A preliminary report on the incidence of clinical and subclinical spontaneous pregnancy loss

The preliminary purpose of this study was to document the incidence of clinical and subclinical spontaneous abortion in women who have no reproductive capability impairment. The relationship between prior oral contraception use and a subsequent increased incidence of spontaneous subclinical abortion was investigated. the incidence of clinically apparent spontaneous abortion ranges from 8.3 percent to 15 percent. Since factors such as increasing maternal age, prior spontaneous abortion, there is no "normal" incidence of abortion that applies to all women. Abortion risk increases with advancing maternal age, particularly after age 35 and especially over age 40. A history of prior spontaneous abortion increases the risk of subsequent spontaneous abortion, especially if the first abortion was associated with a normal karyotype. The effects of increasing gravidity are controversial; some investigators claim this factor constitutes an increasing risk for spontaneous abortion; others dispute the relevance of gravidity.

A PRELIMINARY REPORT ON THE INCIDENCE OF CLINICAL AND SUBCLINICAL SPONTANEOUS PREGNANCY LOSS by Martha E. Joy A project submitted to the faculty of the University of Utah in partial fulfillment of the requirements for the degree of Doctor of Pharmacy College of Pharmacy University of Utah i June 1983 UNIVERSITY OF UTAH COLLEGE OF PHARMACY FINAL READING APPROVAL TO THE DOCTOR OF PHARMACY COMMITTEE OF THE UNIVERSITY OF UTAH COLLEGE OF PHARMACY: I have read the clinical research project report of Martha E. Joy in its final form and have found that 1) its format, citations, and bibliographic style are consistent and acceptable; 2) its illustrative materials including figures, tables, and charts are in place; and 3) the final manuscript is satisfactory to the Supervisory Committee and is ready for submission to the Doctor of Pharmacy Committee. i Date JflMLUUjL - Chairman, Supervisory Committee Approved for the Department of Pharmacy Practice Chairman Approved for the Doctor of Pharmacy Committee / Chairman^y'Doctor of Pharmacy/ Committee UNIVERSITY OF UTAH COLLEGE OF PHARMACY SUPERVISORY COMMITTEE APPROVAL of a clinical research project report submitted by Martha E. Joy We, the undersigned, have read this clinical research project report and have found it to be of satisfactory quality for a Doctor of Pharmacy Degree. Date Chairman, Supervisory Committee ic/te/fi ? Date Member, Supervisory Committee PI OVJL.^) W Date • V o u Member, Supervisory Committee DEDICATION Dedicated to Mom and Dad who gave me everything and never asked for anything in return. Within each of us lies the power of our consent to health and to sickness, to riches and to poverty. It is we who control these, and not another. Richard Bach TABLE OF CONTENTS Page LIST OF TABLES vi 1 INTRODUCTION Objectives 1 Background ^ Sources of Bias in Studies 1 Subclinical Abortion 3 The Normal Menstrual Cycle 4 Oral Contraceptive Effects 5 8 METHODS Study Population 8 Inclusion and Exclusion Criteria 8 Ovulation and Pregnancy Determinations 9 Analysis RESULTS 1 0 DISCUSSION 1 2 CONCLUSION 1 6 TABLES • . . . . 17 APPENDIXES 2 5 REFERENCES 3 0 CURRICULUM VITAE 33 i LIST OF TABLES Page TABLE 1. Overall Study Results 18 TABLE 2. Spontaneous Abortions Per Cycle 19 TABLE 3. Maintained Pregnancies Per Cycle 20 TABLE 4. Contraceptives Used Prior to Study Entry in Relation to Spontaneous Abortions and Maintained Pregnancies. . 21 TABLE 5. Age Range of Study Group in Relation to Spontaneous Abortions and Maintained Pregnancies 22 TABLE 6. Statistical Analysis of Total Pregnancies Per Cycle. . 23 TABLE 7. Statistical Analysis of Spontaneous Abortions Per Cycle 24 vi INTRODUCTION Obj ectives The primary purpose of this study was to document the incidence of clinical and subclinical spontaneous abortion in women who have no reproductive capability impairment. The relationship between prior oral contraceptive use and a subsequent increased incidence of spontaneous subclinical abortion was investigated. Background The incidence of clinically apparent spontaneous abortion ranges 1 2 from 8.3 percent to 15 percent. ' Since factors such as increasing maternal age, prior spontaneous abortion, and possibly increasing gravidity increase the relative risk of abortion, there is no "normal" 2 incidence of abortion that applies to all women. Abortion risk in- creases with advancing maternal age, particularly after age 35 and 3_g especially over age 40. A history of prior spontaneous abortion • , u 4,6,8,9 increases the risk of subsequent spontaneous abortion, especially if the first abortion was associated with a normal 8 10 karyotype. ' The effects of increasing gravidity are controversial; some investigators claim this factor constitutes an increasing risk for spontaneous abortion;^'^ others dispute the relevance of ., 12,13 gravidity. Sources of Bias in Studies Factors affecting empirically determined rates of spontaneous abortions have been described in the literature under two major 2 categories: observational factors and artifactual factors. 