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4 Successful Treatment of Recurrent Miscarriage by the Normalisation of Folliculo-Luteal Function

4 Successful Treatment of Recurrent Miscarriage by the Normalisation of Folliculo-Luteal Function

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82



5



Recurrent Miscarriage and Folliculo-Luteal Function



Altogether, 510 patients participated in our study, and in the therapy, out of

which 102 did so repeatedly. In the analysis of FLF and pregnancy outcome

(N = 684), we also included the data of a further 72 pregnancies of our patients,

where the average luteal P was determined but did not reach the physiological value.

As control group, we used the data of pregnant women – with the same group

size as the treatment group – who had also had two or more preceding abortions but

did not have any treatment before conception and were admitted to our institute with

their pregnancies.



5.4.2



Treatment Protocol



We used clomiphene citrate (CC) (Clostilbegyt, EGIS) and/or low-dosage corticoid

treatment (LDCT) in the treatment group to normalise FLF, together with regular

luteal P control. We applied CC between the 5th and 9th day of the cycle, with an

initial dose of 5 × 100 mg if the P level was below 15 ng/ml and 5 × 50 mg if the P

value was over 15 ng/ml, and increased the dose by 5 × 50 mg per cycle until the

physiological average was achieved (21.0 ng/ml) but at least until we reached the

physiological minimum (17 ng/ml). We used LDCT continuously administered in

the form of 0.5 mg dexamethasone (DEX) every evening (see Chap. 4). We suggested that the patient use traditional contraceptive methods until the physiological

values were reached. We advised patients to get pregnant only after the physiological value was achieved, along with the continued application of the dosage required

for normalisation.

The main goal of our studies was to investigate pregnancy outcomes during our

treatment method in comparison with the untreated control group, to analyse FLF

and pregnancy outcomes and to draw theoretical conclusions based on our representative patient population.



5.4.3



Results



Table 5.4 summarises the characteristics of the treatment and the control group. We

failed to demonstrate significant differences between the patient characteristics of

the two groups.

The baseline average luteal serum P values in all 510 patients (13.6 ± 3.3 ng/ml,

average ± SD) was significantly (p < 0.001) lower than the physiological

(21.0 ± 2.0 ng/ml) (Table 5.4). The average P value exceeded the 17 ng/ml physiological threshold in 18 % of patients and was under 10 ng/ml (usually considered as

the physiological minimum) in 16 % of patients. Pregnancy took place under the

course of 1–11 cycles in case of physiological FLF (3.1 cycle on average). The average monthly pregnancy rate was 35 %, and the cumulative pregnancy rates over 3,

6, 9 and 11 months were 72 %, 91 %, 98 % and 100 %, respectively. In patients

(N = 85) who did not conceive for over 2 years after their last abortion (over 24–240

cycles, 45 cycles on average), we observed similar monthly and cumulative



5.4



83



Successful Treatment of Recurrent Miscarriage



Table 5.4 Baseline characteristics of patients



Variables*

Age, years – average ± SD

Range

>35 years – N (%)

Body mass index, kg/m2

Abortions in the anamnesis

Average ± SD

Range

2 abortions N (%)

3 abortions N (%)

4 abortions N (%)

5 abortions N (%)

≥6 abortions N (%)

≥1 late-term abortion

Live birth in the anamnesis

Sec. infertility (>2 years)



Treated group average

P > 17 ng/ml

N = 510

31.2 ± 5.5

20–45

101 (20 %)

22.8 ± 3.5



Untreated control group

N = 510

31.3 ± 5.5

21–42

101 (20 %)

22.9 ± 2.6



3.0 ± 1.2

(3–10)

230 (45 %)

161 (32 %)

70 (14 %)

29 (6 %)

20 (4 %)

149 (30 %)

146 (29 %)

89 (17 %)



3.0 ± 1.2

(3–9)

230 (45 %)

161 (32 %)

70 (14 %)

29 (6 %)

20 (4 %)

142 (28 %)

156 (31 %)

75 (15 %)



*



The difference in the characteristics between the two group is not significant



pregnancy rates with physiological FLF (pregnancy occurred over 1–10, 3.2 cycles

on average).

Pregnancy outcomes are presented in Table 5.5. Birth rates were significantly higher in the treatment group than in the untreated control group (95.1 %

and 59.6 %), while abortion rates were significantly elevated in the untreated

group (39.4 % and 4.5 %). Out of the 28 abortions occurring in the treated

group, 19 (3.0 %) took place in the first and nine (1.4 %) in the second trimester

(>14 weeks).

