Spontaneous conception after a successfulattempt at in vitro fertilization/intracytoplasmic sperm injection

Bernadette Hennelly, S.R.N., Robert F. Harrison, M.D., Joan Kelly, S.R.N.,Saji Jacob, M.R.C.O.G., and Tom Barrett, M.R.C.O.G.

Human Assisted Reproduction Ireland, Rotunda Hospital, Dublin, Ireland

Objective: To determine the incidence of spontaneous pregnancy in women who were not actively under-going therapy after a successful attempt at IVF/intracytoplasmic sperm injection and to characterize its patternof occurrence.

Design: Retrospective postal questionnaire.

Setting: An assisted reproduction unit at a university-based teaching hospital.

Patient(s): Five hundred thirteen replies were received from 530 questionnaires mailed.

Intervention(s): None

Main Outcome Measure(s): Spontaneous pregnancy. Women who did and did not conceive spontaneouslyafter successful IVF treatment were compared in terms of their age, duration of infertility, previousreproductive history, and indication for treatment at the time of assisted reproduction.

Result(s): The rate of spontaneous conception among the survey respondents was 20.7%. Younger women(#34 years of age) had a higher rate of spontaneous conception, as did those with a shorter duration ofinfertility. Women with unexplained infertility and endometriosis also were more likely to conceive. Few ofthose who had undergone intracytoplasmic sperm injection conceived, whereas 21.6% of those whose partnershad had sperm quality sufficient for IVF later conceived spontaneously.

Conclusion(s): The chances of spontaneous conception after successful ART therapy are significant in somegroups of patients. This has implications for the practice of assisted reproduction and the obstetric care ofpatients who conceive with treatment. Contraceptive advice may need to be provided to couples who undergoIVF/intracytoplasmic sperm injection. (Fertil Sterilt 2000;73:774–8. ©2000 by American Society forReproductive Medicine.)

Key Words: ART, success, incidence, subsequent, spontaneous conception

The positive placebo effect found in infer-tile couples undergoing investigation andtreatment is well documented (1). It can evenbe seen in the pre and post end of the linetherapy IVF/intracytoplasmic sperm injec-tion (ICSI) (2– 6). Much less well appreci-ated are the chances of spontaneous preg-nancy after a successful attempt at assistedreproduction.

The ability to supply such informationwould be an important part of the counselingprocess that should accompany all assistedreproductive technology (ART) procedures.Multiple pregnancy is a distinct possibilitywith IVF/ICSI (7). The unplanned, spontane-

ous conception of additional children at a laterdate could have unforeseen social and eco-nomic implications. These warrant consider-ation before therapy is initiated, particularly inolder couples.

Information in the literature is scant anddiverse (8, 9). However, such an importantdetail should surely be included in the infor-mation given to patients as part of the decision-making process of informed consent. To rem-edy this situation at our center, we undertookthis study to discover the subsequent reproduc-tive history of couples who previously hadachieved a live birth with us through IVF/ICSIand did not want any further fertility therapy.

Received September 25,1999; revised andaccepted November 8,1999.Reprint requests: Robert F.Harrison, M.D., HumanAssisted ReproductionIreland, Rotunda Hospital,Dublin 1, Ireland (FAX: 353-1-8727831).

FERTILITY AND STERILITY tVOL. 73, NO. 4, APRIL 2000

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MATERIALS AND METHODS

PatientsThe study was approved by the Hospital Ethics Commit-

tee/Institutional Review Board. It included couples who hadhad successful pregnancies and birth as a result of IVF (10)or ICSI (11) cycles at the Human Assisted ReproductionUnit of the Rotunda Hospital in Dublin, Ireland, betweenJuly 1990 and March 1998. Patients who had conceived aftersubsequent IVF attempts were not included. The study wasconfined to couples who had indicated to us that they hadfinished active conceptive therapy.

Four hundred sixty-nine such couples had conceived afteran attempt at IVF. Another 44 had conceived after ICSIbegan to be used in 1995. Full results for both IVF and ICSIhave been published annually in the Rotunda Hospital Re-ports since the clinic opened in October 1989 (12).

