Relationship Between Extra-Long Interpregnancy Interval and Adverse Perinatal Outcomes in Chinese Women

doi:10.21203/rs.3.rs-827641/v1

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Research Article

Relationship Between Extra-Long Interpregnancy Interval and Adverse Perinatal Outcomes in Chinese Women

https://doi.org/10.21203/rs.3.rs-827641/v1

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Objective To evaluate the association between extra-long interpregnancy interval and adverse perinatal outcomes.

Methods A retrospective cohort study on women experiencing their second delivery between 2017 and 2018 in a maternal and child health hospital was conducted to evaluate the association between the extra-long interpregnancy interval (IPI) and adverse perinatal outcomes. IPI ≥180 months was defined as extra-long IPI. Logistic regression analysis was performed to explore the adverse perinatal outcomes in different IPI groups, and compared with the predicted risks at 24–59, 60–119, 120–179, and 180-month IPI, with the 12–23-month interval serving as a reference.

Results After adjusting for all possible confounding factors, there was an increased risk of premature rupture of membranes (aOR 1.83, 95% CI 1.13–2.97 and aOR 3.30, 95% CI 1.40–7.74) in the IPI of 60–119 and 120–179 months among women with age-appropriate maternity. However, the effects of extra-long IPI on adverse perinatal outcomes did not significantly differ among women with advanced maternal age.

Conclusions These results indicate that long IPI (60–179 month) is an independent risk factor for premature rupture of membranes. Extra-long IPI (≥180 months) was not associated with an increase in major morbidity, but extra-long IPI often coexists with advanced age, so we still need to pay attention to the maternal risk factors associated with extra-long IPI.

Obstetrics & Gynecology

extra-long interpregnancy interval

adverse perinatal outcomes

advanced maternal age

two-child policy

Since the early 1920s, researchers have been investigating the impacts of interpregnancy interval on perinatal outcomes^1,2. Interpregnancy interval (IPI) is defined as the interval between the first delivery and the conception of the subsequent pregnancy^3,4.

Previous studies investigating the association between IPI and adverse perinatal outcomes have focused on the effects of short IPI⁵ such as perinatal death following a live birth⁶, low birth weight⁷, preterm delivery⁸, anemia⁹, placenta previa, and placental abruption¹⁰. To reduce the risk of these events, the World Health Organization (WHO) recommends that individuals wait at least two years following a live birth and six months following a spontaneous or induced abortion before conceiving again¹¹. Studies have also reported that long IPI is associated with increased risks for adverse perinatal outcomes, including infant mortality (≥ 60 months)¹², higher diastolic BP of the offspring¹³, fewer C-sections, premature rupture of membranes (> 59 months)¹⁴, preterm birth, and large for gestational age (≥ 60 months)^15,16,.

To the best of our knowledge, this is the first study conducted at extra-long IPI (≥ 180 months)¹⁷. With the introduction of the two-child policy in China^18,19, many families are choosing to have a second child shortly after giving birth to the first child. The long-standing implementation of the one-child policy suggests that many women have a long IPI, and possibly extra-long IPI^20,21. Previous studies have indicated that women with long IPI account for a moderate proportion of the population. Lin’s study reported that the proportion of women with IPI ≥ 120 months was 9.7% (923/9552)²². Qin’s study reported that the proportion of women with long IPI ≥ 97 months was 21.8% (723/3310)²³.

Age is another key factor leading to adverse perinatal outcomes. It is generally believed that the most appropriate childbearing age for women is 25–29 years old²⁴. Early or late childbirth will increase the risk of adverse pregnancy outcomes²⁵. For example, advanced maternal age is associated with increased reproductive birth risks, including intrauterine growth restriction, pregnancy induced hypertension, placenta previa, and adverse birth outcomes^26,27.

With the introduction of the two-child policy in 2016, many women who were willing to have a second child were at advanced maternal age. The China National Health Commission predicted that 60% of the 90 million women would be 35 years old or older, which would result in an increased risk of complications in pregnancy and pose more challenges to health authorities in managing maternal and child health²⁸. Previous studies have indicated that the proportion of women older than 35 years of age who had a second child varied from 22.0% (729/3310)¹⁷ to 34.5% (3298/9952)²².

Under the influence of China’s two-child policy, women with extra-long IPI attracted our attention. As extra-long IPI often coexists with advanced age, pregnancy and maternal characteristics associated with extra-long IPI may vary by maternal age²⁹. Although the association between short and long IPI with increased risk of perinatal death was widely reported, these associations varied by age, geographic setting, income lifestyle, and prior obstetric outcome^2,12,14.

