Interpregnancy interval: Optimizing time between pregnancies

INTRODUCTION — Pregnancy spacing (ie, the time interval between one pregnancy and the next) is clinically relevant because it may increase the risk for some adverse pregnancy outcomes. Short intervals between pregnancies are more commonly associated with adverse effects than long intervals. Counseling patients about optimal intervals between pregnancies may be helpful to reduce future complications.

The degree to which pregnancy spacing alters adverse pregnancy outcomes is unclear, but important, since individuals have some control over such spacing and thus could potentially reduce adverse outcomes. A short interpregnancy interval could be avoided by providing postpartum/postabortion patients with contraception and information about the potential clinical complications of a short time between pregnancies. Avoiding a long interpregnancy interval is more problematic since becoming pregnant at the desired time may be precluded by factors such as availability of a partner, subfertility, economic or occupational issues, or illness [1].

This topic will review terminology, data, and controversies regarding the effects of the interpregnancy interval on pregnancy outcome and provide recommendations on pregnancy spacing.

TERMINOLOGY — In 2005, the World Health Organization (WHO) brought together a group of 37 international experts to review available evidence on the relationship between different birth spacing intervals and maternal, infant, and child health outcomes. A report by this group recommended that clinicians use the following nomenclature to describe birth-to pregnancy intervals, but these terms have not been adopted universally [2]:

●Interpregnancy interval – The time spent not pregnant prior to the index pregnancy (also known as the birth-to-pregnancy interval). This interval can begin with a nonlive birth (miscarriage, stillbirth).

●Birth-to-birth interval – The time between the index live birth and the preceding live birth. This measure does not consider nonlive births (miscarriages, stillbirths) that occurred between live births; therefore, it can be the same for two individuals, even though one may have conceived once during the interval while the other conceived multiple times. In addition, it does not consider the duration of the index pregnancy; if the index pregnancy ends in a preterm birth (PTB), the birth-to birth interval can be short whereas the interpregnancy interval may not be.

●Inter-outcome interval – The time between the outcome of the index pregnancy and the outcome of the previous pregnancy. The starting point and/or the end point with this measure can be a nonlive birth (miscarriage, stillbirth), and the end point accounts for a PTB in the index pregnancy.

●Birth-to-conception interval – The time between conception of the index pregnancy and the previous live birth. This measure does not consider nonlive births (miscarriages, stillbirths) that occurred before conception.

For simplicity and to analyze data from studies using different definitions, the WHO working group used the single term "birth-to-pregnancy interval" in their report and converted older data such that a birth-to-pregnancy interval would be equivalent to an interpregnancy interval, a birth-to-birth interval minus nine months, an inter-outcome interval minus nine months, or a birth-to-conception interval.

DEFINITIONS OF SHORT AND LONG BIRTH-TO-PREGNANCY INTERVALS — The definitions for short and long interpregnancy intervals have not been standardized and, thus, vary among studies [2-7]. The following World Health Organization (WHO) definitions are generally accepted [2]:

●Short interval – A short birth-to-pregnancy interval can be considered ≤6 to 18 months because ≤6 months is associated with elevated maternal risk and ≤18 months is associated with elevated perinatal risk, possibly with some residual elevated risk associated with an 18 to 27 month interval.

●Long interval – A long birth-to-pregnancy interval can be considered >60, but intervals >35 months are also associated with some elevated risk.

EPIDEMIOLOGY

●United States – In a report by the United States Centers for Disease Control and Prevention that included birth certificate data from 36 states, approximately 30 percent of females in the United States had an interpregnancy interval <18 months (4.7 percent <6 months, 10.7 percent 6 to 11 months, and 13.8 percent 12 to 18 months), 50 percent had an interval of 18 to 59 months, and 20 percent had an interval ≥60 months [8].

Young maternal age was a risk factor for a short interpregnancy interval: more than two-thirds of teenagers ages 15 to 19 years and 35 percent of those ages 20 to 29 years had a short interval (<18 months).