Data CollectionThe information used in the study was derived from a

questionnaire (available on request). This was drawn up withinput from the medical, nursing, and counseling staff. It wasinitially pilot-tested on 30 women to ensure that they under-stood the questions asked and had no difficulty in respond-ing. The questionnaire then was sent with an accompanyingexplanatory letter (to ensure informed consent) to each pa-tient who was known to have been delivered of an infantafter IVF or ICSI treatment at our hospital unit and who hadnot returned for further therapy. To ensure as comprehensivea survey as possible, when an initial reply was not receivedwithin 1 month, another questionnaire was mailed. Whennecessary, telephone calls were made and the questionnairewas completed over the phone.

Data Processing and Statistical AnalysisAll the relevant answers to the questionnaire were entered

into a Microsoft Excel (Redmond, WA) spreadsheet andanalyzed using Data Desk version 6 (Data Desk, Ithaca,NY). Medians were used rather than means as most datawere skewed. Thex2 test was used for categorical outcomes.

RESULTS

GeneralFive hundred thirty questionnaires were sent out. Five

hundred thirteen (94%) replies were received and analyzed.One hundred six (20.7%) of the 513 respondents reportedthat they had had a subsequent spontaneous pregnancy. Tenof them had had two spontaneous pregnancies; in five cases,the first pregnancy ended in miscarriage and in two cases, itwas ectopic. For the purposes of data analysis, only the firstpregnancy was counted. Among the respondents who hadhad one subsequent pregnancy, 14 (13%) of those pregnan-cies ended in miscarriage and three (2.8%) were ectopic. Allthe pregnancies occurred within 2 years of the IVF/ICSIpregnancy success.

Age at the Time of ART SuccessThe median age of those respondents who did not con-

ceive again after their ART success was 34 years, the sameas that of those who did conceive again. The age-relatedfrequency distribution is shown in Table 1. Younger patientswere found to have a significantly higher chance of conceiv-ing spontaneously than those who were older (P5.0124).

Duration of Infertility Before First ARTSuccess

The median duration of infertility before the successfulattempt at IVF/ICSI was 4 years for respondents who con-ceived and also for those who did not conceive. However, asshown in Table 2, when the duration of infertility beforeconception was subdivided into 5-year intervals and thepercentage of the column total was calculated, there was atrend toward conception among those who had not beentrying as long (P5.834). It is interesting to note that thistrend occurred not just in the group of women who had beeninfertile for ,5 years (the largest group), but also in thegroup who had been infertile for 5–9 years (also a largegroup).

T A B L E 1

Maternal age at the time of ART treatment andtreatment outcome.

Age (y)No.

pregnantNo. not

pregnant (%) Total

,25 0 1 (0.2) 125–29 11 28 3930–34 56 175 23135–39 37 152 189.40 2 51 53

Total 106 407 513

Note: x2 5 12.78,P5.0124.

Hennelly. Spontaneous conception. Fertil Steril 2000.

T A B L E 2

Duration of infertility before ART success and spontaneouspregnancy afterward.

Duration ofinfertility (y)

No.pregnant

No. notpregnant Total

,5 57 222 2795–9 43 160 20310–14 6 22 28$15 0 3 3

Total 106 407 513

Note: x2 5 .834,P5.84.

Hennelly. Spontaneous conception. Fertil Steril 2000.

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Presence of Primary Infertility at the Time ofART Therapy

Four hundred seven (79%) of the 513 respondents had nothad a previous pregnancy before their successful ART at-tempt. This parameter appeared to have no role in the oc-currence of a subsequent spontaneous pregnancy (x2 52.565,P5.1).

Relation to Clinical Indication for ARTOf the 513 respondents, 153 had had unexplained infer-

tility before their ART attempt. A tubal factor was present in128 cases and significant endometriosis was present in 92cases. Forty-five of the women were anovulatory and 5 werethought to have a cervical factor. In 95 cases, a male factorwas identified.

