Objective
We sought to assess the influence of birth spacing on neonatal morbidity, stratified by gestational age at birth.
Study Design
This was a population-based retrospective cohort study using Ohio birth records, 2006 through 2011. We compared various interpregnancy interval (IPI) lengths in multiparous mothers with the rate and risk of adverse newborn outcomes. The frequency of neonatal intensive care unit admission or neonatal transport to a tertiary care facility was calculated for births occurring after IPI lengths: <6, 6 to <12, 12 to <24, 24 to <60, and ≥60 months, and stratified by week of gestational age. Neonatal morbidity risk was calculated for each IPI compared to 12 to <24 months (referent), and adjusted for the concomitant influences gestational age at birth, maternal race, age, and prior preterm birth.
Results
We analyzed 395,146 birth outcomes of singleton nonanomalous neonates born to multiparous mothers. The frequency and adjusted odds of neonatal morbidity were lowest following IPI of 12 to <24 months (4.1%) compared to short IPIs of <6 months (5.7%; adjusted odds ratio [adjOR], 1.40; 95% confidence interval [CI], 1.32–1.49) and 6 to <12 months (4.7%; adjOR, 1.19; 95% CI, 1.13–1.25), and long IPIs 24 to <60 months (4.6%; adjOR, 1.12; 95% CI, 1.08–1.17) and ≥60 months (5.8%; adjOR, 1.34; 95% CI, 1.28–1.40), despite adjustment for important confounding factors including gestational age at birth. The lowest frequency of adverse neonatal outcomes occurred at 40-41 weeks for all IPI groups. The frequency of other individual immediate newborn morbidities were also increased following short and long IPIs compared to birth following a 12- to <24-month IPI.
Conclusion
IPI length is a significant contributor to neonatal morbidity, independent of gestational age at birth. Counseling women to plan an optimal amount of time between pregnancies is important for newborn health.
Many years of research have shown that both short and long interpregnancy intervals (IPIs) are associated with adverse outcomes, such as birth defects, preterm birth, low birthweight, and maternal morbidity. These complications are likely a result of a multifactorial effect. Several postulated mechanisms contributing to these adverse outcomes include folate depletion, continued presence of inflammatory response markers, maternal anemia, and hormonal dysregulation, which occur in late pregnancy and postpartum periods. A recent study from India and Pakistan demonstrated that both young maternal age and short IPIs increased the risk for infant mortality. An IPI of 18 to <24 months has been postulated to have the lowest maternal and feto-infant risks. Congenital anomalies are typically seen with shorter and longer IPIs. Neural tube defects are commonly reported in shorter IPIs, likely due to the folate depletion theory. Cleft palate has been reported in longer (>60 month) IPIs. Shorter IPIs increase the odds for neonatal mortality, even after adjusting for factors such as small for gestational age, low birthweight, and other variables. Management recommendations for short IPI have included ultrasound assessments for fetal anomalies and growth, biophysical profile assessment of fetal well-being, and cervical length assessment to determine risk for preterm labor. Appropriate birth spacing remains a public health concern and should be addressed by health care providers as a means to reduce infant mortality.
Our study examines a population-based cohort of births in Ohio with the immediate outcomes data of transfer to neonatal intensive care unit (NICU) or tertiary care center as markers of aggregate neonatal morbidity, as an indication of illness, based on live birth records, stratified by IPI. Adjustment for maternal age, race, and gestational age at birth was performed to quantify the independent effect of IPI on newborn outcomes.
Materials and Methods
The protocol for this study was approved, and a deidentified data set was provided by the Ohio Department of Health. This study was exempt from review by the institutional review board at the University of Cincinnati, Cincinnati, OH.
We performed a population-based retrospective cohort study including all births that occurred in the state of Ohio during a 6-year period, 2006 through 2011, using Ohio live birth records which were recorded on the US Standard Certificate of Live Birth, 2003 version. Our analyses were limited to singleton births between 20-42 weeks of gestation to multiparous mothers with a recorded IPI, N = 395,146. We excluded births complicated by major congenital anomalies.
