Achievement of second parenthood in an ART programme using frozen donor semen: cohort follow-up

F. Guerif, M.H. Saussereau, C. Barthelemy, M. Lanoue, C. Lecomte, V. Ract, J. Lansac and D. Royere1

CECOS, Biologie de la Reproduction, Département de Gynécologie-Obstétrique et Reproduction Humaine, Centre Hospitalier Universitaire Bretonneau, 37044 Tours, France

1 To whom correspondence should be addressed. e-mail: royere{at}med.univ-tours.fr


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
BACKGROUND: This study was designed to determine the efficacy of a programme using frozen donor semen in a cohort of patients returning for treatment after previously conceiving through donor insemination (DI). METHODS: The cohort included 222 couples with secondary infertility (previous live birth) in one University Hospital Centre. The treatment sequence involved DI cycles until completion. Live births, drop-out for personal or medical reasons and recourse to IVF with donor semen (IVF-D) were recorded for all patients. Live births were expressed as both rate per cycle and crude cumulative rate. RESULTS: At the end of the DI cycles, 65% of couples in the cohort achieved second parenthood. Most of them (77%) succeeded after only four DI cycles. The majority of couples who stopped treatment did so for personal reasons. CONCLUSIONS: Patients involved in a second parenthood project belong to a ‘selected’ population. Management and counselling of such patients need to reconcile the early efficacy of DI cycles, the invasiveness of the IVF-D procedure and the availability of donor semen.

Key words: cohort/crude cumulative live birth rate/donor insemination/frozen donor semen/secondary infertility


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Donor semen has long been used as a means of achieving conception for couples with azoospermia, severe male infertility or genetic diseases that may be transmitted by natural parenthood. The widespread use of ICSI has considerably reduced the frequency of donor insemination (DI) (Palermo et al., 1992Go). However, DI still remains an alternative way to achieve parenthood for some couples (i.e. non-obstructive azoospermia, genetic or viral risk related to male partner). As acquired immunodeficiency syndrome (AIDS) was increasing in frequency, the use of frozen donor semen was initiated in France before 1980 by the French CECOS Federation (Centre d’Etude et de Conservation des OEufs et du Sperme). Frozen donor semen may be used for artificial insemination (Byrd et al., 1990Go; Patton et al., 1992Go; Wainer et al., 1995Go; Botchan et al., 2001Go) or for IVF (IVF-D) (Mahadevan et al., 1983Go; Cohen et al., 1985Go; Vekemans et al., 1987Go; Morshedi et al., 1990Go).

Whatever the method of assisted reproductive technology (ART) used, patients need to be clearly informed about their chances of finally having a baby. The cumulative chances of achieving a live birth after a given number of cycles are obviously more meaningful than the live birth rate per cycle. We have already reported on the crude cumulative live birth rate following DI cycles followed, if necessary, by IVF-D cycles using frozen donor semen in primary infertile couples (Guerif et al., 2002Go). The choice of primary infertility was guided in this study by the need to keep the fertility status of couples homogeneous. Indeed the results of DI cycles with frozen donor semen according to fertility status reported in the literature are very varied. Some studies have reported better results for couples having achieved a previous pregnancy using DI cycles (Kovacs et al., 1988Go; Federation CECOS et al., 1989Go; Shenfield et al., 1993Go; Tan et al., 1994Go; Croucher et al., 1998Go; Williams and Alderman, 2001Go), while others have reported similar results in couples with primary and secondary infertility (Robinson et al., 1993Go). Thus the actual chances for couples initiating DI cycles with frozen donor semen after a first live birth remained to be evaluated on a cohort follow-up basis.

A monocentre cohort study (CECOS-Tours) was therefore designed to assess the crude cumulative live birth rate in couples who had previously succeeded in DI cycles and who had at least one artificial insemination by donor (AID) cycle in order to achieve a second parenthood. All patients were followed until completion, i.e. the birth of a live baby, or ceasing treatment for medical or personal reasons or switching to IVF-D.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
A cohort of 222 couples who achieved a successful pregnancy a few years previously using DI with frozen donor semen was referred to the CECOS of Tours between January 1991 and December 1997 to try to achieve second parenthood through the use of frozen donor semen. During this period of 7 years, 981 consecutive DI cycles were performed. During the period of the study, patients were not charged in France for any number of DI cycles. The general procedure for donor recruitment, donor selection and semen cryopreservation has been described elsewhere (Federation CECOS et al., 1989Go).

