dosage required for normalisation. P and E2 values were controlled in each cycle until

conception took place. Patients in the placebo group took identical-looking pills in

similar numbers together with regular luteal P and E2 control until conception took

place. Because of the frequent blood sampling, we designed our study for a duration

of 1 year, although in most patients conception occurred much earlier.

The main goal of our study was to investigate the birth rates with physiological

FLF and the prevalence of various obstetrical complications in the two groups and

to analyse the relations of FLF and pregnancy outcomes in all pregnancies. For the

statistical methods and hormone measurements applied, see Chap. 1.



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