Objective
We sought to assess the relationship between a short interpregnancy interval (IPI) following a pregnancy loss and subsequent live birth and pregnancy outcomes.
Study Design
A secondary analysis of women enrolled in the Effects of Aspirin in Gestation and Reproduction trial with a human chorionic gonadotropin–positive pregnancy test and whose last reproductive outcome was a loss were included in this analysis (n = 677). IPI was defined as the time between last pregnancy loss and last menstrual period of the current pregnancy and categorized by 3-month intervals. Pregnancy outcomes include live birth, pregnancy loss, and any pregnancy complications. These were compared between IPI groups using multivariate relative risk estimation by Poisson regression.
Results
Demographic characteristics were similar between IPI groups. The mean gestational age of prior pregnancy loss was 8.6 ± 2.8 weeks. The overall live birth rate was 76.5%, with similar live birth rates between those with IPI ≤3 months as compared to IPI >3 months (adjusted relative risk [aRR], 1.07; 95% confidence interval [CI], 0.98–1.16). Rates were also similar for periimplantation loss (aRR, 0.95; 95% CI, 0.51–1.80), clinically confirmed loss (aRR, 0.75; 95% CI, 0.51–1.10), and any pregnancy complication (aRR, 0.88; 95% CI, 0.71–1.09) for those with IPI ≤3 months as compared to IPI >3 months.
Conclusion
Live birth rates and adverse pregnancy outcomes, including pregnancy loss, were not associated with a very short IPI after a prior pregnancy loss. The traditional recommendation to wait at least 3 months after a pregnancy loss before attempting a new pregnancy may not be warranted.
Pregnancy loss is the most frequent complication of early pregnancy (most commonly occurring <10 weeks’ gestation) and affects approximately 12-15% of clinically recognized pregnancies. After a pregnancy loss, couples often seek counseling on how long they should wait before attempting to conceive. The length of delay is of particular concern for women who may be subfertile or who are >35 years of age.
Most studies addressing interpregnancy interval (IPI) concentrate on the interval between live births and subsequent pregnancies. There is considerable evidence that an IPI <18 months after a term or preterm delivery is associated with an increased risk for poor maternal and perinatal outcome. However, there is significant controversy as to what the optimal timing is for the next pregnancy following a pregnancy loss.
It is common practice for obstetricians to recommend waiting at least 3 months before attempting a new pregnancy after an early pregnancy loss, while the World Health Organization (WHO) recommends a minimum IPI of at least 6 months after a spontaneous or elective abortion. However, there are few data to support these recommendations and contemporary studies demonstrate an inverse relationship between the rate of live birth and increasing IPI. Furthermore, published studies consist mostly of retrospective studies without uniformity in documentation of gestational age and outcomes, and the majority do not address very short IPI (<3 months). Thus, our primary objective was to assess the relationship between the interval between pregnancy loss and subsequent live birth in a large cohort of women, recruited from multiple clinical centers in the United States, who were actively trying to conceive following a pregnancy loss. Our secondary objective was to explore the relationship between IPI and subsequent pregnancy complications including periimplantation and clinical loss, preterm birth, preeclampsia, and gestational diabetes.
Materials and Methods
This study is a secondary data analysis of women enrolled in the Effects of Aspirin in Gestation and Reproduction (EAGeR) trial. The EAGeR trial, a block-randomized, multicenter, double-blinded, placebo-controlled trial of preconception low-dose aspirin or placebo, enrolled 1228 women, aged 18-40 years, with a history of 1-2 pregnancy losses. Details of the study design and protocol have been published previously. Women were stratified by eligibility criteria. The original eligibility stratum included women actively trying to conceive with a history of only 1 prior pregnancy loss at <20 weeks’ gestation during the past year, up to 1 prior live birth, up to 1 elective termination/ectopic pregnancy, regular menstrual cycles of 21-42 days in length during the preceding 12 months, no history of diagnosed or treated infertility, and aged 18-40 years. Women in the expanded stratum included women who had 1 or 2 pregnancy losses, including those at >20 weeks’ gestation, with pregnancy losses occurring >1 year prior to enrollment, and with up to 2 prior live births. All other criteria were identical between the 2 strata. Of note, 14 women withdrew immediately following randomization and were excluded from further analysis because they contributed no observed follow-up time.