As Table 3 shows, statistically significant differenceswere found in the occurrence of subsequent spontaneouspregnancies (P,.0535) when the various main causes ofinfertility that necessitated the use of IVF/ICSI were consid-ered. Those who were most likely to conceive spontaneouslyhad unexplained infertility or endometriosis. Patients whohad a tubal factor were less likely to conceive again.

Of the overall group, 13.7% of the respondents whounderwent ART for male factor infertility conceived again.However, these data include patients who underwent ICSIafter it was introduced in 1995, 4.6% of whom subsequentlyconceived spontaneously (Table 4). This is significantlyworse than the rate of spontaneous pregnancy in the overallgroup (P5.0058).

Among the 51 patients who underwent IVF alone before1995, the rate of spontaneous pregnancy was 21.6%. Unlikethe ICSI group, which contained patients with severe malefactor infertility (11), many of whom would not have beenconsidered for IVF before 1995, the patients who weretreated before ICSI was available had poor spermiogramsbut adequate sperm after swim-up to allow for IVF.

DISCUSSION

Most couples who want to conceive children are happyhowever it happens. Those who have achieved this goalthrough IVF/ICSI (13) and then suddenly conceive withoutaid also are extremely happy. But these feelings can betinged with surprise and apprehension. Many of these pa-tients thought that the reproductive chapter of their lives wasclosed. They had put the pain of childlessness behind them.An unexpected pregnancy may raise many issues. Theseindividuals did not contemplate this situation when theysought treatment with ART, and it may take time for them tocome to terms with it.

In the Human Assisted Reproduction Unit at RotundaHospital in Dublin, in accord with the guidelines of theMedical Council of Ireland (14), patients enter the programonly if they have a valid clinical indication for IVF/ICSI.They must have undergone a full infertility investigation andexplored all other therapeutic options. These patients trulyundertake IVF as a last resort. Therefore, it was surprising tofind that 20.7% of those for whom IVF proved successfullater conceived spontaneously. This incidence is muchhigher than that reported from France (8). Olivennes et al.reported that 8.9% of their patients had spontaneous preg-nancies after the birth of a child conceived through IVF. Arecent Japanese study found a cumulative pregnancy rate of18% at 60 months after the delivery of an infant conceivedthrough IVF (9).

The figure we obtained is likely to be a true representationof our clinic population. Our survey response rate of 94%was much higher than others have obtained (15) and thepopulation our clinic serves is very stable. Only patients wholive in Ireland are recruited to our program, and for much ofthe study period, it was the only ART program that wasoperating full-time in the Republic of Ireland. Our standardprotocol (10, 11) involves thorough counseling and a highdegree of contact between patient and staff throughout thetreatment period. The rapport that develops through thisapproach ensures a high degree of feedback in regard totreatment outcome, even from couples who later move toanother address.

T A B L E 3

Cause of infertility in 513 women in whom ART treatmentwas successful.

Cause ofinfertility

No.pregnant

No. notpregnant Total

Male factor* 13 82 95Tubal factor 19 109 128Unexplained 39 114 153Anovulation 8 32 40Endometriosis 26 66 92Cervical factor 1 4 5

Total 106 407 513

Note: x2 5 10.89,P5.0535.* Includes 44 patients who underwent ICSI; 2 became pregnant.

Hennelly. Spontaneous conception. Fertil Steril 2000.

T A B L E 4

Comparison of pregnancies achieved after a successful IVFand ICSI were performed for male factor infertility.

Type oftreatment

No.pregnant

(%)No. notpregnant Total

ICSI 2 (4.55) 42 (95.5) 44IVF 104 (22.2) 365 (77.8) 469Total 106 407 513

Note: x2 5 7.626,P5.0058.

Hennelly. Spontaneous conception. Fertil Steril 2000.

776 Hennelly et al. Spontaneous conception after ART success Vol. 73, No. 4, April 2000

In this study, all the spontaneous pregnancies reportedoccurred during the 2 years after the ART birth success. Thisis similar to the findings of Shimizu et al. (9), who also notedthat most such pregnancies occurred within 2 years. Themean interval from the delivery of the infant conceivedthrough IVF to the last menstrual period before the sponta-neous conception was 14.8 months.