Reasons for infertility in patients who initiated DI treatment comprised non-obstructive azoospermia (55.2%), severe (<1 x 106 sperm/ml) or moderate (1–10 x 106 sperm/ml) oligozoospermia (33.5%), obstructive azoospermia (7.7%), genetic disease (1.8%), severe (total sperm motility <5%) asthenozoospermia (1.4%) and anejaculation (0.4%). It should be mentioned that with the increased use of ICSI, there was a progressive decrease in the percentage of patients with severe or moderate oligozoospermia or asthenozoo spermia from 1991 until 1997.

Only women who had already conceived (live birth) with previous DI cycles were included in the cohort. Female infertility factors that could affect the outcome of treatment were detected before the initiation of DI cycles. This involved recording of medical history, current physical examination, basal body temperature charts, serum hormone assessment, transvaginal ultrasonographic examination and evaluation of cervical mucus. Tubal patency was confirmed by hysterosalpingography or laparoscopy. In addition, all couples attended an interview to discuss the psychological aspects of artificial procreation with donor semen prior to inclusion on the waiting list.

All DI cycles were performed using intracervical insemination. Approximately 20% of couples were inseminated for the second DI treatment using the same donor’s sperm as during the first treatment. One insemination was performed per cycle with at least 2.0 x 106 motile sperm per straw (0.25 ml). For women with normal ovulatory cycles (46%), the appropriate time for insemination was estimated on the basis of basal body temperature charts, transvaginal ultrasonographic evaluation and examination of cervical mucus. The use of ovarian stimulation (54%) was indicated for ovulatory disorders (including luteal defect and cervical mucus abnormalities). Ovarian stimulation was performed with clomiphene citrate (Clomid®, Marion Merell SA, Puteaux, France), HMG (Neopergonal®, Metrodine® Serono Laboratories, Paris, France; Humegon®, Organon Pharmaceuticals, Saint-Denis, France) or recombinant FSH (Follitropine alpha, Gonal F®, Serono Laboratories; Follitropine beta, Puregon®, Organon Pharmaceuticals). Except for cervical abnormalities for which low doses of gonadotrophins were preferred, antiestrogens were used first, then gonadotrophins, and then possibly a combination of antiestrogens and gonadotrophins in severe ovulatory disorders. Monitoring involved serum estradiol assessment and transvaginal ultrasonographic evaluation of follicular growth. The criterion for timing the administration of HCG was the presence of one or two pre-ovulatory follicles. The cancellation rate was 15%, with a similar distribution between multifollicular growth (three or more pre-ovulatory follicles), insufficient follicular growth and cervical mucus quality. Intracervical insemination was performed on the day of HCG administration (5000 IU, i.m. Gonadotrophine Chorionique Endo®, Organon Pharmaceuticals). After six and again after 12 DI cycles, previously failed DI cycles were assessed in order to decide whether to continue DI cycles, to proceed to IVF-D cycles or to stop all further treatment. Proceeding to IVF-D between the first and the sixth DI cycle was mainly decided when a poor or unsatisfactory response was observed in previous DI cycle(s). Poor response was defined by follicular growth defect despite increasing doses of gonadotrophins. Unsatisfactory response was mainly observed in polycystic ovary patients, when it was impossible to prevent multiple ovulations.

Only live births were taken into account. Spontaneous abortions, ectopic pregnancies and pregnancies lost beyond 12 weeks were considered as failed cycles. The end-point of patients’ follow-up was either live birth or withdrawal from the programme. Discontinuing patients were divided into three groups: stopping for medical reasons, stopping for personal reasons and switching to IVF-D. Some patients were denied further treatment for medical reasons involving poor prognosis (poor response to hormonal stimulation, age over 40 years). Other patients discontinued further treatment for personal reasons (lost to follow-up, decision to postpone further treatment, moved). Patients were considered as lost to follow-up when they failed to return to follow-up appointments for >12 months. Live birth rate, turning to IVF-D and drop-out for medical or personal reasons were recorded for each couple.

Statistical methods
The results are given as mean values ± SD and were analysed using Statview 4.1 (Abacus Concepts, Berkeley, CA, USA). ANOVA was used, followed by post hoc comparisons or contingency tables, depending on the parameter being evaluated, with P < 0.05 as the threshold of statistical significance.


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
From 1991 to 1997, 222 couples who had previously conceived through DI returned to DI for a total of 981 DI cycles in the CECOS of Tours, France.