The trial was conducted at 4 clinical sites in the United States with recruitment from 2007 through 2011. Women were followed for up to 6 menstrual cycles while trying to conceive and through delivery if they became pregnant. The study was approved by the institutional review board at each site, with each site serving as the institutional review board designated by the National Institutes of Health under a reliance agreement. All participants gave written informed consent prior to randomization.
Medical records were obtained documenting at least 1 of the up to 2 prior pregnancy losses with hCG, ultrasound, and/or histology. Each woman underwent an extensive questionnaire at baseline regarding her medical and obstetric history. Medical records were abstracted by trained study personnel. The majority of women (n = 653, 96.5%) had a medically documented date of last loss. For the remaining 24 women (3.5%), we relied on their self-reported date of last loss. Similarly, the majority of women (n = 589, 87.0%) had a medically documented gestational age of last loss, with an additional 86 women having a self-reported gestational age of loss.
Data for this study assessing IPI and pregnancy outcomes were limited to women whose last reproductive outcome was a pregnancy loss (n = 1074/1214, 88.5%) and subsequently became pregnant (n = 677/1214, 55.8%). Pregnancy was ascertained by a urine pregnancy test (clinic and/or home with the majority [89%] having both) and confirmed by a 6- to 7-week ultrasound. IPI was defined as the time between previous loss and the last menstrual period of the confirmed pregnancy. IPI was categorized by 3-month intervals (0-3, >3-6, >6-9, >9-12, and >12 months).
The primary outcome was live birth. Secondary outcomes included pregnancy loss, types of pregnancy loss, and obstetric complications (preeclampsia, gestational diabetes, and preterm birth <37 weeks). Periimplantation loss was defined as a pregnancy loss <5 weeks with no gestational sac visible on ultrasound. Preembryonic loss was defined as a pregnancy loss at 5 0/7 to 5 6/7 weeks with visible gestational sac and/or yolk sac, but no visible embryo on ultrasound. Embryonic loss was defined as a pregnancy loss at 6 0/7 to 9 6/7 weeks of an embryo with crown-rump length (CRL) <10 mm and no visible cardiac activity on ultrasound. Fetal loss was defined as a pregnancy loss at 10 0/7- 19 6/7 weeks with documented fetal cardiac activity ≥10 weeks (CRL ≥30 mm) or passage of conceptus with CRL measuring at least 30 mm. Stillbirth was defined as a pregnancy loss of a fetus at ≥20 weeks’ gestation without signs of life at the time of delivery. Clinically confirmed loss was defined as any stillbirth, preembryonic, embryonic, fetal loss, or other (including ectopic pregnancy). Preeclampsia was defined as having a systolic pressure ≥140 mm Hg and/or diastolic pressure ≥90 mm Hg that did not antedate the pregnancy and presented >20 weeks’ gestation on ≥2 occasions at least 4 hours apart and proteinuria ≥0.3 g in a 24-hour urine specimen or 1+ on dipstick. Preterm birth was defined as any delivery <37 weeks (including spontaneous and medically indicated preterm births).
Participant demographic, lifestyle, and reproductive history characteristics between IPI were compared using χ 2 or where appropriate Fisher exact test for categorical variables, and analysis of variance for continuous variables. Multivariable Poisson regression with robust error variance (to correctly estimate SE) was used to assess the relative risk (RR) of live birth, periimplantation loss, clinical loss, or pregnancy complication by IPI category (0-3, >6-9, >9-12, and >12 vs reference of >3-6 months; and ≤3 months vs reference of >3 months). Models adjusted for potential confounders that were selected a priori and included factors known to be associated with IPI and pregnancy or live birth success, and not on the causal pathway. Final models were adjusted for maternal age, race, body mass index (BMI), eligibility stratum, and gestational age of last loss. We compared results to models that additionally adjusted for self-reported months trying to achieve most recent pregnancy to adjust for potential undiagnosed and untreated subfertility. We conducted several sensitivity analyses including additionally adjusting for treatment group (eg, aspirin or placebo), intercourse frequency in the prior 12 months, and additional demographic, lifestyle, or reproductive history characteristics. As much of the literature makes comparisons between an IPI of ≤6 months vs a longer IPI, we also estimated the RR for live birth, pregnancy loss, and any pregnancy complication for women with an IPI ≤6 months vs >6 months along with assessing differences in very short IPI (0-1, >1-2, and >2-3 months).
