ORIGINAL ARTICLE: ASSISTED REPRODUCTION
Interpregnancy interval and singleton pregnancy outcomes after frozen embryo transfer Molly M. Quinn, M.D.,a Mitchell P. Rosen, M.D.,b Isabel Elaine Allen, Ph.D.,c Heather G. Huddleston, M.D.,b Marcelle I. Cedars, M.D.,b and Victor Y. Fujimoto, M.D.b a Department of Obstetrics and Gynecology, University of California Los Angeles, Los Angeles, California; b Department of Obstetrics, Gynecology and Reproductive Sciences, University of California San Francisco, San Francisco, California; c Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California
Objective: To describe the relationship between interpregnancy interval (IPI) and perinatal outcomes in singleton live births after frozen embryo transfer (FET). Design: Retrospective analysis of the Society for Assisted Reproductive Technology Clinical Outcome Reporting System cohort including patients with a history of live birth from ART who returned for an FET cycle between 2004 and 2013. Setting: Not applicable. Patient(s): A total of 19,270 singleton live births from FET subsequent to a live birth. Intervention(s): None. Main Outcome Measure(s): Odds for preterm delivery (<37, <34, <28 weeks) and low birth weight (<2,500, <1,500 g) adjusted for age, body mass index, and history of prior preterm delivery. Result(s): Of 74,456 autologous FET cycles following an index live birth, 24,091 resulted in a repeat live birth, with 19,270 singleton live births. An IPI of <12 months occurred in 19% of cycles. Adjusted odds (aORs) for preterm delivery at <37 weeks were signiﬁcantly increased for an IPI of <6 months (aOR 2.05, 95% conﬁdence interval [CI] 1.48–2.84), 6 to <12 months (aOR 1.26, 95% CI 1.06–1.49), and 18 to <24 months (aOR 1.23, 95% CI 1.06–1.43) when compared with the reference interval of 12 to <18 months. Additionally, an IPI of <6 months was associated with increased odds for low birth weight (aOR 3.06, 95% CI 2.07–4.52) and very low birth weight (aOR 5.65, 95% CI 2.96–10.84) compared with an IPI of 12 to <18 months. Conclusion(s): In this nationally representative population, an interval from delivery to start of an FET cycle of <12 months is associated with increased odds for preterm delivery among singleton live births. Consistent with data for patients undergoing fresh IVF, the data support delaying FET 12 months from a live birth. (Fertil SterilÒ 2019;-:-–-. Ó2019 by American Society for Reproductive Medicine.) Key Words: Birth spacing, frozen embryo transfer (FET), interpregnancy interval, low birth weight, preterm delivery Discuss: You can discuss this article with its authors and other readers at https://www.fertstertdialog.com/users/16110-fertilityand-sterility/posts/43915-27274
short interval between live birth and subsequent conception, or interpregnancy interval (IPI), has been associated with adverse perinatal outcomes, including preterm delivery, low birth weight, and small for gestational age, in the naturally conceiving population (1–4).
Offspring of women who conceive by assisted reproductive technology (ART) have increased risk of unfavorable pregnancy outcomes when compared with singleton live births from fertile populations (5, 6). We have previously demonstrated that an IPI of <12 months was associated
Received November 6, 2018; revised January 28, 2019; accepted February 12, 2019. M.M.Q. has nothing to disclose. M.P.R. has nothing to disclose. I.E.A. has nothing to disclose. H.G.H. has nothing to disclose. M.I.C. has nothing to disclose. V.Y.F. has nothing to disclose. Financial support was provided by the National Center for Advancing Translational Sciences, National Institutes of Health, University of California San Francisco–Clinical & Translational Science Institute grant number UL1TR001872. Reprint requests: Molly M. Quinn, M.D., David Geffen School of Medicine at the University of California Los Angeles, Department of Obstetrics and Gynecology, 10833 Le Conte Avenue, 27-139 Center for Health Sciences, Los Angeles, California 90024-1740 (E-mail: [email protected]
). Fertility and Sterility® Vol. -, No. -, - 2019 0015-0282/$36.00 Copyright ©2019 American Society for Reproductive Medicine, Published by Elsevier Inc. https://doi.org/10.1016/j.fertnstert.2019.02.018 VOL. - NO. - / - 2019
with increased risk of preterm delivery in singleton live births from fresh IVF in a national cohort (7); and others, using statewide surveillance data, have shown an increased risk of preterm delivery in live births from ART following intervals of <12 months (8). In recent years observational studies have suggested that a strategy of freezing suitable embryos with planned frozen embryo transfer (FET) may be associated with improved placentation and an attendant reduction in risk in placentally derived adverse pregnancy outcomes, including preterm delivery and low birth weight (9, 10). These ﬁndings, however, were not 1
ORIGINAL ARTICLE: ASSISTED REPRODUCTION conﬁrmed in subsequent randomized controlled trials of fresh vs. frozen embryo transfer (11–13). To date, the relationship between IPI and pregnancy outcomes has not been explored within the infertility population speciﬁcally undergoing FET. Therefore, we investigated the association between short IPI and pregnancy outcomes in FET cycles, to determine whether the mode of transfer has an impact on the relationship between IPI and adverse pregnancy outcomes.