The exposure of interest, IPI, was defined as time from the most recent prior birth to the subsequent conception of the index birth. The date of prior birth is recorded in the US birth certificate, which was used for data analyzed in this study. The variable “interval” is calculated as the amount of time in months from the prior birth to the current birth. We created the variable “interpregnancy interval” by converting the gestational age of the current (index) birth into months and subtracting it from the interbirth “interval” variable. We stratified IPI into time periods divided into 6-month intervals. We then analyzed the frequency of adverse outcomes in numerous strata of IPI lengths and identified the 12- to <18-month and 18- to <24-month groups to have similarly low risks and therefore combined them into 1 referent group. The following IPI lengths were ultimately categorized for the purposes of this study: 0 to <6, 6 to <12, 12 to <24, 24 to <60, and ≥60 months. The IPI category associated with the lowest rate of adverse outcome (12 to <24 months) was used as the referent group for comparisons.
The primary outcome for this study was neonatal morbidity. Because only immediate newborn outcomes occurring within the first 24-48 hours after birth are documented in the birth record, we defined neonatal morbidity as admission to a NICU or transfer of the neonate to a tertiary care facility as a marker of newborn illness. We chose NICU admission as an outcome because it is an indicator of newborn illness at any gestational age, whether preterm, term, or postterm birth. We added transport of the newborn to a tertiary care facility to the composite variable of neonatal morbidity to account for sick babies born at hospitals in Ohio without a NICU. The National Vital Statistics System in the United States defines the variable for NICU admission on the birth certificate as “admission into a facility or unit staffed and equipped to provide continuous mechanical ventilator support for a newborn” and the variable for neonatal transport as “transfer of the infant within 24 hours after delivery.” The variable “gest_comb,” combined estimate of gestational age, which takes into account a combination of last menstrual period, ultrasound, and clinical dating–as is commonly defined in clinical practice–was also used in this study. Fetal growth restriction (FGR) was defined as birthweight less than the 5th and 10th percentile for gestational age.
We conducted a population-based retrospective cohort study to measure the effect of IPI on adverse newborn outcomes. We first compared differences in baseline maternal demographic, behavioral, socioeconomic, prenatal, and delivery characteristics among births within the 5 IPI categories. The frequency of composite and individual neonatal morbidities were calculated and compared for births following various IPI lengths, and then further stratified by weeks of gestational age from 32-42 weeks. Analyses were not stratified at earlier weeks of gestation because nearly all neonates would be expected to be admitted to NICU at <32 weeks of gestational age. Crude risk was calculated comparing births following short and long IPI lengths compared to the referent IPI of 12 to <24 months. Multivariate logistic regression was then used to estimate the risk of IPI on composite morbidity after accounting for the coexisting influences of gestational age at birth, maternal race, age, and prior preterm birth. A full model of potential confounders was initially constructed choosing baseline factors with significant differences noted in univariate comparisons and those with biologic plausibility. Stepwise backward selection yielded a final parsimonious model including statistically influential and biologically plausible covariates. The adjusted odds ratios (adjOR) were then demonstrated in sequential models to show the relative influence of each final covariate on the primary outcome. Significant differences were defined as comparisons with probability value of < .05 and 95% confidence interval (CI) not inclusive of the null value of 1.0. Statistical analyses were performed using STATA Release 12 software (StataCorp, College Station, TX).
Results
The total number of nonanomalous live births in Ohio during the study period was 892,733. We excluded multiple gestations (n = 32,282), births <20 weeks (n = 565) and >44 weeks (n = 39), and births to women with missing age (n = 566) or erroneous appearing maternal age ≥55 years (n = 11). Analyses were then limited to 395,146 births to multiparous mothers with sufficient data to determine IPI, 46% of the remaining study cohort. There were minimal missing data, ≤2%, for pregnancy characteristics and outcomes of interest including gestation age at delivery, gestational hypertension, gestational diabetes, FGR, and mode of delivery. There were also minimal missing data on the primary outcomes of interest: only 1.0% missing data for NICU admission and 0.33% missing data on infant transfer. Body mass index and number of prenatal care visits had 10% missing data.