Results
Of the 677 women who became pregnant and whose last reproductive outcome was a pregnancy loss, 2.7% of women became pregnant within the first month, 33.2% became pregnant within 3 months, and 65.7% became pregnant within 6 months. The median IPI was 4.3 months (interquartile range, 2.6–7.4 months) and the median time from most recent pregnancy loss to study entry was 13.8 weeks (interquartile range, 7.4–31.0 weeks). There were no significant differences among IPI categories for demographic and lifestyle characteristics ( Table 1 ).
| Characteristics | Total n = 677 | Interpregnancy interval | P value | ||||
|---|---|---|---|---|---|---|---|
| 0-3 mo (n = 225) 33.2% | 3-6 mo (n = 220) 32.5% | 6-9 mo (n = 118) 17.4% | 9-12 mo (n = 37) 5.5% | >12 mo (n = 77) 11.4% | |||
| Demographics and lifestyle, mean ± SD | |||||||
| Age | 28.6 ± 4.6 | 28.5 ± 4.4 | 28.9 ± 4.8 | 28.4 ± 4.6 | 28.8 ± 5.0 | 28.5 ± 4.6 | .84 |
| BMI | 25.4 ± 6.1 | 25.1 ± 5.8 | 25 ± 6.3 | 25.9 ± 5.7 | 25.6 ± 6.3 | 26.6 ± 7.0 | .30 |
| Race, n (%) | .21 | ||||||
| White | 657 (97.0) | 218 (96.9) | 216 (98.2) | 116 (98.3) | 35 (94.6) | 72 (93.5) | |
| Non-white | 20 (3.0) | 7 (3.1) | 4 (1.8) | 2 (1.7) | 2 (5.4) | 5 (6.5) | |
| Education, n (%) | .12 | ||||||
| >High school | 607 (90.0) | 201 (89.3) | 204 (92.7) | 107 (90.7) | 31 (83.8) | 64 (83.1) | |
| ≤High school | 70 (10.3) | 24 (10.7) | 16 (7.3) | 11 (9.3) | 6 (16.2) | 13 (16.9) | |
| LDA treatment, n (%) | 351 (51.9) | 118 (52.4) | 114 (51.8) | 56 (47.5) | 19 (51.4) | 44 (57.1) | .77 |
| Smoking in past year, n (%) | .81 | ||||||
| Never | 604 (89.8) | 206 (92.4) | 193 (88.1) | 106 (90.6) | 33 (89.2) | 66 (85.7) | |
| Sometimes [<6 times/wk] | 48 (7.1) | 13 (5.8) | 18 (8.2) | 7 (6) | 3 (8.1) | 7 (9.1) | |
| Daily | 21 (3.1) | 4 (1.8) | 8 (3.7) | 4 (3.4) | 1 (2.7) | 4 (5.2) | |
| Alcohol consumption in past year, n (%) | .35 | ||||||
| Never | 454 (67.8) | 160 (71.4) | 139 (64.1) | 82 (70.1) | 21 (58.3) | 52 (68.4) | |
| Sometimes | 199 (29.7) | 62 (27.7) | 69 (31.8) | 31 (26.5) | 14 (38.9) | 23 (30.3) | |
| Often | 17 (2.5) | 2 (0.9) | 9 (4.2) | 4 (3.4) | 1 (2.8) | 1 (1.3) | |
| Physical activity, n (%) | 1.00 | ||||||
| Low | 171 (25.3) | 60 (26.7) | 53 (24.1) | 31 (26.3) | 10 (27.0) | 17 (22.1) | |
| Moderate | 287 (42.4) | 94 (41.8) | 93 (42.3) | 50 (42.4) | 15 (40.5) | 35 (45.5) | |
| High | 219 (32.4) | 71 (31.6) | 74 (33.6) | 37 (31.4) | 12 (32.4) | 25 (32.5) | |
| Reproductive history | |||||||
| Previous live births, n (%) | .01 | ||||||
| 0 | 304 (44.9) | 82 (36.4) | 93 (42.3) | 63 (53.4) | 22 (59.5) | 44 (57.1) | |
| 1 | 260 (38.4) | 104 (46.2) | 84 (38.2) | 40 (33.9) | 10 (27.0) | 22 (28.6) | |
| 2 | 113 (16.7) | 39 (17.3) | 43 (19.6) | 15 (12.7) | 5 (13.5) | 11 (14.3) | |
| Previous pregnancy losses, n (%) | .72 | ||||||
| 1 | 436 (64.4) | 147 (65.3) | 144 (65.5) | 74 (62.7) | 26 (70.3) | 45 (58.4) | |
| 2 | 241 (35.6) | 78 (34.7) | 76 (34.6) | 44 (37.3) | 11 (29.7) | 32 (41.6) | |
| Gestational age of previous loss, a n (%) | .05 | ||||||
| <8 wk | 293 (43.4) | 101 (45.1) | 92 (41.8) | 44 (37.3) | 17 (46.0) | 39 (51.3) | |