It is of interest that the cumulative rate of conceptionleading to live birth is 14.3% at 12 months in untreatedinfertile couples (1). The report from Olivennes et al. (8)does not include such information. However, they do statethat 40% conceived again through another attempt at IVF.The way in which this figure was calculated and the initialpregnancy rate the first time conception occurred after IVFare not given. Other data (16) suggest that a previouslysuccessful IVF cycle is a positive prognostic indicator for asecond IVF attempt compared with a previous natural con-ception (31% vs. 19.4%).

Like Shimizu et al. (9), we found no relation between anatural conception before the IVF success and a spontaneouspregnancy afterward. This differs from studies on IVF ther-apy (17), which report that patients with secondary unex-plained infertility have a significantly better chance of suc-cess. We found no statistically significant differences in therates of positive outcomes among patients undergoing ARTfor various indications (18).

Patients with unexplained infertility and those with endo-metriosis were most likely to have a spontaneous pregnancyafter IVF success in this study. This finding calls into ques-tion the early use of ART in the management of unexplainedinfertility because spontaneous conception can be readilyexpected in these cases (1). In patients with endometriosis,subsequent spontaneous pregnancy could be the result of theknown effect pregnancy itself has on endometriosis.

When we analyzed couples in which the woman had atubal factor and her male partner had a severe male factor(the ICSI group), we found a much lower rate of spontaneousconception. In the study by Shimizu et al. (9), patients withsevere male factor infertility (sperm count of,0.1 3 106/mL) were not included. Before ICSI was introduced in 1995(11), only men who had subnormal semen parameters (19)but a sperm density of.5 3 106/mL and a good swim-upresult (20) would have been considered for IVF (21). In suchcases, the prognosis for spontaneous conception after IVFsuccess was 21.6% in this study, compared with 4.6% for theICSI group. These findings call into question the presentdefinition of male factor infertility. Further revision of spermparameters downward is indicated (19).

In this study, age was significantly correlated with thechance of spontaneous conception. This is in agreement withthe findings of Shimizu et al. (9). It also fits with what isknown about the chance of spontaneous conception with(22, 23) or without (1) IVF treatment. The chance of a

spontaneous pregnancy after a successful IVF cycle shouldbe considered when the number of embryos to be transferredis determined for younger women. This is particularly im-portant today when the detrimental impact of multiple preg-nancy is widely recognized (7) and in units like ours whereselective reduction is not an option (24).

The duration of infertility undoubtedly is related to age,albeit not entirely. In the population we serve, marriage isfrequently postponed until the couple are in their 30s. How-ever, the interplay between age and duration of infertilitymay explain why, despite a definite trend, statistical analysisof the duration of infertility did not quite reveal significance.This is somewhat different from studies of IVF therapy itself(22, 23).

There is a perception among patients who conceivethrough IVF/ICSI that they cannot conceive in any otherway. Our data clearly show that this is not true for as manyas one in five couples, particularly those who are youngerand have been infertile for a shorter period, women withendometriosis, couples with unexplained infertility, and menwith a mild male factor problem.

The volume of data collected and the incidence docu-mented warrant the inclusion of the chance of subsequentspontaneous pregnancy in discussions with couples who areconsidering the use of ART. Contraceptive advice also mayneed to be given, particularly when multiple pregnancy hasresulted from previous ART treatment. There also are im-plications for obstetric practice, particularly the mode ofdelivery. Many infants conceived through ART are deliveredby cesarean section (25). This may be due in part to a beliefthat a scar in the uterus is inconsequential because the patientwill not become pregnant again.

In our unit, the positive placebo effect of being placed onthe waiting list for ART treatment and conceiving after anunsuccessful IVF attempt was already evident. To this in-formation, we now add the chance of spontaneous pregnancyoccurring after a successful ART outcome. However, thenumber of such pregnancies that would have occurred with-out the prior success is unknown. These spontaneous preg-nancies may be related to the ovarian stimulation given inthe past or to the physiologic effects of pregnancy on thepituitary and endocrine systems. The most likely cause,however, is the relief from stress (13) that undoubtedlyoccurs after an infertile couple finally has a child.

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