We analyzed pregnancy characteristics of multiparous mothers in Ohio during the study period. The frequency of IPI <6 months was 7.3%; 6 to <12 months, 13.5%; 12 to <24 months, 27.5%; 24 to <60 months, 34.8%; and ≥60 months, 16.3%. Women giving birth after a short IPI of <12 months were more frequently of black race, unmarried, lower socioeconomic status (SES) and educational status, and had limited amount of prenatal care with ≤5 prenatal visits ( Table 1 ). In addition, women with short IPIs were younger but had higher parity, more previous preterm births, were more likely to be cigarette smokers and obese, compared to women within the referent IPI (12 to <24 month) group. Women with IPIs >2 years were older, also more commonly of black race, low SES, and cigarette smokers compared to those giving birth after a 12- to <24-month IPI. Women with long IPIs were less likely to have a low educational level or limited prenatal care, more likely to be married, but had higher frequency of medical risks including obesity, chronic hypertension, pregestational diabetes, and preeclampsia.
| Characteristic | 0 to <6 mo n = 29,034 (7.3%) | 6 to <12 mo n = 53,559 (13.5%) | 12 to <24 mo n = 108,626 (27.5%) | 24 to <60 mo n = 137,719 (34.8%) | ≥60 mo n = 64,491 (16.3%) |
|---|---|---|---|---|---|
| Demographic factors | |||||
| Age, y | 25.3 (5.2) | 27.0 (5.4) | 28.1 (5.3) | 28.9 (5.2) | 31.7 (4.9) |
| Race | |||||
| Caucasian | 21,445 (73.9) | 42,741 (79.8) | 90,250 (83.1) | 109,932 (79.8) | 47,806 (74.1) |
| Black | 6372 (21.9) | 8699 (16.2) | 13,874 (12.8) | 20,858 (15.1) | 12,975 (20.1) |
| Social behaviors and socioeconomic factors | |||||
| Married | 14,168 (48.8) | 34,452 (64.33) | 77,416 (71.3) | 91,075 (66.1) | 35,438 (54.9) |
| ≤High school education | 8319 (28.8) | 11,455 (21.5) | 17,196 (15.9) | 18,632 (13.6) | 7936 (12.3) |
| Insurance | |||||
| Medicaid | 15,868 (54.6) | 21,250 (39.7) | 35,007 (32.2) | 48,379 (35.1) | 25,241 (39.1) |
| Private insurance | 8734 (30.1) | 23,791 (44.4) | 58,145 (53.5) | 48,379 (35.1) | 25,241 (39.1) |
| Tobacco use | 9112 (31.4) | 12,610 (23.5) | 22,176 (20.4) | 34,581 (25.1) | 20,904 (32.4) |
| Prenatal care | |||||
| Limited (≤5 visits) | 4548 (15.7) | 6144 (11.5) | 9092 (8.4) | 9288 (6.7) | 4156 (6.4) |
| Pregnancy characteristics | |||||
| Parity | 2 (1–3) | 1 (1–2) | 1 (1–2) | 1 (1–2) | 1 (1–2) |
| Prior preterm birth | 2075 (7.4) | 3079 (5.7) | 5491 (5.0) | 7320 (5.3) | 3587 (5.6) |
| Prepregnancy BMI | 27.0 (6.7) | 26.4 (6.5) | 25.8 (6.2) | 27.3 (6.9) | 26.4 (6.4) |
| Obese (BMI ≥30) | 8040 (27.7) | 12,215 (22.8) | 22,946 (21.1) | 32,661 (23.7) | 18,393 (28.5) |
| Chronic hypertension | 438 (1.53) | 741 (1.40) | 1491 (1.40) | 2403 (1.76) | 2050 (3.22) |
| Pregestational diabetes | 202 (0.71) | 336 (0.63) | 632 (0.59) | 1041 (0.76) | 903 (1.42) |
| Preeclampsia | 730 (2.55) | 1382 (2.61) | 2827 (2.63) | 4463 (3.27) | 2886 (4.53) |
The rate of adverse maternal outcomes of gestational hypertension, gestational diabetes, and cesarean delivery was directly proportional to IPI, with the longest IPIs having the highest rate of these complications, P values < .001 ( Table 2 ). FGR <5th and <10th percentile occurred with higher frequency in shorter and longer IPIs compared to the referent of 12 to <24 months, in a U-shaped distribution, P < .001 ( Table 2 ).