Older maternal age was a risk factor for a long interpregnancy interval: 30 percent of females ages 30 to 44 years had a long interval (≥60 months). Other risk factors included having less than a bachelor's degree (23 versus 13 percent with a bachelor's degree or higher) and being unmarried (24 versus 19 percent for married females). Females who self-identified as Hispanic race/ethnicity and not born in the United States had the highest percentage of long interpregnancy intervals of all racial and ethnic groups (30 percent), followed by females self-identifying as non-Hispanic Black individuals (24 percent), Hispanic individuals born in the United States (22 percent), and non-Hispanic White individuals (16 percent).

●Other regions – In a systematic review examining factors associated with a short interpregnancy interval in low- and middle-income countries in Africa, Asia, and Latin America, shorter duration of breastfeeding and female sex of the previous child were the only factors consistently associated with a short birth interval [9]. Younger maternal age, lower income, and lower educational attainment were less consistently associated with a short interval.

In a study from Ethiopia, factors associated with a short birth interval were economic status in the poorest wealth quintile (adjusted odds ratio [aOR] 1.82, 95% CI 1.39-2.39) and death of the preceding child (aOR 1.97, 95% CI 1.59-2.45) [10].

ASSOCIATIONS BETWEEN BIRTH SPACING AND PREGNANCY OUTCOME — Both short and long birth-to-pregnancy intervals have been associated with adverse pregnancy outcomes, as shown in the table (table 1). Meta-analyses and individual studies have helped characterize the effect of birth spacing on adverse perinatal outcomes, though both contain the limitations described below, particularly as individual studies differ in their ability to account for confounding factors such as comorbidities, income level, or lifestyle differences.

Most studies on birth spacing are observational and, thus, are limited to identifying associations rather than establishing causation. The principle that associations do not prove causation is important to discuss when counseling patients about birth spacing, where the observational data are frequently limited to relatively weak associations.

Limitations of available data — Many variables influence pregnancy outcomes. Identifying the association between birth spacing, specific risk factors, and pregnancy outcomes is complex, as the degree of confounding by some variables is difficult to measure. Some examples:

●After a stillbirth or neonatal death, individuals often wish to conceive again quickly. If the underlying cause of the stillbirth or neonatal death remains or recurs, a short interpregnancy interval may falsely appear to be associated with perinatal mortality.

●Breastfeeding both improves infant survival and lengthens the interval between pregnancies due to lactational amenorrhea and, thus, may reduce the incidence of short interpregnancy intervals and their associated risks. On the other hand, breastfeeding may also deplete the mother of essential nutrients (eg, folate), thereby worsening the subsequent pregnancy outcome.

Conversely, lack of breastfeeding results in faster resumption of ovulation and potentially a shorter interpregnancy interval, in turn increasing the risk of the adverse outcomes associated with closely spaced births.

●Maternal behaviors and choices may affect both the timing and outcome of pregnancy. In some cases, close birth spacing is the unintended result of incorrect or inconsistent use of contraception and in others, if intentional, may be due to later initiation of childbearing [11].

●Outcome of pregnancy following a long interpregnancy interval is likely confounded by the biological consequences of aging (eg, aging oocytes [increase in risk for aneuploidy] and increasing prevalence of hypertension and diabetes [which increase the risk for preeclampsia]).

Several investigators have argued that the apparent association between short birth spacing and obstetric complications simply reflects the prevalence of short interpregnancy intervals among individuals predisposed to adverse outcomes based on confounding factors (eg, young maternal age, lower socioeconomic status, lifestyle, and the outcome of the previous pregnancy) rather than a biologic phenomenon. Supporting this hypothesis, studies have shown increased adverse outcomes when pregnancy intervals are compared among different individuals ("between-mother analysis"), but when pregnancy intervals are compared using the same individual with two pregnancies ("within-mother analysis"), adverse outcomes are less frequent [12-14].