2 Obser- vational factors relate to the confirmation of a spontaneous abortion. For instance a subclinical abortion may be missed due to delayed pregnancy confirmation and/or lack of clinical symptoms, or alternatively falsely confirmed due to sporadically delayed menses from isolated anovulatory cycles or ovulatory cycles with prolonged follicular phases. Additionally, induced abortions may be falsely reported as spontaneous abortions, artificially elevating the reported incidence of spontaneous abortions. Artifactual factors include memory artifact, compensation artifact, recurrence artifact, and selection artifact. Memory artifact is particularly significant in retrospective studies, where the longer the interval between the abortion and the time of questioning the more likely it may be forgotten. A compensation artifact refers to the voluntary decision to either persist or desist from further pregnancy attempts according to the outcome of previous pregnancies. For instance, the experience of a prior spontaneous abortion may cause the woman to become discouraged and desist from further pregnancy attempts. A recurrence artifact is purely statistical and its influence on study design is variable, depending on the length of the study period. Since the probability for the occurrence of a spontaneous abortion is more likely the longer the study period, and the risk for a subsequent abortion higher once one or more prior abortions have occurred, the longer the study period the higher the reported incidence of spontaneous abortion will be. A selection artifact refers to the period in time when observation is started. Retrospective studies requiring a pregnancy of 3 certain gestational age for entry are biased by the age selected. Prospective studies which follow a confirmed pregnancy are biased by the exclusion of early abortions which may or may not be apparent to the women but escape medical evaluation. The selection artifact is absent if recruitment is confined to nonpregnant women. Retrospective studies have reported higher incidences of spontaneous abortions, while prospective studies have reported lower incidences. Both types of studies are subject to the various biases previously discussed and include only those abortions which are clinically apparent. Abortion incidences from retrospective studies are considered to be most accurate with ranges of 13-15 percent reported. ^ P r o s p e c t i v e studies which recruit women already pregnant have reported incidences of spontaneous abortions less than ten percent due to the exclusion of early clinical abortions not medically evaluated and therefore not included.^'^ The most ideal study re- cruits nonpregnant women and observes subsequent pregnancies and losses.^ Subclinical Abortion The notion of subclinical abortion is derived from the confirmation of elevated human chorionic gonadotropin- (HCG) in women with missed periods who subsequently menstruate with either normal or moderately increased flow."^"4 Although the existence of subclinical abortion is confirmed by such studies, it does not give any indication of the frequency with which it occurs. In an attempt to estimate the frequency of both clinical and subclinical spontaneous abortion, Chartier and co-investigators prospectively screened a group of 4 infertile women who demonstrated objective evidence of ovulation. Conception was confirmed by the presence of HCG in the serum. The incidence of total abortion derived from this group was 37 percent. 16 Pregnancy loss projections based on the number of abnormal versus normal fertilized ova recovered from hysterectomy specimens give an incidence of spontaneous abortion of 29 percent."