| Characteristic | 0 to <6 mo n = 29,034 (7.3%) | 6 to <12 mo n = 53,559 (13.5%) | 12 to <24 mo n = 108,626 (27.5%) | 24 to <60 mo n = 137,719 (34.8%) | ≥60 mo n = 64,491 (16.3%) | P value a |
|---|---|---|---|---|---|---|
| Maternal outcomes | ||||||
| Gestational hypertension | 730 (2.5) | 1382 (2.6) | 2827 (2.6) | 4463 (3.2) | 2886 (4.5) | < .001 |
| Gestational diabetes | 1312 (4.5) | 2317 (4.3) | 4777 (4.4) | 7700 (5.6) | 5390 (8.4) | < .001 |
| Route of delivery | ||||||
| Vaginal | 21,611 (74.5) | 39,325 (73.5) | 78,781 (72.6) | 97,107 (70.6) | 44,010 (68.3) | < .001 |
| Cesarean | 7392 (25.5) | 14,204 (26.5) | 29,745 (27.4) | 40,490 (29.4) | 20,431 (31.7) | |
| Neonatal characteristics | ||||||
| Birthweight, g | 3238 (573) | 3354 (541) | 3383 (529) | 3277 (587) | 3357 (536) | < .001 |
| Neonate male sex | 14,890 (51.3) | 27,433 (51.2) | 55,603 (51.2) | 70,713 (51.3) | 33,007 (51.2) | .952 |
| Growth restriction, birthweight <10th percentile | 2665 (9.2) | 4031 (7.5) | 7204 (6.6) | 10,094 (7.3) | 6278 (9.7) | < .001 |
| Growth restriction, birthweight <5th percentile | 1099 (3.8) | 1626 (3.0) | 2938 (2.7) | 4240 (3.1) | 2817 (4.4) | < .001 |
| Large for gestational age, birthweight >10th percentile | 2478 (8.9) | 6009 (11.5) | 13,344 (12.6) | 16,212 (12.1) | 6836 (10.9) | < .001 |
| Macrosomia, birthweight >4000 g | 2016 (6.9) | 4974 (9.3) | 10,955 (10.1) | 13,062 (9.5) | 5239 (8.1) | <.001 |
a χ 2 Statistic for comparison among 5 groups for each characteristic or P value associated with analysis of variance comparison for birthweight.
The lowest rate of neonatal morbidity (NICU admit or neonatal transfer), 4.6%, occurred in the 12- to <24-month IPI group. The rate was increased with both shorter and longer IPIs. The frequency of each of the individual neonatal morbidity measures including assisted ventilation at delivery, mechanical ventilation >6 hours after birth, 5-minute Apgar score of <7, and use of surfactant was also lowest in the 12- to <24-month IPI group, but increased with shorter or longer IPIs, P values < .001 ( Table 3 ).