By contrast, a study using both between- and within-mother analyses, within a single large cohort, found that short interpregnancy interval (<6 months) was associated with an increased risk for preterm birth (PTB) in both groups, suggesting that biologic phenomenon, and not simply maternal factors, may contribute to the association [15]. Another study found a short interpregnancy interval (<6 months) was associated with a reduced risk for severe maternal morbidity (not including transfusion) in both within- and between-mother comparisons (aRR 0.58, 95% CI 0.46-0.72 and aRR 0.81, 95% CI 0.74-0.88, respectively) [16]. On the other hand, a long interpregnancy interval (>60 months) was associated with an increased risk for severe maternal morbidity (not including transfusion) in both within- and between-mother comparisons (aRR 2.23, 95% CI 1.81- 2.74 and aRR 1.95, 95% CI 1.82-2.08, respectively). Lastly, a study consisting of over 700,000 consecutive first- and second-live born sibling pairs of multiparous mothers (99 percent of Han Chinese ethnicity and less than 35 years of age) found that those with short (<6 months) or longer (≥36 months) interpregnancy intervals had greater odds of adverse birth outcomes such as PTB (odds ratio [OR] 1.96, CI 1.87-2.06) and low birth weight (OR 1.88, CI 1.79-1.98) compared with an interval of 18 to 23 months [17]. The associations were attenuated in the matched sibling analysis (PTB: OR 1.4, CI 1.3-1.51, low birth weight: OR 1.3, CI 1.21-1.40), supporting the role of biologic factors but suggesting that unmeasured confounders also contribute to the findings and require further study. Interestingly, a short interpregnancy interval <6 months was not associated with increased risk for extreme PTB (less than 28 weeks). Strengths of this study include the large size, homogeneous population, and matched-sibling analysis, which incorporated information about first-born siblings (eg, low birth weight) into the model to control for some unmeasured confounders. Additional studies are needed before extrapolating the results to mothers over 35 years of age.

Such inconsistencies, as well as methodologic limitations of studies, prompted an expert work group to make suggestions for the ideal design, analysis, results reporting, and interpretation of studies on birth spacing and perinatal outcomes to mitigate potential sources of bias [18]. Their report serves as an excellent guideline for investigators conducting birth spacing research.

WHY BIRTH SPACING MAY AFFECT PREGNANCY OUTCOME — Several hypotheses have been proposed to explain the relationship between interpregnancy intervals and adverse pregnancy outcomes, but none have been proven.

●Maternal depletion hypothesis – According to this hypothesis, maternal nutrients (particularly iron and folate) may not be replenished sufficiently between closely spaced pregnancies, particularly among breastfeeding mothers, and this may lead to adverse pregnancy outcomes such as fetal growth restriction (FGR) [19-21].

While maternal depletion may be more prevalent and severe in low-income countries due to undernutrition, the maternal depletion hypothesis may also apply to mothers in high-income countries [4,22,23]. Multiple studies from high-income countries have reported low serum levels of folate during the postpartum period [24-27]. One study observed a greater risk of FGR (higher risk for a small for gestational age infant) after a short interpregnancy interval among nonusers of folic acid supplements and noted that the risk diminished among supplement users and with increasing interpregnancy interval length, presumably because there was more time to replenish folate through diet [28]. Iron deficiency is also common in reproductive-age patients in whom iron intake is not increased to account for increased requirements during pregnancy and postpartum. A large study including data from 18 Latin American countries reported a 30 percent increase in maternal anemia when the interpregnancy interval was less than six months [29].

●Infection, inflammation hypothesis – Infectious and inflammatory disorders of the genital tract that occur in one pregnancy and do not completely resolve before the subsequent pregnancy have been hypothesized to contribute to adverse pregnancy outcomes in closely spaced pregnancies [30-32]. In particular, ongoing inflammation of the genital tract may predispose to preterm prelabor rupture of membranes and subsequent preterm birth (PTB) [32].

Alternatively, persistent abnormal microbial states in the genital tract may link short interpregnancy interval to adverse pregnancy outcomes. Alterations in the vaginal microbiome may occur abruptly after delivery and persist for at least a year in some cases [33].

●Physiologic regression hypothesis – This hypothesis has been proposed to explain the association between long interpregnancy intervals and adverse pregnancy outcome. It asserts that pregnancy causes important time-limited, favorable, physiologic adaptations of the reproductive system, such as an increase in blood flow to the uterus, that eventually end and, thus, are no longer available to women with a prolonged interpregnancy interval [4].