| 8-13 wk | 347 (51.4) | 118 (52.7) | 112 (50.9) | 67 (56.8) | 20 (54.1) | 30 (39.5) | |
| 14-19 wk | 35 (5.2) | 5 (2.2) | 16 (7.3) | 7 (5.9) | 0 (0.0) | 7 (9.2) | |
| Gestational age of prior loss b | 8.6 ± 2.8 | 8.3 ± 2.5 | 8.7 ± 3 | 9.2 ± 3 | 8.1 ± 2.4 | 8.2 ± 3.1 | .07 |
| D and C performed on prior loss, n (%) | 230 (34.0) | 77 (34.2) | 75 (34.1) | 44 (37.3) | 13 (35.1) | 21 (27.3) | .71 |
| Eligibility criteria, n (%) | < .001 | ||||||
| Original | 344 (50.8) | 118 (52.4) | 119 (54.1) | 67 (56.8) | 22 (59.5) | 18 (23.4) | |
| Expanded | 333 (49.2) | 107 (47.6) | 101 (45.9) | 51 (43.2) | 15 (40.5) | 59 (76.6) | |
| Months trying for most recent pregnancy, mean ± SD | 4.3 ± 4.9 | 3.6 ± 4.6 | 3.9 ± 3.9 | 4.4 ± 4.2 | 5.8 ± 6 | 6.8 ± 7.3 | < .001 |
| Ever tried for >12 mo to become pregnant, n (%) | 31 (4.7) | 7 (3.1) | 7 (3.2) | 6 (5.1) | 2 (5.7) | 9 (12.2) | .01 |
| Intercourse in past 12 mo, n (%) | .44 | ||||||
| ≥3-6 times/wk | 226 (34.0) | 78 (35.3) | 74 (34.4) | 35 (29.9) | 11 (30.6) | 28 (36.8) | |
| 1-2 times/wk | 329 (49.5) | 106 (48) | 109 (50.7) | 62 (53) | 22 (61.1) | 30 (39.5) | |
| ≤2-3 times/mo | 110 (16.5) | 37 (16.7) | 32 (14.9) | 20 (17.1) | 3 (8.3) | 18 (23.7) | |
a n = 675; 589 Documented (continuous) and 86 self-report (categorical <8, 8-13, and 14-19 wk)
b n = 589 with documented loss recorded continuously (self-report assessed categorically <8, 8-13, and 14-19 wk).
All women had a previous pregnancy loss <19 weeks, with a mean gestational age of loss at 8.6 ± 2.8 weeks (range, 2–19 weeks). In all, 35 women (5.2%) had a previous pregnancy loss between 14-19 weeks. Reproductive histories stratified by IPI group are shown in Table 1 . Rates of dilation and curettage in the previous pregnancy were similar for the different IPI groups. The number of previous pregnancy losses was similar among IPI ≤3 months vs >3 months as well as individual 3-month IPI groups. Groups differed slightly regarding prior live births with relatively fewer nulliparous women with an IPI <3 months.
The overall live birth rate in our cohort was 76.5% (518/677). Live birth rates for IPI ≤3 months vs >3 months were 80.4% (181/225) and 74.6% (337/452), respectively ( Table 2 ). After adjustment for age, race, BMI, eligibility criteria, gestational age of previous loss, and months tried to conceive for most recent pregnancy, there was no significant difference in rate of achieving a live birth for IPI ≤3 months as compared to >3 months (adjusted relative risk, 1.07; 95% confidence interval, 0.98–1.16) ( Figure 1 ). A finer breakdown of IPI categories by 3-month intervals demonstrated highest live birth rates for the 0-3 month IPI group (80.4%) with the lowest occurring in the >12 month IPI group (65.0%). However, there were no statistically significant differences in live birth rates among 0-3, >6-9, >9-12, and >12 month IPI groups compared to the reference of >3-6 months. Live birth rates remained similar when the 0-3 month IPI group was further broken down by 1-month intervals, with 83.3%, 85.9%, and 76.2% achieving a live birth for 0-1, >1-2, and >2-3 month IPI groups, respectively.