MATERIALS AND METHODS Study Design and Population This is a retrospective analysis of the Society for Assisted Reproductive Technology Clinic Outcome Reporting System (SART CORS) cohort, which contains comprehensive data from more than 91% of all IVF cycles in the United States (14). Data were collected and validated by SART and reported to the Centers for Disease Control and Prevention in compliance with the Fertility Clinic Success Rate and Certiﬁcation Act of 1992 (Public Law 102-493). The data in the SART CORS are validated annually, with some clinics having onsite visits for chart review based on an algorithm for clinic selection. During each visit, data reported by the clinic were compared with information recorded in patients’ charts. Ten out of 11 data ﬁelds selected for validation were found to have discrepancy rates of %5% (15). The study population included patients from SART CORS with a history of live birth from ART who returned to the same clinic for a subsequent FET cycle from 2004 to 2013. Cycles using embryos derived from donor oocytes were excluded. Subjects were identiﬁed by SART ID number. Because the research involved only unidentiﬁable and coded information, it was determined not to involve human subjects and was therefore exempted from further review by the University of California San Francisco institutional review board. The study was approved by the SART Research Committee.
Primary Predictor Interpregnancy interval was deﬁned as the interval from live birth to subsequent start of an FET cycle resulting in a repeat live birth. This was divided into 6-month intervals for consistency with prior literature. Female age at treatment cycle start, ethnicity, body mass index (BMI), geographical region in United States, and prior history of preterm delivery were also collected as independent variables.
Outcome Measures Gestational age at delivery was deﬁned as calendar time between the date of ET and live birth þ 14 days þ embryo day at transfer (e.g., þ3 days for cleavage-stage embryo). This was dichotomized to obtain the primary outcome of interest, preterm delivery, deﬁned as <37 weeks’ gestation. Given the increasing morbidity associated with more extreme preterm delivery, an additional variable was deﬁned for deliveries occurring at <32 weeks (very premature). Birth weight was a secondary outcome measure of interest. Consistent 2
with prior literature, low birth weight was deﬁned as <2,500 g and very low birth weight as <1,500 g.
Statistical Methods Analysis was restricted to FET cycles resulting in singleton live birth. Demographic and clinical characteristics of women with singleton live births from FET were stratiﬁed by IPI. Continuous variables were analyzed with analysis of variance (ANOVA) and categorical variables via c2 test. When the oneway P value was < .05, pairwise comparisons were performed with Bonferroni correction for multiple comparisons. Singleton gestational age at delivery and birth weight were stratiﬁed by 6-month IPI intervals and compared by ANOVA. Univariate logistic regression models were built to investigate the impact of IPI (with reference IPI 12 to <18 months, the largest group) on preterm delivery (<37 weeks and <32 weeks) and birth weight (<2,500 g and <1,500 g). Multivariate logistic regression was performed to adjust for maternal age, BMI, and history of prior preterm delivery based on associations demonstrated in the literature and directed acyclic graphs of the framework for a causative relationship of IPI on pregnancy outcomes. A stratiﬁed analysis was then performed to assess the impact of ethnicity on the association between IPI and preterm delivery. Results were considered signiﬁcant with P values < .05 for unadjusted analyses, and when the 95% conﬁdence intervals (CIs) did not include 1 in multivariate analysis. All logistic regression models were checked for misspeciﬁcation and appropriateness of model ﬁt. Analyses were performed using STATA, version 14 (StataCorp).