In the current study, we investigate the association between extra-long IPI and adverse perinatal outcomes due to the two-child policy in China. We also explore the extent to which the associations between extra-long IPI and adverse perinatal outcomes vary by maternal age to clarify the impact of extra-long IPI on perinatal outcomes and provide evidence to promote reproductive health.

Study Population

Data were selected from medical records of the Shunde Maternal and Child Health Hospital affiliated with Guangdong Medical University. A total of 2089 cases of advanced maternal age (≥ 35 years) who delivered newborns at ≥ 28 weeks of gestation between 1 January 2017 and 31 December 2018 were selected. A total of 4887 cases of age-appropriate maternity (20–34 years) were selected as controls, according to the discharge date. Demographic and clinical data, which included maternal postpartum readmissions up to 42 days after delivery and baby transfers and readmissions up to 28 days after birth²¹, were obtained from obstetrical and newborn medical records.

As the current study focused on differences in perinatal outcomes between women of age-appropriate maternity and advanced maternal age, we excluded 2448 primiparous and 491 multiparous women with > 2 parity, and 60 parturients with twin pregnancies. Because short IPI can increase the risk of adverse perinatal outcomes^{3, 5–10,30}, those with IPI < 12 months (n = 262) were excluded. A total of 3715 parturients were included in this study.

Exposure and Outcome Definitions

IPI is defined as the time in months between the first eligible birth and the conception of the subsequent pregnancy during the study period. To calculate this value, we subtracted the gestational week of delivery and modeled the categorical variable, which was classified as follows: 12–23 months, 24–59 months, 60–119 months, 120–179 months, and ≥ 180 months. IPI ≥ 180 months was defined as extra-long IPI^15,16,22.

Maternal age at delivery was divided into age-appropriate maternity (20–34 years), advanced maternal age (35–39 years), and ultra-advanced maternal age (≥ 40 years).

Outcomes were classified as (1) pregnancy complications, which included gestational diabetes mellitus, pregnancy-induced hypertension, pregnancy eclampsia, premature rupture of membranes, placental abruption, placenta previa, intrahepatic cholestasis of pregnancy, pelvic adhesion^{3–6, 31}, and coagulation dysfunction; and (2) delivery outcomes, which included premature delivery (between > 28 and < 37 weeks of gestation), oligohydramnios, polyhydramnios, turbid amniotic fluid, placenta retention³², 24-hour postpartum hemorrhage, postpartum hemorrhage (cesarean section, ≥ 1000 ml; vaginal delivery, ≥ 500 ml)³³, stillbirth, neonatal anemia⁹, birth weight, low birth weight (birth weight < 2,500 g)¹⁴, macrosomia (birth weight ≥ 4,000 g)¹⁵, neonatal malformation³⁴, fetal distress, neonatal asphyxia, respiratory distress syndrome, and 5-minute Apgar score¹⁶. Gestational age was calculated according to the last menstrual period and confirmed by ultrasonography during the first trimester. All perinatal outcomes were diagnosed at the Shunde Maternal and Child Health Hospital affiliated with Guangdong Medical University using the International Classification of Disease, 10th Revision Codes.

Statistical Analysis

Quantitative variables were analyzed by one-way ANOVA, and the data were expressed as means and standard deviations. Linear regression analysis was used to analyze the significant results of one-way ANOVA in different IPI. Qualitative variables were analyzed by the chi-square test. Multivariate logistic regression analysis was used to analyze the adverse perinatal outcomes with statistically significant differences in the chi-square test.

The prenatal outcome frequency and adjusted OR were calculated for each IPI category using an IPI of 12–23 months as the reference category, as it was likely to have the lowest rate of adverse perinatal outcomes in the literature^35,36. For each outcome, we adjusted covariates, including age, occupation, marital status, educational level, number of pregnancies, history of induced abortion, and history of cesarean section, as potential confounders of the association between IPI and adverse perinatal outcomes. The adjusted ORs for perinatal outcomes were estimated after accounting for statistically significant and biologically plausible confounding variables. A p-value < 0.05 (typically ≤ 0.05) was statistically significant, and the null value (OR = 1.0) was not contained within the 95% confidence interval. SPSS 25.0 software was used for all statistical analyses.