Preterm birth, IUGR and neonatal weight under 2500 g occurred significantly

less frequently in the treated than in the untreated group. Miscarriage occurred with

physiological FLF (P > 17 ng/ml) in 28 cases (4.5 %, 28/627), out of which 14

patients received repeated treatment – altogether 18 times – resulting in birth in each

case (two cases with twin birth). None of the births in our patient population were

born with Down syndrome, and also all results of amniocentesis were normal.

Pregnancy was achieved with verified subseptated, septated and bicornuate

uterus in 46 cases out of our patient population. All the 46 pregnancies were associated with physiological FLF and ended in mature birth with one exception.

Miscarriage occurred in one patient during the first trimester (2.2 %), whose following pregnancy with physiological FLF resulted in mature birth.

The examination of FLF and pregnancy outcome (N = 684) showed that the average luteal P and E2 differed significantly (p < 0.001) between pregnancies ending in

abortion, preterm birth or mature birth (P, 14.6 ± 2.2, 20.2 ± 2.7, 29.6 ± 3.9 ng/ml;

E2, 175 ± 28, 276 ± 30, 390 ± 45 pg/ml). We found a similar difference (p < 0.001)



89.1 %**

408/458

10.9 %**

50/458

4.3 %**

20/458



Treated group

P > 17 and

≤23 ng/ml

N = 133

All pregnancies

3.0 %**

4/133˙

2.2 %**

3/133

0.8 %**

1/133

6.3 %**

2/32

2.0 %**

2/101

0.8 %

1/133

96.2 %**

128/133

63.3 %**

81/128

36.7 %**

47/128

14.8 %**

19/128

0.7 %+

3/436



2.5 %+ 11/436



Treated group

P > 23 ng/ml

N = 494

All pregnancies

4.8 %

24/494

3.2 %

16/494

1.6 %

8/494

4.2 %

4/95

5.0 %

20/399

0.4 %

2/494

94.7 %

468/494

97.6%+ 425/436

Odds ratio

95 % CI*

12.7

8–20

12.1

7–20

7.2

3–15

27.2

9–79

10.5

6–17

2.4

1–12

12.2

8–18

31.6

16–59

31.6

16–59

35.6

11–114



10.1 %



9.5 %



90.5 %



83.8 %



1.1 %



National

Average

15.1 %



5



Mature birth/singular pregnancy

patients

Preterm birth/singular

pregnancy patients

IUGR/singular pregnancy

patients



I. trim. abortion/pregnancy

patients

II. trim. abortion/pregnancy

patients

Age ≥35 years, abortion/

pregnancy patients

Age < 35 years, abortion/

pregnancy patients

Extrauterine pregnancy/

pregnancy patients

Birth/pregnancy patients



Variables

Abortion/pregnancy patients



Untreated control

group

N = 510

39.4 %

201/510

28.8 %

147/510

10.6 %

54/510

54.5 %

55/101

35.7 %

146/409

1.0 %

5/510

59.6 %

304/510

55.0 %

164/298

45.0 %

134/298

19.8 %

59/298



Treated group

P > 17 ng/ml

N = 510

First pregnancies

5.3 %**

27/510

3.7 %**

19/510

1.6 %**

8/510

5.9 %**

6/101

5.1 %**

21/409

0.6 %

3/510

94.1%** 480/510



Table 5.5 Pregnancy outcomes after two or more abortions



84

Recurrent Miscarriage and Folliculo-Luteal Function



48.7 %

145/298

3.3 %

10/304

2.0 %

6/304

4/6, 4/6

5/6



13.5 %**

62/458

1.0 %

5/480

4.4 %

21/480

6/21, 3/21

9/21

0.2 %

1/480

46.9 %

60/128

3.9 %

5/128

6.6 %

31/468

9/31, 3/31

13/31

0.2 %

1/468



2.5 %+

11/436





**



Odds ratio between the untreated group and the treated group (P > 23 ng/ml)

Significance (p < 0.001) between the untreated and treated group (P > 17 ng/ml and P > 17 – ≤23 ng/ml)

+

Significance (p < 0.001) between the two treated groups: P > 17 – ≤23 ng/ml and P > 23 ng/ml



*



Triplet birth/birth patient



Twin birth/birth patients

Preterm birth, IUGR,

Mean weight <2500



Newborn weight <2500 g/

singular pregnancy patients

Preeclampsia/pregnancy patients

3.5

1–9



36.6

19–69



1.6 %



9.3 %



5.4

Successful Treatment of Recurrent Miscarriage

85



86



5



Recurrent Miscarriage and Folliculo-Luteal Function



between the luteal P and E2 values of pregnancies ending in the birth of eutrophic

newborns and newborns with retardation (P, 19.6 ± 2.5 and 28.5 ± 4.8 ng/ml; E2,

256 ± 28.6 and 375 ± 41 pg/ml) (Fig. 5.4).