RESULTS Of 74,456 autologous FET cycles following an index live birth, 24,091 resulted in a repeat live birth, with 19,270 singleton live births. An IPI of <12 months occurred in 19% of cycles resulting in singleton live birth. Baseline characteristics, including age, ethnicity, history of prior preterm delivery, and BMI, were stratiﬁed by IPI. Patients with an IPI of 6 to <12 months or R24 months were slightly older than those with an IPI of 12 to <18 months or 18 to <24 months (36.5 5.5 years for 6 to <12 months; 35.9 5.0 years for 12 to <18 months; 35.9 4.9 years for 18 to <24 months; 36.3 4.7 years for R24 months; P< .001). Additionally, 33% of those with an IPI of <6 months had a prior preterm delivery, a preterm delivery rate substantially greater than all other groups. Finally, there were small, but signiﬁcant, differences in mean BMI between groups (Table 1). In univariate analyses, an IPI of <6 months was associated with increased odds for all adverse perinatal outcomes explored, including preterm delivery <37 weeks (odds ratio [OR] 2.46, 95% CI 1.93–3.14), <32 weeks (OR 5.29, 95% CI 3.24–8.64), and <28 weeks (OR 5.89, 95% CI 2.89–12.00) compared with the reference IPI of 12 to <18 months. Additionally, an IPI of <6 months was associated with increased odds for low (OR 2.99, 95% CI 2.19–4.09) and very low birth weight (OR 5.32, 95% CI 3.02–9.39) compared with an IPI of 12 to <18 months. Interpregnancy intervals of 6 to <12 months (OR 1.19, 95% CI 1.04–1.36) and 18 to <24 months (OR 1.16, 95% CI 1.02–1.31) were also associated VOL. - NO. - / - 2019
Fertility and Sterility®
TABLE 1 Baseline demographic and clinical characteristics of women with singleton live births from autologous FET cycles stratiﬁed by IPI. Variable Age (y) at cycle start Ethnicity (white) Prior preterm delivery BMI (kg/m2)
<6 mo (n [ 389)
6 to <12 mo (n [ 2,901)
12 to <18 mo (n [ 5,285)
18 to <24 mo (n [ 3,952)
‡24 mo (n [ 6,743)
35.8 5.7 188 (48) 372 (33)e,f 25.7 5.9g,h
36.5 5.5 1,484 (51) 2,797 (18)b 24.8 5.2i
35.9 5.0 2,806 (53) 5,140 (18)b 24.6 5.1
35.9 4.9 2,127 (54) 3,869 (20)b 24.3 4.9f
36.3 4.7 3,500 (52) 6,577 (24) 24.7 5.2
< .001c NSd < .001d < .001c
Note: Values are presented as mean SD or number (percentage). NS ¼ nonsigniﬁcant. a P< .001 compared with 12 to <18 months and 18 to <24 months. b P< .001 compared with R 24 months. c ANOVA. d 2 c . e P< .001 compared with 6 to <12 months, 12 to <18 months, and 18 to <24 months. f P¼ .002 compared with R24 months. g P¼ .018 compared with 12 to <18 months. h P¼ .001 compared with 18 to <24 months. i P¼ .003 compared with 18 to <24 months. Quinn. Pregnancy spacing and FET outcomes. Fertil Steril 2019.
with increased odds for preterm delivery <37 weeks when compared with an IPI of 12 to <18 months (Table 2). In multivariate analyses, the impact of IPI on pregnancy outcomes was adjusted for maternal age, history of preterm delivery, and BMI. The adjusted odds (aOR) of preterm delivery at <37 weeks (aOR 2.05, 95% CI 1.48–2.84), <32 weeks (aOR 5.02, 95% CI 2.81–8.99), and <28 weeks (aOR 7.10, 95% CI 3.31–15.23) remained signiﬁcantly increased for an IPI of <6 months compared with 12 to <18 months. Additionally, an IPI of <6 months remained associated with increased odds for low birth weight (aOR 3.06, 95% CI 2.07– 4.52) and very low birth weight (aOR 5.65, 95% CI 2.96– 10.84) compared with an IPI of 12 to <18 months. Finally, adjusted odds for preterm delivery <37 weeks were increased for IPI of 6 to <12 months (aOR 1.26, 95% CI 1.06–1.49) and 18 to <24 months (aOR 1.23, 95% CI 1.06–1.43) compared with the reference IPI of 12 to <18 months (Table 2). An IPI of R24 months was not associated with increased odds for adverse pregnancy outcomes. In an analysis stratiﬁed by ethnicity, IPIs of <6 months (aOR 2.40, 95% CI 1.55–3.70) and 6 to <12 months (aOR 1.38, 95% CI 1.10–1.73) were associated with increased odds for preterm delivery <37 weeks among those individuals of self-reported white ethnicity, whereas IPIs of <6 months (aOR 1.69, 95% CI 1.04–2.76) and 18 to <24 months (aOR 1.31, 95% CI 1.05–1.63) were associated with increased odds for preterm delivery <37 weeks (compared with the reference IPI of 12 to <18 months) among those who reported non-white ethnicity. There was, however, no difference in the aOR for prematurity by ethnicity at an IPI of <6 months. In an analysis restricted to patients without a prior history of preterm delivery, an IPI of <6 months (OR 2.06, 95% CI 1.31–3.24), 6 to <12 months (OR 1.24, 95% CI 1.01–1.52), and 18 to <24 months (OR 1.25, 95% CI 1.04–1.50) remained associated with increased odds for preterm delivery compared with those who had an IPI of 12 to <18 months.