COUNSELING — Discussing the risks of short and long interpregnancy intervals (table 1) with patients prior to a subsequent pregnancy may reduce the risk of birth spacing-related adverse pregnancy outcomes. The following recommendations are based on our interpretation of findings from observational studies, expert opinion, and our clinical experience.

What is the optimal interval between pregnancies?

After a live term birth — We concur with expert groups [2,34] that the optimal interpregnancy interval appears to be 18 to 24 months for most individuals, with modifications for advanced maternal age and pregnancy loss.

●Short interpregnancy intervals appear to increase the risk for preterm birth (PTB) and low birth weight. In a systematic review, interpregnancy intervals <6 months after a live birth were associated with both an increased risk of PTB from any cause (adjusted odds ratio [aOR] ≥1.20 in 10 of 14 studies) and an increased risk of spontaneous PTB (aOR ≥1.20 in one of two studies) (without adjustment for previous preterm or term birth) [35]. In another systematic review, interpregnancy intervals <6 months were associated with a 60 percent increase in risk of low birth weight (LBW; birth weight <2500 grams) when compared with intervals of 18 to 23 months (pooled aOR 1.61, 95% CI 1.39-1.86) [36].

●Long interpregnancy intervals may increase risks for preeclampsia and labor dystocia. In a cross-sectional study including nearly 650,000 births, an interval >24 months increased the risk of labor dystocia by 50 percent after adjustment for multiple factors including gestational weight gain, smoking, age, race, parity, and newborn weight [37]. (see 'After a pregnancy complicated by preeclampsia' below)

The American College of Obstetricians and Gynecologists (ACOG) recommends advising patients to avoid interpregnancy intervals <6 months, where data suggesting adverse outcomes are most compelling, and counseling about the modest risks and benefits of intervals <18 months [34]. ACOG also acknowledges the methodologic flaws of many studies, making it unclear as to whether the associations related to interpregnancy interval are causal or due to confounders. (See 'Limitations of available data' above.)

Both the World Health Organization (WHO) and the United States Agency for International Development (USAID) recommend an interpregnancy interval >2 and <5 years after a live term birth [2]. The WHO acknowledges that an interpregnancy interval of 18 to 24 months is associated with the lowest relative risk of poor perinatal outcome after a previous live birth [3,7,23,36,38,39] but states that guidelines of "2 years" versus "18 months" are more easily understood by the general public, even though a recommendation of >18 months better reflects the data.

Older individuals — For older individuals planning pregnancy, an interpregnancy interval of 12 rather 18 months may be a reasonable approach, as it acknowledges the increasing risk of subfertility and infertility with advancing age (after the mid-30s) but still avoids the increased risks of pregnancy complications, including maternal mortality or severe morbidity, associated with a very short interpregnancy interval, typically defined as <6 months [40-42].

Available data on the interaction between birth spacing and older age of the birthing parent are limited. However, in a retrospective study, the association of PTB and LBW among females with a short interpregnancy interval was actually attenuated with increasing maternal age [43].

After a preterm birth — Preterm birth (PTB) may be idiopathic or related to pregnancy complications such as preeclampsia, preterm prelabor rupture of membranes, or abruption. For individuals who have had a PTB, delaying the next conception for 18 to 24 months may be particularly important since both a previous PTB and an interpregnancy interval <6 months are established risk factors for PTB [35,44,45].

●In a multinational cohort study, the pooled absolute risks of recurrent PTB in patients with interpregnancy intervals <6 months versus 18 to 23 months were 22.4 and 17 percent, respectively [45] versus 5.3 and 3.3 percent if the previous birth was at term.

●In systematic reviews, interpregnancy intervals <6 months have been associated with both an increased risk of PTB from any cause, an increased risk of spontaneous PTB, and an increased risk of low birth weight [35,36]. The data are described in more detail above. (See 'After a live term birth' above.)

After a pregnancy conceived by in vitro fertilization — Similar to recommendations for individuals of older age, when considering the timing of a subsequent in vitro fertilization (IVF) pregnancy, it may be prudent to weigh the potential risks of not becoming pregnant if IVF is delayed against the limited but reassuring outcome data for individuals who wait 12 and 18 months following a live birth before undergoing another IVF conception.