*"^ There are no studies which indicate to what extent these results are applicable to normal populations. Applying a correction factor to empirically determined incidences of spontaneous abortions to account for subclinical abortions increases the overall abortion rate in the normal population 2 to about 20 percent. Speculative mathematical calculations suggest 18 that about 78 percent of all conceptions are eventually aborted. It is estimated that about one-third of all early pregnancy losses are 18 due to chromosomal abnormalities. The Normal Menstrual Cycle A normal menstrual cycle can be described in three separate phases: the follicular, the ovulatory, and the luteal phase. The follicular phase lasts 8-21 days, resulting in follicular maturation and ovulation. Major hormonal influences during this stage include Follicle Stimulating Hormone (FSH) and estradiol, with low estradiol levels at the beginning of the cycle stimulating FSH release and high estradiol levels at the end of the cycle inhibiting FSH release. At sufficiently high levels of estradiol, Lutenizing Hormone (LH) release is stimulated resulting in the midcycle LH surge and ovulation on about day 14. Within about 24 hours of the LH surge, rupture of the follicle and release of the ovum takes place. This marks the beginning of the luteal phase with LH and estradiol levels dropping rapidly following ovulation. Primary hormones supporting the luteal phase are progester- one and estradiol. Gonadotropin concentrations remain low. Beginning 10-12 days after ovulation the corpus luteum enters a stage of regression with normal time from LH surge to menses being approximately 14 days. Should pregnancy take place, survival of the corpus luteum is prolonged by emergence of HCG. HCG first appears at 9-13 days after ovulation. Gonadotropins FSH and LH are secreted by the anterior pituitary in response to hypothalamic release of gonadotropin releasing factor. The ovarian hormones, estrogen and progesterone, stimulate the endometrium to secretory and deciduous phases, respectively. Oral Contraceptive Effects Combination oral contraceptive agents prevent ovulation by inhibition of gonadotropin secretion at either the hypothalamic or pituitary 19 level. Through a negative feedback mechanism the progestational agent suppresses LH secretion and the estrogenic agent suppresses FSH and LH secretion. Secondary mechanisms of contraceptive action in- clude a hostile endometrial environment not receptive to implantation of the fertilized ovum and a thickened cervical mucus impervious to sperm transport. Progestogen effects predominate when both estrogen and progestogen are given together. Suppression of both basal and reserve gonadotropic (FSH and LH) release occurs in women maintained on oral contraceptive agents after 9 as few as three months of low dose oral contraceptives. Suppression of endogenous ovarian estrogen production has also been reported to occur after three months of low dose oral contraceptives. Recovery of gonadotropin and estradiol concentrations to pretreatment levels occurs 9 20 within the first cycle after discontinuation of oral contraceptives. ' Return to normal hypothalamic-pituitary-ovarian axis function is rapid following oral contraceptive use. Although 87-97 percent of women will resume normal ovulation within three cycles following the use of oral contraceptive agents, a delay 21 in the return of spontaneous ovulation has been reported. Ovulation usually occurs between three to four weeks following discontinuation 20 of oral contraceptives. The delay in return to the normal midcycle rise of LH has been attributed to a prolongation of the follicular phase in the first post-oral contraceptive cycle. Since normal pre- menses follicular stimulation does not occur in oral contraceptive users until after the agent is discontinued, the subsequent follicular phase is prolonged. Monthly conception rates following oral contraceptive agents, as compared to prior users of other contraceptive methods, are con22 siderably lower. Conception rates are particularly low for the first three post-pill months and the delay in conception may be 13 22 months or greater for 25 percent of prior oral contraceptive users. Former oral contraceptive use has been reported to decrease fertility 23 rates for up to 42 months after discontinuing the agents. The overall conception pattern during the 12 months after oral contraceptives are discontinued shows distinct peaks in the conception rate 24 at intervals of about four months. The reasons for such a pattern are purely speculative and a subclinical pregnancy loss followed by a period of infertility is one possible explanation which fits the 7 pattern. Fertility impairment is independent of the length of time on 23 oral contraceptive agents. The incidence of clinically evident spontaneous abortion following oral contraceptive use is not signifi25-27 cantly increased. Prior users of intrauterine devices have also been reported to have lower monthly fertility rates than prior users 22 of other contraceptive methods other than oral contraceptives. This effect is seen primarily in the first