P a (ng/ml)

p < 0.001



45



p < 0.001



40

p < 0.001

35

30

25

20

15

10

5

0

Miscarriage Preterm birth

Term birth

IUGR newborn Eutroph nbb

N = 49

N = 17

N = 186

N = 15

N = 188

amean luteal progesterone in cycle of conception b preterm and term births together



E2 a (pg/ml)

p < 0.001



600



p < 0.001



550

500

450



p < 0.001



400

350

300

250

200

150

100

50

0

Miscarriage

N = 49

a mean



Preterm birth

N = 17



IUGR newborn. Eutroph nbb

N = 15

N = 188



Term birth

N = 186



luteal oestradiol in cycle of conception



b



preterm and term births together



Fig. 5.4 The relationship between serum progesterone and oestradiol levels and pregnancy

outcome



5.4



Successful Treatment of Recurrent Miscarriage



87



We found a strong and significant correlation between the luteal P and E2 values

and the length of pregnancy (weeks) (r = 0.93 − 0.89; p < 0.001) in conception cycles

with P values between 11 and 23 ng/ml (Table 5.6 and Fig. 5.5). No pregnancies

were conceived under the average P level of 11 ng/ml (FLI grade III) and – except

for two preterm births (3.0 %) – every pregnancy with an average P value between

11 and 17 ng/ml (FLI grade II) ended in abortion. The typical P value of preterm

birth was 20.2 ± 2.7 ng/ml, and average P value in IUGR was 19.6 ± 1.5 ng/ml (FLI

grade I). Average luteal P in the case of singular, mature and eutrophic newborns

was 29.4 ng/ml (physiological FLF).

Table 5.6 Correlations of progesterone and oestradiol in recurrent miscarriage

Progesterone (P)*

Parameters compared

P – length of pregnancy

(weeks)

P – length of pregnancy

(weeks) average P between 11

and 23 ng/ml

P – newborn weight

P – newborn weight percentile

P – newborn length

P – newborn BPD



**



***



r

0.72



N

252



0.93



140



0.84

0.78

0.76

0.71



203

203

203

203



Oestradiol (E2)*

Parameters compared

E2 – length of

pregnancy(weeks)

E2 – length of pregnancy

(weeks) average E2 between

100 and 350 pg/ml

E2 – newborn weight

E2 – newborn weight percentile

E2 – newborn length

E2 – newborn BPD



r*

0.81



N***

108



0.89



62



0.89

0.78

0.75

0.73



80

80

80

80



*



Progesterone and oestradiol: average luteal values in the conception cycle

Each correlation is highly significant (p < 0.001)

***

Number of pregnancies with exception for twins

**



Progesterone and length of pregnancy

R = 0.9310

Length of pregnancy (week)



45

y = 4,6773x – 54,515

R2 = 0.8668



40

35

30

25

20

15

10

5

0

10



15



20



25



30



35



Progesterone (ng/ml)



Fig. 5.5 The relationship between average progesterone in the conception cycle and pregnancy

length in women with recurrent miscarriage (N = 252)



5



88



Recurrent Miscarriage and Folliculo-Luteal Function



We also demonstrated significant (p < 0.001) correlation between the luteal P

(and E2 levels) and the weight (r = 0.84 − 89), weight percentile (r = 0.80), length

(r = 0.76) and biparietal diameter (r = 0.71) of the newborns (Table 5.6, Figs. 5.6 and

5.7). The foetal parameters become more favourable with the increase of luteal P

and E2 levels, which suggests better uteroplacental circulation.

Progesterone and weight of born

R = 0.8411



5000



Weight of newbron (g)



4500



y = 1,2509x – 76,249

R 2 = 0.7075



4000

3500

3000

2500

2000

1500

1000

500

10.0



15.0



20.0



25.0



30.0



35.0



40.0



Progesterone (ng/ml)



Fig. 5.6 The relationship between average progesterone in the conception cycle and newborn

weight in women with recurrent miscarriage (N = 203)



Progesterone and weight percentile

R = 0.7825



100

90



y = 44,528x – 58,597

R2 = 0.6124



Weight percentile (%)



80

70

60

50

40

30

20

10

0

10



15



20



25



30



35



40



Progesterone (ng/ml)



Fig. 5.7 The relationship between average progesterone and newborn weight percentile values in

women with recurrent miscarriage (N = 203)



p < 0.001

p < 0.001



p < 0.001

p < 0.001

p < 0.001



2561 ± 725 g

50 ± 8 cm

37 ± 24





Significance



18.7 ± 1.5

277 ± 80

N = 133



The apparently optimal P and E2 range



*



Progesterone (ng/

ml)