Population studied
The mean age of the women in the cohort was 32.7 ± 3.0 years (range 26–40). The duration of initial infertility of the couples ranged from 1 to 10 years (3.5 ± 1.8 years). The mean number of DI cycles required to achieve the first birth was 4.4 ± 3.1 (range 1–15). The interval between the first birth and the first cycle of the second course was 36 ± 14 months (range 7–85). An average of 4.4 ± 3.3 DI cycles per couple was performed in this second course (range 1–12).

Outcome of DI cycles
The outcome of 981 DI cycles is shown in Table I. The mean live birth rate per DI cycle in this cohort was 14.8%, with the highest rate during the first DI cycle (18.9%). The live birth rate per cycle was similar from the first to the third DI cycle (17.0–18.9%), then began to decrease from the fourth cycle (13.9%). The rate stabilized thereafter (8.7–11.4%) until the twelfth cycle (6.7%). The crude cumulative live birth rate reached 57.7 and 65.3% overall after six and 12 DI cycles respectively. Crude cumulative live birth rates are shown in Figure 1. Among the couples who did not achieve a pregnancy terminating with a live birth, 9.5% turned to IVF-D and 25.2% dropped out. Couples more often stopped further treatment for personal reasons than for medical reasons (82 versus 18% respectively). Personal reasons for discontinuing treatment included decision to postpone further treatment (67%), loss to follow-up (21%), adoption (8%), move (2%) and divorce (2%). The frequency of couples who dropped out or turned to IVF-D was higher after the sixth and twelfth DI cycles. Beyond six DI cycles, the proportion of couples who stopped all further treatment was higher compared with couples who turned to IVF-D (25 and 7.9% respectively). Similarly, after 12 DI cycles, the proportion of couples who dropped out was higher compared with couples who turned to IVF-D (60 versus 33.3% respectively).


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Table I. Outcome of 981 DI cycles involving 222 couples
 


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Figure 1. Couples initiating a second parenthood project in an ART programme with frozen donor semen. Crude cumulative live birth rate per DI cycle.

 
After 981 DI cycles, 63.1% of couples (145/222) achieved second parenthood for a 14.8% live birth rate per cycle (145/981). In the 140 singleton births, the sex ratio was 1.03. The rate of multiple deliveries (twins only) was 3.4%.

The crude cumulative live birth rate did not differ significantly between the two main male infertility factors leading couples to choose frozen semen donor insemination (69 versus 58% for azoospermic and oligozoospermic patients respectively). Similarly, the mean number of DI cycles necessary to achieve a live birth did not differ between azoospermic and oligozoospermic patients (3.2 ± 2.4 versus 3.3 ± 2.6 respectively).

Couples were allocated to four groups, depending on the outcome of DI cycles [live birth (LB), stopping for personal reasons (SPR), stopping for medical reasons (SMR) and turning to IVF-D (IVF-Dt)]. The characteristics of these four groups of patients are shown in Table II. The mean age of women, the number of DI cycles for the first course and the duration of infertility did not differ between groups. The mean number of DI cycles for the second course was significantly lower in the LB group compared with the first course (3.3 ± 2.5 versus 4.2 ± 2.7 respectively; P < 0.05).


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Table II. Characteristics of couples in relation to the DI cycles
 

    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
This study was designed to evaluate, on a cohort follow-up basis, the success rate of a second course of ART using frozen donor semen.

Outcomes varied for patients who initiated the second course of DI cycles (live births for 65% of couples, end of treatment for 25% and 10% turning to IVF-D). Couples discontinued treatment mostly for personal reasons rather than for medical reasons.

Before starting infertility treatment in a given unit, patients need to be clearly informed about their chances of having a live baby according to each available ART technique. We followed the same rules as in our previous study involving couples with primary infertility in our ART programme using frozen donor semen (Guerif et al., 2002Go). First, results were expressed as live births, which undoubtedly is the most meaningful figure for couples and clinicians. Secondly, as the chances of achieving a live birth after a specified number of cycles remains the best information for a couple, results were expressed as cumulative live birth rate (Wilcox et al., 1993Go). Thirdly, no assumptions were performed by life table analysis in order not to overestimate the chances of success (Stolwijk et al., 1996Go; Land et al., 1997Go). Our results are therefore expressed as crude cumulative live birth rate.