In a study among patients delivering singletons following assisted reproductive technology (ART), intervals from a live birth to the next fresh IVF treatment cycle of less than 6 months and 6 to 12 months were associated with increased risks of PTB and LBW in singleton live births compared with intervals of 12 to <18 months, whereas intervals of ≥18 months showed no additional risks [46]. Findings were similar when intervals from a live birth to a frozen embryo treatment cycle were assessed. A different study by the same group identified that, following an ART-conceived live birth, delivery-to-ART-cycle intervals (DCIs) of <6 months and ≥24 months were associated with modest (5.1 to 6.8 percent) but significant decreases in the likelihood of clinical pregnancy and live births when compared with DCIs of 12 to <18 months [47].

After a pregnancy complicated by preeclampsia — Longer interpregnancy intervals are associated with an increased risk of developing preeclampsia [29,48-50] and shorter interpregnancy intervals are associated with a reduced risk [13].

Among individuals with a history of preeclampsia and a subsequent pregnancy with the same partner, interpregnancy intervals beyond one and two years have conferred an approximate 10 percent increased risk of preeclampsia per year since the prior pregnancy (aOR 1.12, 95% CI 1.11-1.13) [51,52], though the contribution of potential increases in body weight could not be assessed. When birth spacing with the same partner is greater than 10 years, the risk for preeclampsia is almost that of a nullipara.

In a Canadian sibling comparison matched analysis that evaluated the association between interpregnancy interval and preeclampsia, an interpregnancy interval of 6 to 11 months was associated with a reduced risk of preeclampsia compared with 18 to 23 months (aOR 0.71; 95% CI, 0.54-0.94), while intervals ≥60 months were potentially associated with an increased risk (aOR 1.39; 95% CI, 0.97-2.00) [13].

Other interventions to reduce the risk for recurrent preeclampsia, such as low-dose aspiring prophylaxis, are reviewed separately. (See "Preeclampsia: Prevention".)

After a cesarean birth — Delaying conception for at least 18 months following a cesarean birth is important to allow for adequate healing of the hysterotomy among individuals planning a trial of labor after cesarean (TOLAC); shorter interpregnancy intervals [53], most prominently <6 months [54], have been associated with uterine rupture during TOLAC.

The absolute risk of a uterine rupture event with interpregnancy intervals <6 months was 2.8 percent in a study specifically evaluating this risk (aOR for rupture 2.66 [95% CI 1.21-5.82] compared with TOLAC at ≥6 months, and aOR 3.05 [95% CI 1.36-6.87] compared with TOLAC at 18 to 59 months); risks of blood transfusion and maternal morbidity were also increased [54]. When interpregnancy intervals <12 versus >12 months were compared, relative risks of uterine rupture, blood transfusion, and maternal morbidity were increased, but did not achieve statistical significance. Of note, the uterine rupture rate for the entire cohort was 0.96 percent (128 uterine ruptures among 13,331 patients with at least one prior cesarean birth who attempted TOLAC).

In a systematic review of seven studies, an interpregnancy interval <6 months was also associated with increased blood transfusions (aOR 3.55, 95% CI 1.56-8.10) and a composite measure of maternal morbidity including bladder, ureter, or bowel injury and uterine artery laceration (aOR 1.92; 95% CI 1.01-3.62) among patients attempting TOLAC [55].

As part of shared decision-making, we inform patients considering TOLAC after an interpregnancy interval <6 months that the risk of uterine rupture is increased compared with a longer interpregnancy interval, but definitive data of absolute risk based on patient-specific factors are not available. (See "Choosing the route of delivery after cesarean birth".)

In contrast to rupture risk, a systematic review found that TOLAC success following spontaneous labor is generally not affected by birth spacing, but study designs varied and data were limited and inconsistent [53].

After a miscarriage — Timing of conception following a miscarriage should be based on when the individual feels ready; there is no biologically supported minimum time to wait to reduce the risk of recurrence or adverse pregnancy outcome.