Oestradiol (pg/ml)

Newborn

parameters

Weight

Length

Weight percentile

Twin births



Progesterone

>17–23 ng/ml



3195 ± 487 g

53 ± 5 cm

55 ± 21 %

2.7 % (6/224)



25.6 ± 2.0

382 ± 84

N = 224



Progesterone

>23–29 ng/ml



p < 0.001

p < 0.001

p < 0.001



p < 0.001

p < 0.001



Significance



3511 ± 466 g

55 ± 3 cm

71 ± 21 %

9.2 % (25/271)



34.9 ± 5.5

474 ± 127

N = 271



Progesterone

>29 ng/ml



Table 5.7 Neonatal parameters in terms of consecutive luteal progesterone value ranges in recurrent miscarriage



3370 ± 509 g

55 ± 4 cm

65 ± 20

4.5 % (9/199)



29.0 ± 1.8

412 ± 88

N = 199



Progesterone*

>26–32 ng/ml



5.4

Successful Treatment of Recurrent Miscarriage

89



90



5



Recurrent Miscarriage and Folliculo-Luteal Function



When comparing foetal parameters arranged by the various P value ranges, we

demonstrated significant (p < 0.001) differences (Table 5.7). This suggests that the

circumstances of implantation and placentation also play a determining role in foetal parameters within births. Optimal placenta function provides better foetal nutrition and thus further development of the complete foetoplacental unit. As we

determined FLF ourselves with the treatment prior to conception, we have the

opportunity to positively influence pregnancy outcome via controlled treatment.

According to the above described interrelations, we revised the hormonal values

initially attributed to physiological FLF. We considered the average luteal P values

(29.6 ± 3.3 ng/ml) of pregnancies that resulted in singular, mature and eutrophic

newborns as physiological from the aspect of reproduction. We separately present

the outcomes of pregnancies conceived with an average P value over 23 ng/ml.

Since recently most authors considered three or more abortions to be the diagnostic

criteria for habitual abortion, we found it useful to separately demonstrate our

results following two and three or more abortions (Table 5.8). We found significant

differences between treated and untreated patients in both groups in almost every

parameter. Likewise, we found significant differences in many parameters between

the two untreated groups. Although preterm birth, IUGR and newborns weighing

under 2500 g occurred more frequently in the treated patients after three or more

abortions than after two abortions, this difference was not significant due to the low

occurrence rates (Table 5.8). With adequate treatment (average P value set over

23 ng/ml) after two abortions, miscarriage (31.5 and 3.0 %), preterm birth (47.1 and

1.5 %) and IUGR (17.8 and 0.5 %) occurring during the third pregnancy can be prevented in 90–98 % of cases. The weight of newborns was 728 g higher on average

than the expected weight in the untreated group (Table 5.8). Since obstetric complications encountered during the third pregnancy after two abortions can be prevented

in such a high proportion, it appears absolutely justified to diagnose RM after two

abortions. Pregnancy outcomes in terms of miscarriages in the anamnesis are shown

in Fig. 5.8.



5.4.4



Discussion



Our data together with our therapeutic results seem to prove that the average of three

P values obtained every other day between the 4th and 9th day after ovulation or

before menstruation is suitable to quantitatively describe FLF. It also appears evident

that the physiological levels of luteal P are definitely higher than we previously

thought (P ≥ 10 ng/ml). Our results contradict the general opinion that the existence

of luteal insufficiency as an individual entity cannot be proven (ASRM 2012).

We modified the initially applied physiological P value (average of 21.0 ng/ml)

that is typical of every birth, based on the strong correlation we demonstrated

between the average luteal P and pregnancy outcome. From the aspect of reproduction, we considered the average luteal P values of pregnancies that resulted in singular, mature and eutrophic newborns as physiological (29.4 ± 3.2 ng/ml). In

pregnancies conceived with an average P value over 23 ng/ml – besides the almost



5.4



Successful Treatment of Recurrent Miscarriage



91



Table 5.8 Pregnancy outcomes after two and after three or more miscarriages



Variables

Abortion/pregnancy

patients

Abortion I. trim./pregnancy

patients

Abortion II. trim./

pregnancy patients

Age ≥ 35 years patients

Age < 35 years patients

Extraut. grav./pregnancy

patients

Births/pregnancy patients

Mature birth/singular

pregnancy patients

Preterm birth/singular

pregnancy patients

IUGR/singular pregnancy

patients

Birth weight <2500 g

Sing.