| Variable | 0 to <6 mo n = 29,034 (7.3%) | 6 to <12 mo n = 53,559 (13.5%) | 12 to <24 mo n = 108,626 (27.5%) | 24 to <60 mo n = 137,719 (34.8%) | ≥60 mo n = 64,491 (16.3%) | P value a |
|---|---|---|---|---|---|---|
| Neonatal morbidity b n = 21,317 | 1960 (6.83) | 2865 (5.42) | 4907 (4.57) c | 7163 (5.27) | 4422 (6.95) | < .001 |
| NICU admission n = 18,758 | 1745 (6.01) | 2499 (4.67) | 4277 (3.94) c | 6295 (4.57) | 3942 (6.11) | < .001 |
| Neonatal transport n = 8113 | 760 (2.62) | 1125 (2.1) | 1957 (1.8) c | 2707 (1.97) | 1536 (2.38) | < .001 |
| Assisted ventilation immediately at delivery | 1169 (4.0) | 1932 (3.61) | 3879 (3.57) c | 5087 (3.7) | 2718 (4.2) | < .001 |
| Mechanical ventilation >6 h n = 2174 | 215 (0.74) | 304 (0.57) | 521 (0.48) c | 692 (0.50) | 442 (0.69) | < .001 |
| 5-min Apgar <7 n = 7167 | 623 (2.15) | 878 (1.64) | 1572 (1.45) c | 2465 (1.79) | 1629 (2.53) | < .001 |
| Surfactant n = 1003 | 109 (0.38) | 161 (0.30) | 225 (0.21) c | 319 (0.23) | 189 (0.29) | < .001 |
| Composite morbidity d n = 15,084 | 1355 (4.73) | 1998 (3.79) | 3514 (3.28) c | 5112 (3.76) | 3105 (4.88) | < .001 |
a χ 2 Statistic for comparison among 5 groups for each characteristic
b NICU admission or neonatal transfer to tertiary facility
c Lowest frequency of each neonatal morbidity category
d Apgar score <7 at 5 min, assisted ventilation >6 h, neonatal transport or neonatal seizures.
To assess the influence of time between pregnancies on newborn outcomes independent of the influence of higher preterm birth rates, we analyzed the data in 2 ways. First, we quantified the frequency and risk of neonatal morbidity individually at each week of gestational age from 32-42 weeks, comparing each IPI category to the referent group of 12 to <24 months. Then we performed logistic regression analyses to estimate the effect of short and long IPI lengths on neonatal morbidity for the entire study cohort (20-44 weeks) and adjusted for gestational age differences among the IPI groups.
Table 4 demonstrates neonatal morbidity stratified by week of gestational age. NICU admit or neonatal transfer occurred more frequently at each week of gestational age following the shortest (<6 months, 5.7%) and longest (≥60 months, 5.8%) IPIs, compared to IPI of 6 to <12 months (4.7%) and 24 to <60 months (4.6%), and was lowest following an IPI of 12 to <24 months (4.1%), P < .001. When comparing neonatal morbidity by IPI group stratified by week of gestational age, the week with lowest frequency was similar regardless of IPI group: 40 weeks following <6-month IPI, at 41 weeks for 6- to <12-month IPI, and at 40 weeks for the remaining IPI groups: 12 to <24 months, 24 to <60 months, and ≥60 months. The effect size of the relative risk increase associated with IPI length was similar at each week of gestation with the highest risks found in the shortest (<6 months) and longest (≥60 months) IPI groups. The magnitude of effect was highest at 40-42 weeks, with the highest relative risk increase of >2-fold found with long IPI ≥60 months and birth at 42 weeks of gestation (odds ratio [OR], 2.05; 95% CI, 1.36–3.08).