three post-contraceptivemonths . ^ In summary, despite the rapid recovery of hypothalamic-pituitaryovarian function and the rapid return to normal ovulatory cycles after oral contraceptives, there is a marked delay in the return to normal fertility rates which is unexplained. Although the occurrence of spontaneous clinical abortion in women conceiving after cessation of oral contraceptive agents is approximately the same as that compared to other methods of contraception, the possibility exists that early subclinical pregnancy loss could be occurring with increased frequency in post-oral contraceptive users. Knowledge of empirically determined clinical and subclinical pregnancy loss is limited to abnormal populations. Estimates of clinical and subclinical pregnancy loss in normal populations are limited to correction factors applied to clinically apparent abortion rates in normal populations and mathematical manipulations based on average coital frequency and the probability of fertilization with each act of unprotected coitus. The primary purpose of this study was to document the incidence of clinical and subclinical spontaneous abortion in a normal population. 8 METHODS Study Population Women between the ages of 19 to 33 who actively desired pregnancy were enrolled in the study for a period of time up to five ovulatory cycles. The total study group included 18 women. Women in the study group reported varied prior contraceptive use, including spermicides (1), barrier methods (8), combination barrier/spermicidal methods (2), intrauterine devices (IUD) (3), and oral contraceptives (4). The group included two women with a prior history of spontaneous abortion, two women with a prior history of induced abortion, six women with a prior history of successful delivery, and eight women with no history of either pregnancy or abortion. Inclusion and Exclusion Criteria Women with a history of infertility problems or menstrual irregularities and those taking agents known to stimulate ovulation or prolactin were excluded. Women with a possible baseline pregnancy test at the time of the study entry were also excluded. Informed con- sent was obtained from each woman prior to enrollment in the study and a photocopy of the consent form was placed in the chart and the second copy given to the participant. The study was reviewed and approved by the Institutional Review Board of the University of Utah. All women were required to be actively desiring pregnancy and to have discontinued all methods of contraception at the time of study entry. A basal body temperature chart was kept by all women during the period of observation. Women were required to be at least 18 years of age. 9 Ovulation and Pregnancy Determinations Evidence of ovulation was objectively confirmed by either a sustained midcycle rise in temperature or luteal phase serum progesterone concentrations >_ 5 ng/mL. Progesterone determinations were made during week three and week four of each cycle. Pregnancy was confirmed by serum concentrations of HCG >_ 5 mlU/mL. Whole blood specimens were collected in sterile tubes, then centrifuged and the serum drawn off. Serum was stored at -20° Celsius until analysis. Serum HCG determina- tions were made during the initial week of enrollment and during week four of each cycle. If a delay in menses occurred, repeat HCG deter- minations were made the following week. If a pregnancy was confirmed, repeat HCG determinations were made weekly for two weeks; thereafter, HCG was measured biweekly for up to eight weeks post-conception. Serum HCG was analyzed by an immunoradiometric assay (RIA) manufactured by Hybritech. There is no reported cross-reactivity be- tween the assay method used and either gonadotropins or other hormones. The assay utilizes a two-site binding technique with the HCG molecule which eliminates cross-reactivity with molecular fragments of HCG. Only certain malignancies such as choriocarcinoma, hydatidiform mole, and some nontrophoblastic malignancies, including testicular tumors, prostatic cancer, breast cancer and lung cancer other than pregnancy 28 are known to cause elevations in serum HCG.