In a 2016 meta-analysis, pregnancy within six months of a miscarriage was not associated with an increased risk of subsequent PTB (relative risk [RR] 0.93, 95% CI 0.58-1.48) and was associated with a decreased risk when a large study with serious methodologic limitations was excluded (RR 0.79, 95% CI 0.75-0.83) [56]. A subsequent study found that conception shortly after a miscarriage (even without waiting for the first period after the miscarriage) was not associated with adverse maternal or neonatal outcomes [57]. On the other hand, conception <7 months after a miscarriage has been associated with increased risk for anxiety and depression in the next pregnancy [58].

After a stillbirth — Pregnancies after a stillbirth are at increased risk of a subsequent stillbirth, but the risk does not appear to be affected by the interpregnancy interval [59-61]. A thorough investigation, including fetal autopsy and genetic counseling, is recommended to determine the possible etiology of the stillbirth. A subsequent pregnancy is best considered after the etiology is determined, if possible, and after addressing modifiable risk factors for stillbirth, which may include maternal obesity, smoking, uncontrolled hypertension, or diabetes.

In a cohort study of birth records from more than 14,000 individuals who had a stillbirth in Finland, Norway, or Western Australia, conception <6 or 6 to 11 months after the stillbirth did not increase risk for stillbirth, PTB, or a small for gestational infant compared with conception at 24 to 59 months [60]. These data are reassuring for individuals who wish to conceive, or unexpectedly conceive, soon after a stillbirth.

PRENATAL AND POSTPARTUM CARE — The increased risks of adverse outcome associated with short and long interpregnancy intervals (table 1) are at most modest, based on low certainty evidence, and will generally be detected in the course of routine prenatal care. Therefore, routine prenatal care is reasonable for patients whose interpregnancy interval is short or long.

Postpartum, we recommend discussing the risks of short and long interpregnancy intervals with patients since birth spacing is partially within the patient's control. Provision of contraception after delivery is a key factor in preventing an unplanned pregnancy soon after a previous birth. (See "Contraception: Postpartum counseling and methods".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: General prenatal care".)

SUMMARY AND RECOMMENDATIONS

●Definitions of short and long interpregnancy intervals – The definitions for short and long interpregnancy intervals have not been standardized. A short birth-to-pregnancy interval can be considered ≤6 to 18 months because ≤6 months is associated with elevated maternal risk and ≤18 months is associated with elevated perinatal risk. A long birth-to-pregnancy interval is considered >60 months. (See 'Definitions of short and long birth-to-pregnancy intervals' above.)

●Importance of pregnancy spacing – Pregnancy spacing (ie, the time interval between one pregnancy and the next) is clinically relevant because it may increase the risk for some adverse pregnancy outcomes. Short intervals between pregnancies, particularly those ≤6 months, are more commonly associated with adverse effects than long intervals and should be avoided (table 1). (See 'Associations between birth spacing and pregnancy outcome' above.)

However, except for the shortest intervals (eg, ≤6 months), the increased risks of adverse outcomes associated with ≤18 months and long interpregnancy intervals are at most modest, based on low certainty evidence, and will generally be detected in the course of routine prenatal care. Therefore, routine prenatal care is reasonable for patients whose interpregnancy interval is short or long. (See 'Prenatal and postpartum care' above and 'Limitations of available data' above.)

●Clinical recommendations – Clinical recommendations for pregnancy spacing should consider the individual's health status, age, fertility, desired family size and child spacing, past obstetric complications, and psychosocial readiness to become pregnant again.

For most individuals who have had a live birth, we suggest an interpregnancy interval of 18 to 24 months (Grade 2C) as this appears to be associated with optimum maternal and neonatal outcome. A shorter interval may be appropriate for those of older age since a reduction in fertility after the mid-30s is a concern. A shorter interval may be appropriate for those of older age, or when a reduction in fertility is a concern. A shorter interval does not appear to have adverse effects in those who have had a miscarriage or stillbirth, and timing decisions should be based on when an individual feels ready. An interval longer than 24 months may increase the risk for dystocia, and an interval longer than 60 months may increase the risk for preeclampsia. (See 'What is the optimal interval between pregnancies?' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Phillip G Stubblefield, MD, who contributed to earlier versions of this topic review.