| Interpregnancy interval | Live birth/total, n (%) | Relative risk (95% CI) | |||
|---|---|---|---|---|---|
| Model 1 | P value a | Model 2 | P value b | ||
| 0-3 mo | 181/225 (80.4) | 1.1 (1–1.2) | .32 | 1.0 (0.9–1.2) | .37 |
| 3-6 mo | 168/220 (76.4) | REF | na | REF | na |
| 6-9 mo | 91/118 (77.1) | 1.0 (0.9–1.1) | .86 | 1.0 (0.9–1.1) | .86 |
| 9-12 mo | 28/37 (75.7) | 1.0 (0.8–1.2) | .95 | 1.0 (0.8–1.2) | .95 |
| >12 mo | 50/77 (64.9) | 0.9 (0.7–1.0) | .09 | 0.9 (0.7–1.1) | .09 |
| ≤3 vs >3 mo | 181/225 (80.4) vs 337/452 (74.6) | 1.1 (1.0–1.2) | .09 | 1.1 (1.0–1.2) | .15 |
a Model 1: adjusted for age, race, body mass index, eligibility criteria, and gestational age of prior loss
b Model 2: adjusted for age, race, body mass index, eligibility criteria, gestational age of prior loss, and months tried to conceive for most recent pregnancy.
The average gestational age of a pregnancy loss that occurred during the trial was 9.9 ± 4.1 weeks ( Table 3 ). The most common type of loss was embryonic (53.4%) followed by preembryonic (27.1%), fetal (6.8%), and stillbirths (3.0%). These were similar for the different IPI groups compared to the reference of >3-6 months, with the exception of a greater risk for periimplantation failure among women with an IPI >12 month vs >3-6 month (adjusted relative risk, 3.70; 95% confidence interval, 1.49–9.19) after adjusting for age, race, BMI, eligibility criteria, gestational age of prior loss, and months tried to conceive for most recent pregnancy ( Table 4 ). The risk of a clinically confirmed loss, however, remained similar between the different 3-month IPI groups.
| Characteristics | Total n = 677 | Interpregnancy interval | P value | ||||
|---|---|---|---|---|---|---|---|
| 0-3 mo (n = 225) 33.2% | 3-6 mo (n = 220) 32.5% | 6-9 mo (n = 118) 17.4% | 9-12 mo (n = 37) 5.5% | >12 mo (n = 77) 11.4% | |||
| Preterm birth, n (%) a | 42 (8.1) | 12 (6.6) | 15 (8.9) | 8 (8.8) | 4 (14.3) | 3 (6.0) | .65 |
| Periimplantation loss, n (%) | 41 (6.0) | 13 (5.8) | 9 (4.1) | 8 (6.8) | 1 (2.7) | 10 (13.0) | .06 |
| Clinical loss, n (%) | 118 (17.4) | 31 (13.8) | 43 (19.6) | 19 (16.1) | 8 (21.6) | 17 (22.1) | .34 |
| Clinical loss type, n (%) b | .53 | ||||||
| Embryonic | 71 (53.4) | 18 (58.1) | 22 (51.2) | 10 (52.6) | 6 (75.0) | 9 (52.9) | |
| Preembryonic | 36 (27.1) | 11 (35.5) | 9 (20.9) | 7 (36.8) | 1 (12.5) | 3 (17.7) | |
| Fetal loss | 9 (6.8) | 1 (3.2) | 5 (11.6) | 0 (0.0) | 1 (12.5) | 1 (5.9) | |
| Stillbirth | 4 (3.0) | 1 (3.2) | 2 (4.7) | 0 (0.0) | 0 (0.0) | 1 (5.9) | |
| Other c | 13 (9.8) | 0 (0.0) | 5 (11.6) | 2 (10.5) | 0 (0.0) | 3 (17.7) | |
| Gestational age of loss, wk | 9.9 ± 4.1 | 10.1 ± 5.5 | 10.1 ± 4.1 | 8.2 ± 1.7 | 11.9 ± 2.9 | 9.9 ± 3.7 | .26 |
| Preeclampsia, n (%) d | 58 (9.0) | 19 (8.8) | 20 (9.4) | 8 (7.2) | 6 (16.7) | 5 (7.3) | .51 |
| Gestational diabetes, n (%) d | 20 (3.1) | 6 (2.8) | 9 (4.2) | 2 (1.8) | 1 (2.8) | 2 (2.9) | .81 |
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