- The assay is sensitive to 5 mlU/mL HCG, has an interassay variation of 4.7-10.7 percent and an intraassay variation of 3.6-7.5 percent (manufacturer's data). Serum progesterone was analyzed using an immunoradiometric (RIA) assay manufactured by Nuclear Medical Systems, Inc. The assay method 10 has a sensitivity to 25 pg/mL progesterone and an interassay variation of 8.1-13.0 percent and an intraassay variation or 6.1-9.0 percent (manufacturer's data). Analysis The difference in the incidence of pregnancies and spontaneous abortions between prior oral contraceptive users and prior users of other contraceptive methods was compared statistically using the Fishers Exact Test. RESULTS A total of 40 cycles were followed in the study period; eight cycles in prior users of oral contraceptives and 32 cycles in prior users of other contraceptive methods. Former oral contraceptive users had been continuous users prior to entry into the study for two months to two and one-half years. Oral contraceptives were discontinued from one week to one and one-half months prior to the study. Women who had used contraceptives other than oral contraceptive agents had not used oral contraceptives within three months of study entry. Prior users of contraceptive methods other than oral contraceptives had discontinued the agents from one day to five months prior to entry into the study. Table 1 lists spontaneous abortions, maintained pregnancies, and total pregnancies in prior oral contraceptive users and prior users of other contraceptive methods. The incidence of spontaneous early preg- nancy loss in non-oral contraceptive users was 50 percent, and the incidence of spontaneous early pregnancy loss in prior oral contraceptive users was 33 percent. The overall incidence of spontaneous preg- nancy loss in the total group was 46 percent. 11 Spontaneous abortions stratified according to cycle are listed in Table 2. These data show that pregnancy losses were equally distributed over the first three cycles of the study. which the maintained pregnancies occurred. Table 3 lists the cycle in Maintained pregnancies occurred during Cycle I, Cycle II, and Cycle IV. Three of the spontaneous pregnancy losses were asymptomatic while three were symptomatic. In the symptomatic group, one loss occurred within three weeks of conception, the second within six weeks of conception, and the third loss occurred more than nine weeks after conception. Symptoms consisted of pain, heavier or longer than usual menstrual flow, or the passage of tissue. All three asymptomatic losses occurred within three weeks of conception. Thus, the later a spontaneous abortion occurred post-conception, the more likely it was to be accompanied by the presence of symptomatology. Prior contraceptive methods employed by members of the study group are listed in Table 4. Barrier methods included the diaphragm, the condom, and the cervical cap. The IUD used by the study subjects ® was the Copper-7 . Spermicidal agents included both contraceptive foam and vaginal suppositories. The greatest number of spontaneous abor- tions per cycle occurred in the combined spermicides/barrier method group (20 percent); the second greatest number per cycle occurred in the barrier group (17 percent). Both the IUD and the oral contracep- tive group had an occurrence of 12.5 percent spontaneous abortions per cycle. None occurred in the spermicides group. Table 5 lists the ages of the women in the group in relation to pregnancy outcome (status). All spontaneous abortions occurred in the 12 group aged >_ 25; none occurred in the group aged _< 24. Most maintained pregnancies (71 percent) occurred in the group aged j< 24. Two women originally enrolled in the study group showed no evidence of ovulation either by serum progesterone concentrations or basal body temperature charts. data analysis. These women were not considered in the All other women showed evidence of ovulatory cycles. No spontaneous losses or pregnancies occurred in either of the two women showing no evidence of ovulation. No pattern could be detected from basal body temperature charts which would be predictive of eventual pregnancy loss. Tables 6 and 7 show the results of the statistical analysis between prior oral contraceptive users and prior users of other methods in terms of spontaneous abortions and total pregnancies. There was no statistically significant difference between the two groups in the frequency of either spontaneous abortions or total pregnancies (p > 0.05). DISCUSSION The design of this study attempted to avoid as many of the factors • which introduce bias as possible. % Observational factors were minimized by the use of the most sensitive method of pregnancy confirmation available. It is possible that some spontaneous pregnancy losses were missed due to the limited sensitivity of the assay method or an early fourth week serum analysis. In an attempt to minimize this limitation, all samples were run in duplicate and any samples that measured between 5-10 MIU/mL HCG or were < 5 MIU/mL and associated with clinical symptoms of a spontaneous abortion were reassayed. All pregnancy tests were per- formed as late in the cycle