Figure 1 shows the IPI characteristics of the study population based on age. In total, 467 (12.6%) women had IPI 12–23 months, 1013 (27.3%) women had IPI 24–59 months, 1155 (31.1%) women had IPI 60–119 months, 852 (22.9%) women had IPI 120–179 months, and 228 (6.1%) women had IPI ≥ 180 months. The older the age, the more women there were with extra-long IPI. Furthermore, 5.0% of advanced maternal age women showed an extra-long IPI (≥ 180 months), and more than one-third of ultra-advanced maternal age women (35.5%) showed an extra-long IPI (≥ 180 months).

There was a significant difference in the unemployment rate among the advanced age women with different IPI (P < 0.05). There was a significant difference in the rate of parturients with secondary school education and below in different IPI among women with age-appropriate maternity and advanced maternal age, respectively (P < 0.001). There was a significant difference in the history of spontaneous abortion among women with age-appropriate maternity with different IPI (P < 0.001). In all age groups, the difference in the history of previous cesarean sections with different IPI was statistically significant (P < 0.05). Because there were only eight cases of smoking, five cases of drinking, and three cases of drug use, these data are not reflected in Table 1.

Table 1

Sociodemographic and Clinical Characteristics according to IPI Category, Group by Maternal Age
Outcome	Total	IPI (month) (n%)					P value
Outcome	Total	12–23	24–59	60–119	120–179	≥ 180
ALL	3715(100)	467(12.6)	1013(27.3)	1155(31.1)	852(22.9)	228(6.1)
Maternal age, y							< 0.001
20–34	1599(100)	413(25.8)	768(48.0)	361(22.6)	42(2.6)	15(0.9)
35–39	1764(100)	49(2.8)	226(12.8)	732(41.5)	669(37.9)	88(5.0)
40-	352(100)	5(1.4)	19(5.4)	62(17.6)	141(40.1)	125(35.5)
Unemployed
20–34	1183(74.0)	314(76.0)	656(76.3)	259(71.7)	32(76.2)	13(86.7)	0.409
35–39	1127(69.0)	35(71.4)	139(61.5)	488(66.7)	491(73.4)	64(72.7)	0.022
40-	237(67.3)	3(60.0)	13(68.4)	44(71.0)	92(65.2)	85(68.0)	0.891
Married
20–34	1545(96.6)	390(94.4)	749(97.5)	351(97.2)	41(97.6)	14(93.3)	0.213
35–39	1746(99.0)	49(100)	223(98.7)	730(99.7)	658(98.4)	86(97.7)	0.056
40-	350(99.4)	5(100)	19(100)	60(96.8)	141(100)	125(100)	0.537
Secondary school education and below
20–34	963(73.0)	234(71.1)	512(75.3)	168(24.7)	73(27.2)	11(35.5)	< 0.001
35–39	862(49.3)	25(52.1)	100(44.4)	298(41.2)	384(57.8)	55(62.5)	< 0.001
40-	194(55.6)	2(40.0)	13(68.4)	29(47.5)	75(53.6)	75(60.5)	0.305
Multiple abortion history (3 times or more)
20–34	51(3.2)	11(2.7)	22(2.9)	16(4.4)	2(4.8)	0(0.0)	0.471
35–39	129(7.3)	1(2.0)	14(6.2)	50(6.8)	57(8.5)	7(8.0)	0.384
40-	34(9.7)	0(0.0)	3(15.8)	3(4.8)	16(11.3)	12(9.6)	0.387
History of spontaneous abortion
20–34	51(3.2)	14(3.4)	25(3.3)	11(3.0)	1(2.4)	0(0.0)	< 0.001
35–39	119(6.7)	4(8.2)	10(4.4)	55(7.5)	41(6.1)	9(10.2)	0.133
40-	21(6.0)	0(0.0)	1(5.3)	5(8.1)	9(6.4)	6(4.8)	0.447
History of ectopic pregnancy
20–34	13(0.8)	3(0.7)	4(0.5)	5(1.4)	1(2.4)	0(0.0)	0.514
35–39	35(2.0)	3(6.1)	6(2.7)	14(1.9)	10(1.5)	2(2.3)	0.377
40-	6(1.7)	0(0.0)	0(0.0)	0(0.0)	1(0.7)	5(4.0)	0.181
Previous cesarean section
20–34	485(30.3)	63(15.3)	271(35.3)	139(38.5)	9(21.4)	3(20.0)	< 0.001
35–39	761(43.1)	17(34.7)	106(46.9)	345(47.1)	268(40.1)	25(28.4)	0.001
40-	154(43.8)	3(60.0)	13(68.4)	30(48.4)	67(47.5)	41(32.8)	0.012