Only couples with a previous live birth after DI cycles were included in the cohort, in order to allow some comparison with previous results reported for couples with primary infertility (Guerif et al., 2002Go). The overall live birth rate per cycle was substantially higher in this study than in the primary infertility cohort study (14.8 versus 10.9% respectively; P < 0.05). Thus the cumulative live birth rate at the end of the DI programme was higher in this study than in the previous study (65.3 versus 58% respectively; P < 0.05). Such results agree with a previous study, where higher cumulative conception rates after 12 cycles were reported for couples having achieved a full pregnancy during an earlier course of treatment (79 versus 54% respectively) (Shenfield et al., 1993Go). Other studies have also reported a higher probability of conceiving in couples who had already conceived (Kovacs et al., 1988Go; Federation CECOS et al., 1989Go; Tan et al., 1994Go; Molloy et al., 1995Go; Croucher et al., 1998Go; Williams and Alderman, 2001Go). Only one study reported a lower number of cycles to achieve a pregnancy for a first course compared with a second course (Botchan et al., 2001Go). However, no data were given for pregnancy rate per cycle or cumulative pregnancy rate in these conditions. In contrast, similar results were reported here for a DI programme depending on the presence or absence of a previous delivery (in whatever way such a pregnancy may be achieved). Additionally, in that study, women had previously been treated by fresh donor sperm insemination and returned later for frozen donor sperm insemination, which is expected to give lower results. Several lines of evidence may explain such a discrepancy between primary and secondary infertility. Indeed, a previous live birth may give a better prognosis for succeeding with the second pregnancy. Various parameters did not show any difference in the outcome of DI cycles between groups of couples with secondary infertility compared with primary infertile couples. As opposed to the first study, the DI outcome was not influenced by patient age in the second study. Similarly, length of infertility was similar between groups compared with the groups in the first study (average 2.7–4.0 versus 5.0–7.4 years for couples with secondary and primary infertility respectively). The live birth rate per cycle beyond the third cycle remained stable in the secondary infertility cohort, whereas it decreased beyond the seventh cycle in the primary infertile cohort. The population involved in the second parenthood project was therefore more homogeneous compared with the primary infertility cohort. It should also be noted that the number of DI cycles to achieve the first pregnancy in the second cohort was similar in the different groups, whatever the outcome of the second course (average number 4.2–5.9 cycles). However, the high cumulative live birth rate after three cycles (43.7%) compared with the final cumulative live birth rate (65.3%) indicates increased selection within this patient population.

Twenty-one of the 222 couples switched to IVF-D after previously failed DI cycles and undertook a total of 31 IVF-D cycles. The crude cumulative live birth rate overall was ~43%, allowing the cohort to achieve nine additional live births after failed DI cycles.

Finally, the total crude cumulative live birth rate reached 69% in the whole cohort referred to our CECOS for second parenthood using both DI and IVF-D. These results were identical to those obtained for couples with primary infertility (Guerif et al., 2002Go). However, the results observed with these different cohorts raise two comments. First, most live births were achieved after DI cycles in the cohort with previous live births (65%). Secondly, the proportion of couples who turned to IVF-D after failed cycles was twice as low in the cohort with previous live births (9.5%) than in the cohort with primary infertility (21%). It may be hypothesized that after a first parenthood project following DI cycles, turning to IVF-D cycles after failed DI cycles may appear too invasive. In the primary infertility cohort study, the results argued for switching to IVF-D after failure of the seventh cycle, since the live birth rate drastically decreased beyond the seventh cycle. In the present study, more than three-quarters of live births were obtained after the fourth cycle. Beyond the fourth cycle, results drastically decreased, then stabilized to almost 10% per cycle. At this point, two alternatives might be suggested. First, patients might turn to IVF-D after failure at the fourth cycle in order to take into account the scarcity of donor semen in our country. Secondly, patients might continue DI for a higher number of cycles if they remain reluctant to experience the invasiveness of IVF, since this could achieve some 25% more pregnancies.

This study is the first to follow-up couples who had previously conceived through DI and who returned for treatment using DI. Using live birth rate as the end-point, 65% couples achieved parenthood, whereas 35% ceased any further DI programme at various stages, mainly for personal reasons. In view of the fact that patients involved in a second parenthood project using frozen donor semen belong to a selected population, counselling of these patients needs to reconcile both the efficacy and invasiveness of the ART procedure with the availability of donor semen.


    Acknowledgement
 
Doreen Raine is kindly acknowledged for correction of the English text.


    References
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
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Submitted on March 27, 2003; accepted on May 29, 2003.