DISCUSSION Using a large, nationally representative database, we demonstrate that an interval from delivery to start of an FET cycle of <12 months is associated with increased odds VOL. - NO. - / - 2019
for preterm delivery <37 weeks among singleton live births, independent of maternal factors such as age, BMI, and history of prior preterm birth. Furthermore, an IPI of <6 months is associated with increased odds for more signiﬁcant prematurity at <32 and <28 weeks, in addition to increased odds for low and very low birth weight offspring. These data, therefore, support delaying the start of an FET cycle 12 months for optimization of perinatal outcomes. A short IPI has been associated with adverse maternal and neonatal outcomes in naturally conceiving populations (1–4), leading Healthy People 2020 to campaign for a reduction in pregnancies occurring within 18 months of delivery, whereas the World Health Organization urges patients to wait 24 months to conceive after a live birth (16, 17). Only recently have data pertaining to patients undergoing assisted reproduction been published. This population is unique given their increased baseline risk for adverse perinatal outcomes (6). Using nationally representative data from SART, we previously demonstrated that an interval from delivery to treatment start of <12 months was associated with increased rates of preterm delivery and low birth weight in singleton live births from fresh IVF, but we did not ﬁnd a beneﬁt from a longer interval (7). Palmsten et al. (8) came to the same conclusion using linked birth certiﬁcate and ART surveillance data from Massachusetts and Michigan. The latter publication included singleton live births from all ART, including fresh IVF and FET. Improvements in embryo cryopreservation techniques and the rise in preimplantation genetic screening for aneuploidy by comprehensive chromosomal screening on trophectoderm biopsies have resulted in increased use of FET. Furthermore, several observational studies suggested an improvement in obstetric and perinatal outcomes in singleton pregnancies following frozen–thawed vs. fresh embryo transfer. A subsequent meta-analysis demonstrated reductions in antepartum hemorrhage, preterm birth, small for gestational age, low birth weight, and perinatal mortality in women who received frozen embryos compared with those undergoing fresh embryo transfer (9). These factors, and the convenience of a scheduled FET, have resulted in increased adoption of planned ‘‘freeze-all’’ IVF cycles with deferred FET. 3
– 5.65 (2.96–10.84)a 1.32 (0.77–2.26) 0.89 (0.52–1.53) 0.96 (0.61–1.50) – 5.32 (3.02–9.39)a 1.30 (0.82–2.05) 0.77 (0.48–1.25) 1.06 (0.72–1.57) – 3.06 (2.07–4.52)a 1.15 (0.90–1.47) 1.21 (0.98–1.51) 1.12 (0.93–1.36)
Quinn. Pregnancy spacing and FET outcomes. Fertil Steril 2019.
Note: All values presented as OR (95% CI). Adjusted odds ratios derived from logistic regression with adjustment for age, BMI, and history of prior preterm delivery. a Statistically signiﬁcant OR and adjusted OR at P< .05.