pregnancy – patients

Preeclampsia/births

patients

Twin births/birth patients

Preterm birth, IUGR,

Birth weight <2500 g

Triplet

births/birth – patient

Newborn weight

(average ± SD)



After 2

miscarriages

untreated

N = 222



After 2

miscarriages

treated

P > 23nglml

N = 228



After ≥ 3

miscarriages

untreated

N = 249



31.5 %*

70/222

24.8 %

55/222

6.7 %*

15/222

42.4 %

14/33

29.6 %*

56/189

0.9 %

2/222

67.6 %*

150/222

67.1 %*

98/146

47.1 %*

48/146

17.8 %

26/146

39.7 %*

58/146



3.0 %

7/228

2.6 %

6/228

0.4 %

1/228

3.4 %

1/29

3.0 %

6/199

0.4 %

1/228

96.5 %

220/283

98.5 %

205/208

1.5 %

3/208

0.5 %

1/208

1.0 %

2/208



46.2 %

115/249

31.7 %

79/249

14.5 %

36/249

55.9 %

38/68

42.5 %

77/181

1.2 %

3/249

52.6 %

131/249

38.0 %

49/129

62.0 %

80/129

21.7 %

28/129

66.7 %

86/129



3.3 %

5/150

2.7 %

4/150

2/4–1/4

3/4

_





5.5 %

12/220

2/12–1/12

2/12

_



3.8 %

5/131

1.5 %

2/1312/2–1/2

2/2

__



2690 ± 596 g*



3418 ± 438 g**



2240 ± 626 g



After ≥ 3

miscarriages

treated

P > 23nglml

N = 266

6.4 %

17/266

3. 4 %

9/266

3.0 %

8/266

4.5 %

3/66

7.0 %

14/200

0.4 %

1/266

93.2 %

248/266

96.5 %

220/228

3.5 %

8/228

0.9 %

2/228

3.5 %

8/228



7.7 %

19/248

7/16 - 2/16

9/16

0.4 %

1/248

3220 ± 640 g



Significance (p < 0.001) between the two untreated groups (2 and ≥3 miscarriages)

Significance (p < 0.01) between the two treated groups (2 and ≥3 miscarriages)



*



**



unchanged prevalence of miscarriage – preterm birth, IUGR and newborns with a

weight under 2500 g occur significantly less often than when using the initially

defined minimum of 17 ng/ml P values (Table 5.5). (Dickey and Holtkamp 1996)

measured a P value similar to our results in the luteal phase of successful pregnancies: they found the luteal P levels to be 27 ng/ml on average in spontaneous cycles

and 32 ng/ml on average in CC-treated cycles.



92



5



Recurrent Miscarriage and Folliculo-Luteal Function



Without treatment



With physiological FLF



%



%



100



100



90



90



80



80



70



70



60



60



50



50



40



40



30



30



20



20



10

0



*2



3



4



5



6



10

0



*2



3



4



5



6



* : Number of previous miscarriages

Miscarriage



Preterm birth



Term birth



Fig. 5.8 Pregnancy outcome without treatment and with physiological FLF (p > 23 ng/ml) in

terms of the number of miscarriages in the anamnesis



The circumstances of implantation and placentation, defined by FLF, play an

essential role in the outcome of pregnancy. This is suggested by the differences

between the luteal P and E2 levels in case of miscarriage, preterm birth and mature

birth and in pregnancies with IUGR and eutrophic newborns. The strong correlation of luteal P and E2 levels with the length of pregnancy and with neonatal

parameters (weight, weight percentile, BPD) further supports this conclusion

(Table 5.6). The occurrence rate of preterm birth, IUGR and newborn weight under

2500 g drastically shrinks (to 3–5 %) with physiological FLF (average P > 23 ng/

ml) compared to the untreated control group. Moreover, preeclampsia did not

occur at all. The fundamental role of FLF in placentation is well demonstrated by

the fact that neonatal parameters differ significantly depending on luteal P and E2

even within births: weight, length and weight percentile (Table 5.7). These connections seem to confirm the substantial role of FLF in the outcome of pregnancy, and

at the same time they imply that other causal roles can only have a secondary role

in the development of RM.

Increased maternal age, especially over the age of 35, together with the number

of miscarriages in any woman’s medical history, is considered to be a determining,

individual risk factor for abortion (Marquard et al. 2010). The occurrence of preterm birth, IUGR, etc. increases proportionally with maternal age (ESHRE 2012).

In light of this, we compared the rate of miscarriages and pregnancy complications

with physiological (P > 23 ng/ml) FLF between women of maternal age under 35

and equal to or over 35 (Table 5.9). There was no significant difference between the



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