The outcomes of week of delivery, 24-hour postpartum hemorrhage, birth weight, and 5-minute Apgar score are shown in Table 2. There was a significant difference in 24-hour postpartum hemorrhage across different IPI (P < 0.001) in the age-appropriate maternity group, but not in advanced and ultra-advanced maternal age groups. The rate of 24-hour postpartum hemorrhage was highest at IPI of 60–119 months (305.00 ± 104–857), but the rate of bleeding volume of women with extra-long IPI (295.33 ± 65.923) decreased. There were significant differences in birth weight across different IPI (P < 0.05) in the ultra-advanced maternal age group, but not in appropriate and advanced maternal age groups. In ultra-advanced parturients, the neonatal birth weight was lowest at IPI of 60–119 months (2.993 ± 0.6087), but women with extra-long IPI had higher neonatal birth weights (3.170 ± 0.5260). There was no statistically significant difference in the week of delivery or 5-minute Apgar score among the three maternal age groups.

Table 2

Quantitative Data of Perinatal Outcomes According to IPI Category, Group by Maternal Age
Outcome	Total	IPI (month)					P value
Outcome	Total	12–23	24–59	60–119	120–179	≥ 180	P value
Week of delivery
20–34	38.52 ± 1.339	38.54 ± 1.295	38.57 ± 1.295	38.40 ± 1.449	38.55 ± 1.064	38.07 ± 1.280	0.203
35–39	38.26 ± 1.569	38.00 ± 1.528	38.21 ± 1.356	38.32 ± 1.484	38.24 ± 1.714	38.10 ± 1.626	0.441
40-	38.07 ± 1.654	38.60 ± 0.548	38.53 ± 1.020	38.76 ± 1.700	38.18 ± 1.257	38.05 ± 1.694	0.149
24-hour postpartum hemorrhage
20–34	290.08 ± 85.647	274.95 ± 75.510	292.38 ± 80.278	305.00 ± 104–857	270.17 ± 71.485	295.33 ± 65.923	< 0.001
35–39	311.87 ± 147.731	299.03 ± 104.575	299.03 ± 104.575	312.58 ± 162.284	317.97 ± 153.334	299.70 ± 70.481	0.429
40-	334.12 ± 191.995	299.00 ± 75.773	364.89 ± 186.754	326.47 ± 125.282	365.25 ± 269.736	309.69 ± 88.579	0.326
Birth weight
20–34	3.192 ± 0.4202	3.185 ± 0.3990	3.202 ± 0.4139	3.175 ± 0.4676	3.218 ± 0.3197	3.237 ± 0.3880	0.846
35–39	3.188 ± 0.4707	3.163 ± 0.5482	3.189 ± 0.4483	3.213 ± 0.4627	3.164 ± 0.4850	3.183 ± 0.4707	0.421
40-	3.160 ± 0.5225	3.292 ± 0.2735	3.400 ± 0.4799	2.993 ± 0.6087	3.188 ± 0.4739	3.170 ± 0.5260	0.025
5-minute Apgar score
20–34	9.96 ± 0.465	9.96 ± 0.461	9.95 ± 0.558	9.97 ± 0.228	10.00 ± 0.000	10.00 ± 0.000	0.898
35–39	9.95 ± 0.402	9.98 ± 0.143	10.00 ± 0.067	9.96 ± 0.269	9.93 ± 0.579	9.93 ± 0.245	0.213
40-	9.93 ± 0.448	10.00 ± 0.000	10.00 ± 0.000	9.79 ± 0.943	9.99 ± 0.084	9.92 ± 0.326	0.050
a) P values were analyzed with One-way ANOVA.

Figure 2 shows the predicted value of 24-hour postpartum hemorrhage and neonatal birth weight among different IPI. The trend of the predictive value of 24-hour postpartum hemorrhage was different among the three maternal groups, as shown in Fig. 2A. In the appropriate maternal age group, the IPI increased, followed by an increase in the rate of postpartum hemorrhage, which then decreased to reach its highest value at IPI of 60–119 months.

The trend of the predicted value of neonatal birth weight was also different among the three maternal age groups, as shown in Fig. 2B. In the appropriate maternal age group, the IPI increased, followed by a decrease in the predictive value of neonatal birth weight, which then increased to reach its lowest value at IPI of 60–119 months, while in the advanced maternal age group, the predictive value of neonatal birth weight was observed to increase first, then decrease to reach a maximum value at IPI of 60–119 months. In the ultra-advanced maternal age group, the predicted value of neonatal birth weight was lowest with extra-long IPI (≥ 180 months).