– 2.99 (2.19–4.09)a 1.12 (0.92–1.37) 1.11 (0.93–1.33) 1.13 (0.97–1.33) – 7.10 (3.31–15.23)a 1.52 (0.79–2.95) 0.65 (0.30–1.39) 0.80 (0.44–1.45) – 5.89 (2.89–12.00)a 1.33 (0.74–2.41) 0.62 (0.31–1.22) 1.03 (0.61–1.71) – 5.02 (2.81–8.99)a 1.31 (0.83–2.07) 1.06 (0.69–1.64) 1.12 (0.77–1.62) – 5.29 (3.24–8.64)a 1.33 (0.90–1.95) 1.10 (0.76–1.60) 1.29 (0.94–1.78) – 2.05 (1.48–2.84)a 1.26 (1.06–1.49)a 1.23 (1.06–1.43)a 1.07 (0.94–1.22) 12 to <18 mo – <6 mo 2.46 (1.93–3.14)a 6 to <12 mo 1.19 (1.04–1.36)a 18 to <24 mo 1.16 (1.02–1.31)a R24 mo 1.11 (0.99–1.23)
aOR Unadjusted OR aOR Unadjusted OR aOR Unadjusted OR aOR Unadjusted OR aOR Unadjusted OR IPI
Preterm delivery <32 wk (n [ 283) Preterm delivery <37 wk (n [ 2,506)
Pregnancy outcomes by IPI: unadjusted and adjusted models.
Preterm delivery <28 wk (n [ 102)
Low birth weight <2500 g (n [ 1,100)
Very low birth weight <1500 g (n [ 181)
ORIGINAL ARTICLE: ASSISTED REPRODUCTION As a result, we sought to explore the relationship between IPI and adverse pregnancy outcomes in singleton live births from FET cycles. Similar to our prior ﬁndings in fresh IVF cycles, a short IPI of <6 or 6 to <12 months was associated with preterm delivery <37 weeks when compared with the reference of IPI of 12 to <18 months in FET cycles. The magnitude of the increased odds for these adverse perinatal outcomes with a short IPI was similar to that seen with short IPI in fresh IVF cycles (7). An IPI of <6 months was also associated with more extreme prematurity and low birth weight in FET cycles. In an analysis stratiﬁed by ethnicity, an IPI of <6 months was associated with increased odds for preterm delivery <37 weeks among those reporting white or non-white ethnicity, whereas an IPI 6 to <12 months was only associated with preterm delivery among those reporting white ethnicity. Although this may represent a modifying effect of ethnicity in the relationship between IPI and preterm delivery, it is also possible that the relationship between IPI 6 to <12 months and preterm delivery was underpowered owing to a smaller sample size of non-white patients with an IPI 6 to <12 months. In contrast to our prior ﬁndings in fresh IVF cycles, we found that an IPI of 18 to <24 months was also associated with increased odds for preterm delivery compared with the reference interval. This is consistent with the J-shaped association between IPI and adverse perinatal outcomes described in the naturally conceiving population, wherein very short and longer intervals are associated with adverse pregnancy outcomes, with a nadir around 18 months (1). However, unlike data from naturally conceiving populations, a longer interval of R 24 months was not associated with adverse outcomes. Although nutritional depletion from a recent pregnancy and delivery is thought to explain the association between short IPI and adverse perinatal outcomes (18), residual confounding is likely to explain any association between longer IPI and poorer outcomes. For example, patients with longer IPI may have more signiﬁcant infertility or a history of a pregnancy complication, such as intrauterine adhesions from a postpartum dilation and curettage requiring interval surgery for correction, thereby delaying subsequent conception and simultaneously rendering the patient at higher risk for adverse pregnancy outcomes. This study is limited by the use of a national database with incomplete collection of variables of interest. Furthermore, many of the variables included in the SART database are self-reported. Notably, date of pregnancy outcome (i.e., live birth) and birth weight at delivery are outcomes often obtained by patient report rather than medical record review. Additionally, over the study period, the predominant method of embryo cryopreservation changed from slow freeze to vitriﬁcation. It is possible that method of cryopreservation may serve as an effect modiﬁer in the relationship between IPI and pregnancy outcome. Unfortunately, the SART database does not capture method of cryopreservation. As such, this could not be explored. Additionally, it is important to note that these data are limited to ART treatment cycles in which the index pregnancy resulted in live birth; as such, recommendations for treatment intervals do not clearly apply to pregnancies ending in a non–live birth outcome. VOL. - NO. - / - 2019
Fertility and Sterility® These data are clinically important because patients undergoing FET may have had embryos frozen before their index delivery and, thus, have an opportunity to defer attempts at subsequent conception without immediate concern for ovarian aging. For patients without supernumerary embryos, a strategy of ovarian stimulation with embryo cryopreservation to allow for a longer IPI may improve perinatal outcomes. In summary, these data suggest a delay of 12–18 months after live birth before initiation of an FET cycle, for optimization of perinatal outcomes. Acknowledgments: The authors thank SART and its members for providing clinical information to the SART CORS database for use by patients and researchers. Without the efforts of SART members, this research would not have been possible.
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