as possible, in order to allow the maximum amount of time between conception and pregnancy testing. It is doubt- ful that any spontaneous abortions in this group were actually purposefully induced since all women desired pregnancy. Selection artifact is absent since recruitment was limited to nonpregnant women as confirmed by baseline pregnancy testing. Memory artifact is not a factor in this study since objective evidence of pregnancy is relied on for documenting fertility. Although all study participants claimed to be actively desiring pregnancy throughout the study period, it is possible that some participants may have been unconsciously modifying pregnancy attempts after they were told of a spontaneous abortion. If there is a compensation type artifact present in this study, it would have to be an unconscious rather than a conscious act. The recurrence arti- fact was minimized in this study by the short period of observation. The maximum amount of time that any individual was observed was five cycles. Although the rate of spontaneous abortion was high in this group, no woman experienced more than one spontaneous abortion during the period of observation. The incidence of spontaneous abortion (46 percent) observed in this study is higher than empirically determined rates of spontaneous 4 11 abortion in normal populations (13-15 percent). ' The 13-15 percent figures refer only to clinically evident spontaneous abortions while the data from this study includes both clinical and subclinical spontaneous abortions. In addition, all prior studies suffer from the types of biases previously discussed. Primary biases in this study design would include observational factors and possibly compensation factors. Observational factors would tend to decrease the incidence of spontaneous abortions determined in this study, although to a 14 lesser degree than the effect on previous studies. If compensation factors do exist in this study, their effects are impossible to predict since all women in the study claimed to be actively desiring pregnancy throughout the period of observation. Data from series of women with abnormal fertility patterns indicate an incidence of 29-37 percent spontaneous abortions which includes both clinical and subclinical losses.^'^ Mathematical pro- jections based on probabilities estimate that 78 percent of all concep18 tions are eventually aborted. The incidence of 46 percent derived from this study is greater than incidences derived from studies of women with abnormal fertility rates and less than rates derived from mathematical projections. Spontaneous abortion rates in this study may be higher than rates derived from abnormal populations since women with abnormal fertility patterns may actually conceive less often than women with normal fertility patterns. Every attempt possible was made in this study to exclude women with a history of either documented or suspected abnormality in fertility in order to study as normal a population as possible. The incidence of spontaneous abortion ob- served in this study may be a more accurate reflection of the actual incidence in normal populations since it includes both clinical and subclinical abortion. Three spontaneous abortions in this study group were clinically apparent and subsequently medically evaluated. The incidence of clinically apparent spontaneous abortion in this group was 23 percent. The incidence of spontaneous abortion in prior oral contraceptive users (33 percent) is lower than that of prior users of other contraceptive methods (50 percent). The initial data suggest that oral 15 contraceptive agents do not increase the incidence of spontaneous subclinical abortion although the study group is too small to form any firm conclusions. The contraceptive group with the greatest number of spontaneous abortions per cycle was the combination barrier/ spermicide group (20 percent). The second largest group was in the barrier contraceptive group (17 percent). The ages of the eight women in the barrier contraceptive group ranged from 22-23 with most (75 percent) 25 years or older. The high incidence of spontaneous loss in this group may be related to the high proportion of older women in this group. The number of women in other groups was too small to per- mit any valid conclusion on the incidence of spontaneous pregnancy loss. No contraceptive method has been identified as a risk factor 22 for subsequent pregnancy loss except possibly the IUD. Risk factors for spontaneous abortion include increasing maternal age, prior spontaneous abortion, and possibly increasing gravi3-8 9-13 dity. ' Since only two women in the study group reported a