| Frequency of neonatal morbidity for each week of gestational age | 0 to <6 mo n = 29,034 (7.3%) | 6 to <12 mo n = 53,559 (13.5%) | 12 to <24 mo n = 108,626 (27.5%) Referent | 24 to <60 mo n = 137,719 (34.8%) | ≥60 mo n = 64,491 (16.3%) |
|---|---|---|---|---|---|
| 32 a n = 1768 | 106 (54.9) | 128 (52.5) | 182 (45.3) | 291 (52.3) | 191 (51.2) |
| OR (95% CI) | 1.47 (1.04–2.08) | 1.33 (0.97–1.83) | 1.0 | 1.33 (1.03–1.72) | 1.27 (0.96–1.68) |
| 33 a n = 2699 | 130 (49.1) | 174 (45.9) | 286 (45.3) | 412 (48.7) | 316 (54.7) |
| OR (95% CI) | 1.16 (0.87–1.55) | 1.02 (0.79–1.32) | 1.0 | 1.15 (0.93–1.41) | 1.45 (1.16–1.82) |
| 34 a n = 4862 | 197 (46.7) | 263 (38.7) | 467 (39.3) | 660 (41.4) | 424 (43.3) |
| OR (95% CI) | 1.35 (1.08–1.69) | 0.99 (0.80–1.18) | 1.0 | 1.09 (0.94–1.27) | 1.18 (1.0–1.41) |
| 35 a n = 7998 | 195 (25.1) | 248 (22.6) | 457 (23.9) | 639 (24.1) | 400 (25.7) |
| OR (95% CI) | 1.07 (0.88–1.30) | 0.93 (0.78–1.11) | 1.0 | 1.01 (0.88–1.16) | 1.10 (0.95–1.29) |
| 36 a n = 16,054 | 222 (14.9) | 290 (12.9) | 514 (12.9) | 689 (12.9) | 410 (13.7) |
| OR (95% CI) | 1.18 (0.99–1.40) | 1.0 (0.85–1.16) | 1.0 | 1.0 (0.88–1.13) | 1.07 (0.93–1.23) |
| 37 a n = 35,680 | 155 (5.8) | 304 (6.7) | 498 (5.4) | 788 (6.2) | 402 (6.1) |
| OR (95% CI) | 1.10 (0.91–1.32) | 1.26 (1.09–1.46) | 1.0 | 1.18 (1.05–1.32) | 1.16 (1.01–1.32) |
| 38 a N = 80,507 | 166 (3.3) | 303 (3.1) | 619 (2.7) | 901 (3.1) | 462 (3.3) |
| OR (95% CI) | 1.20 (1.01–1.43) | 1.12 (0.98–1.29) | 1.0 | 1.12 (1.01–1.25) | 1.22 (1.08–1.38) |
| 39 a n = 127,172 | 193 (2.20) | 363 (2.12) | 692 (1.92) | 979 (2.15) | 536 (2.74) |
| OR (95% CI) | 1.14 (0.98–1.35) | 1.10 (0.97–1.26) | 1.0 | 1.12 (1.02–1.24) | 1.44 (1.29–1.62) |
| 40 a n = 64,082 | 102 (2.19) b | 208 (2.24) | 326 (1.76) b | 435 (1.99) b | 260 (2.68) b |
| OR (95% CI) | 1.25 (1.0–1.57) | 1.28 (1.08–1.53) | 1.0 | 1.13 (0.98–1.31) | 1.54 (1.31–1.81) |
| 41 a n = 23,258 | 49 (2.55) | 71 (1.95) b | 125 (1.90) | 194 (2.50) | 101 (3.02) |
| OR (95% CI) | 1.36 (0.97–1.89) | 1.03 (0.77–1.38) | 1.0 | 1.33 (1.06–1.66) | 1.61 (1.24–2.1) |
| 42 a n = 8751 | 26 (3.3) | 29 (2.00) | 44 (1.85) | 87 (3.12) | 50 (3.72) |
| OR (95% CI) | 1.79 (1.09–2.92) | 1.08 (0.67–1.73) | 1.0 | 1.71 (1.18–2.46) | 2.05 (1.36–3.08) |
| Overall 32-42 wk | 1541 (5.7) | 2381 (4.7) | 4210 (4.1) | 6075 (4.6) | 3552 (5.8) |
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