history of prior spontaneous abortion, the group was too small to permit any observations on the influence of prior spontaneous abortion on subsequent pregnancy loss. Since increasing gravidity has not been clearly identified as a risk factor for spontaneous abortion, no attempt was made to look for an association in this study. Stratifi- cation of the study group according to age revealed that 100 percent of the spontaneous abortions occurred in the group aged _> 25. The small size of the various age groups in the study group probably would not permit an age-related trend to become apparent. been reported to particularly increase after age 35. Abortion risk has 3—8 Since the oldest woman in the study group was age 33, it was not possible to confirm this observation in the present study group. Although not as striking, a reciprocal relationship was seen in relation to pregnancy maintenance since 71 percent of the maintained pregnancies occurred in the group aged j< 24. CONCLUSION The incidence of spontaneous abortion in this study was 46 percent. No statistically significant difference in the number of pregnancies or spontaneous abortions between different prior methods of contraception was found. Since the number of women discontinuing oral contraceptives was so small, no firm conclusions can be made regarding any differences at this time. An increased incidence of spontaneous abortion occurred in the group aged >_ 25 years in this study. 18 Table 1. Overall Study Results Prior Users of Contraceptives Other Than Oral Contraceptives Prior Oral Contraceptive Users 32 8 40 5 1 6 Total Pregnancies 10 3 13 Total Women 14 4 18 Parameter Cycles Spontaneous Abortions Total Maintained Pregnancies 19 Table 2. Spontaneous Abortions Per Cycle Percentage of Spontaneous Number of Women Spontaneous Abortions Abortion per Total Women Cycle I 18 3 17 Cycle II 12 2 17 Cycle III 6 1 17 Cycle IV 3 0 0 Cycle V 1 0 0 40 6 TOTAL .... . . . 20 Table 3. Maintained Pregnancies Per Cycle Cycle Number of Women Maintained Pregnancies Percentage of Spontaneous Abortion per Total Women Cycle I 18 4 22 Cycle II 12 2 17 Cycle III 6 0 0 Cycle IV 3 1 33 Cycle V 1 0 0 TOTAL 40 21 Table 4. Contraceptives Used Prior to Study Entry in Relation to Spontaneous Abortions and Maintained Pregnancies Contraceptive Number of Women Spermicides Barrier Method Combination Barrier/ Spermicides Number of Cycles Spontaneous Abortion Maintained Pregnancy Percentage of Cycles with Spontaneous Abortion 1 0 0 18 3 17 5 1 20 12.5 IUD Oral Contraceptive agents TOTAL 18 40 Table 5. Age Range of Study Group in Relation to Spontaneous Abortions and Maintained Pregnancies Age (years) Number Spontaneous Abortions Maintained Pregnancies Total 19-21 2 0 2 2 22-24 5 0 3 3 25-27 5 3 28-30 2 1 1 2 31-33 4 2 0 2 18 6 7 13 TOTAL ... 1 4 Table 6. Statistical Analysis of Total Pregnancies per Cycle Oral Contraceptives Prior Users of Contraceptives Other Than Oral Contraceptives Total Number of Cycles with Pregnancies 3 10 13 5 22 27 8 32 40 Number of Cycles without Pregnancies TOTAL p > 0.05 24 Table 7. Statistical Analysis of Spontaneous Abortions per Cycle Prior Users of Oral Contraceptives Prior Users of Contraceptives Other Than Oral Contraceptives Total Number of Cycles with Pregnancy Losses 1 5 6 Number of Cycles without Pregnancy Losses 7 27 34 8 32 40 TOTAL p > 0.05 APPENDIXES 26 THE INCIDENCE OF SPONTANEOUS PREGNANCY LOSS IN WOMEN DISCONTINUING ORAL CONTRACEPTIVE AGENTS Consent Form Background Information You are invited to participate as one of 40 women in this research study evaluating the number of miscarriages following the use of birth control pills as compared to other contraceptive methods. During the first few months after stopping birth control pills, women experience difficulty in getting pregnant. The purpose of this study is to investigate the possibility that early pregnancy loss not detectable by either the woman (e.g., by presence of a heavier than usual menstrual flow) or her physician (e.g., by physical exam) may be a factor involved in difficulty getting pregnant. The availability of a new blood test which measures human chorionic gonadotropin (HCG) is able to detect pregnancies before the first missed period. This test differs from the usual pregnancy tests which use a urine sample to detect pregnancy usually two weeks after the first missed period. Research Study Design Women who enroll in the study will be required to discontinue all methods of birth control in order to become pregnant. A baseline pregnancy test will be performed at the time of enrollment. For women discontinuing oral contraceptives weekly blood progesterone (for evidence of ovulation) and HCG concentrations will be checked until onset of the first menstrual period. Thereafter, weekly blood tests will be checked starting with week 3 of the menstrual cycle and continuing until onset of menstruation; the cycle repeating itself each month. Women discontinuing other methods of contraception will be enrolled during the first week of the menstrual cycle and weekly blood tests performed in the same manner starting with week 3 of the menstrual cycle and continuing until onset of menstruation. If pregnancy should be confirmed, HCG concentrations will be continued weekly for the first month, thereafter only as the clinical situation dictates. All women will be asked to maintain daily basal body temperature charts during the entire period of study enrollment. Women will be enrolled in the study for a period of time not exceeding six months. All blood tests will be collected by routine means with 5 mL or 1 teaspoonful of blood taken for each test. Risks The risks involved in the study are: local pain and a very slight risk of infection at the site of the blood draw. 27 Benefits I understand that all pregnancy and ovulation tests with this study will be available to me at no cost. ture thermometers and charts will be given to me at addition, I will receive free pregnancy testing and pleting the study. done in connection Basal body temperano cost. In $50.00 after com- Additional Study Guidelines In agreeing to participate, I understand that the study is voluntary and that if I choose to withdraw from the study, I will continue to receive the same care as others not choosing to participate. I also understand that I can quit the study at any time I desire. If I have any additional questions regarding this research, I can call Dr. Maurice Emery (581-3044) or Ms. Martha Joy (581-5941) or Dr. Michael Caudle (581-7647). I realize that my records will be maintained with strict confidentiality by study investigators. My records will not be made available to anyone outside the confines of the study or clinic unless special permission is granted by me. Medical Treatment of Compensation for Physical Injury: In the event you sustain physical injury resulting from the research project in which you are participating, the University of Utah will provide you, without charge, emergency and temporary medical treatment not otherwise covered by insurance. Furthermore, if your injuries are caused by negligent acts or omissions of University employees acting in the course and scope of their employment, the University may be liable, subject to limitations prescribed by law, for additional medical costs of other damages you sustain. If you believe that you have suffered a physical injury as a result of participation in this research program, please contact the Office of Research Administration, phone number 581-6901. Signature Investigator Date 28 ORAL CONTRACEPTIVE STUDY EVALUATION FLOW SHEET Name Number Age Home Address_ Work Number Home Number Date of Entry Meeting Place for Blood Tests _ _ Day of Cycle Entered Into Study Significant Past Gynecologic/Obstetric History Prior Contraceptive Method Previous Pregnancies Menstrual History Chronic Disease Other Miscellaneous Check List of Tests Date Blood Drawn Initials Results Comments Baseline Pregnancy Test Cycle 1 3rd Week 4th Week Cycle 2 3rd Week 4th Week Cycle 3 3rd Week 4th Week Cycle 4 3rd Week 4th Week (continued) 29 Date Blood Drawn Cycle 5 3rd Week 4th Week Cycle 6 3rd Week 4th Week Initials Results Comments Other Comments Meetings Date Planned Date Seen Initials Comments REFERENCES 1. Roth DB: The frequency of spontaneous abortion. Int J Fertil 1983; 8:431. 2. Jensen RS: infertility. 3. Naylor AF: Spontaneous abortion incidence in the treatment of Am J Obstet Gynecol 1982; 143:451, Sequential aspects of spontaneous abortion: age, parity, and pregnancy compensation artifact. maternal Soc Biol 1974; 21:195. 4. Warburton D and Fraser FC: Spontaneous abortion risks in man: data from reproductive histories collected in a medical genetics unit. 5. Am J Hum Genet 1964; 16:1. Leridon H: Facts and artifacts in the study of intrauterine mortality: a reconsideration from pregnancy histories. Popul Stud 1976; 30:319. 6. Tietze C, Guttmacher AF, et al: planned pregnancies. 7. Unintentional abortion in 1,497 JAMA 1950; 142:1348. Stevenson AC, Dudgeon MY, et al: Observations on the results of pregnancies in women residents in Belfast. Ann Hum Genet 1959; 23:395. 8. Polard BJ, Miller JR, et al: Reproductive counseling in patients who have had a spontaneous abortion. Am J Obstet Gynecol 1977; 127:685. 9. 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