The incidence of each pregnancy complication according to IPI is shown in Table 3. The incidence of pregnancy eclampsia was statistically significant among different IPI in the appropriate maternal age group (P < 0.05), but not in advanced maternal age and ultra-advanced maternal age groups. The highest rate of eclampsia (1.9%) was at IPI of 60–119 months, and a decreased rate was seen for extra-long IPI (0.0%). The incidence of premature rupture of membranes was statistically significant among different IPI in appropriate and advanced maternal age groups (P < 0.05), but not in the ultra-advanced maternal age group. The highest rate of premature rupture of membranes (26.2%) was at IPI of 120–179 months, and a decreased rate was seen for extra-long IPI (13.3%). In age-advanced parturients, the highest rate of premature rupture of membranes (24.5%) was at IPI of 12–23 months, and a decreased rate was seen for extra-long IPI (22.7%). There was no significant difference in the other outcomes across different IPI among the three maternal age groups.

Table 3

Rates of Maternal Adverse Pregnancy Complications
Outcome	Total	IPI (month) (n%)					P value
Outcome	Total	12–23	24–59	60–119	120–179	≥ 180	P value
GDM
20–34	325(20.3)	67(16.2)	157(20.4)	89(24.7)	9(21.4)	3(20.0)	0.075
35–39	680(38.5)	20(40.8)	80(35.4)	266(36.3)	283(42.3)	31(35.2)	0.139
40-	185(52.6)	2(40.0)	6(31.6)	33(53.2)	78(55.3)	66(52.8)	0.391
Pregnancy induced hypertension
20–34	8(0.5)	2(0.5)	2(0.3)	4(1.1)	0(0.0)	0(0.0)	0.426
35–39	36(2.0)	1(2.0)	2(0.9)	11(1.5)	19(2.8)	3(3.4)	0.237
40-	10(2.8)	0(0.0)	2(10.5)	1(1.6)	4(2.8)	3(2.4)	0.326
Pregnancy eclampsia
20–34	11(0.7)	1(0.2)	3(0.4)	7(1.9)	0(0.0)	0(0.0)	0.028
35–39	41(2.3)	0(0.0)	4(1.8)	17(2.3)	16(2.4)	4(4.5)	0.494
40-	14(4.0)	0(0.0)	0(0.0)	4(6.5)	9(6.4)	1(0.8)	0.115
PROM
20–34	255(15.9)	49(11.9)	120(15.6)	73(20.2)	11(26.2)	2(13.3)	0.009
35–39	284(16.1)	12(24.5)	35(15.5)	100(3.7)	117(17.5)	20(22.7)	0.047
40-	60(17.0)	0(0.0)	5(26.3)	11(17.7)	19(13.5)	25(20.0)	0.287
Placental abruption
20–34	9(0.6)	3(0.7)	2(0.3)	3(0.8)	0(0.0)	1(6.7)	0.215
35–39	10(0.6)	0(0.0)	0(0.0)	3(0.4)	6(0.9)	1(1.1)	0.290
40-	3(0.9)	0(0.0)	0(0.0)	1(1.6)	0(0.0)	2(1.6)	0.431
Placenta previa
20–34	15(0.9)	1(0.2)	6(0.8)	8(2.2)	0(0.0)	0(0.0)	0.063
35–39	24(1.4)	1(2.0)	2(0.9)	8(1.1)	12(1.8)	1(1.1)	0.757
40-	9(2.6)	0(0.0)	0(0.0)	3(4.8)	3(2.1)	3(2.4)	0.069
Intrahepatic cholestasis of pregnancy
20–34	12(0.8)	2(0.5)	6(0.8)	4(1.1)	0(0.0)	0(0.0)	0.835
35–39	16(0.9)	1(2.0)	3(1.3)	4(0.5)	8(1.2)	0(0.0	0.459
40-	3(0.9)	0(0.0)	1(5.3)	0(0.0)	1(0.7)	1(0.8)	0.288
Pelvic adhesions
20–34	30(1.9)	4(1.0)	15(2.0)	10(2.8)	1(2.4)	0(0.0)	0.436
35–39	50(2.8)	1(2.0)	5(2.2)	22(3.0)	20(3.0)	2(2.3)	0.955
40-	13(3.7)	0(0.0)	1(5.3)	3(4.8)	5(3.5)	4(3.2)	0.958
Coagulation dysfunction
20–34	4(0.3)	1(0.2)	2(0.3)	1(0.3)	0(0.0)	0(0.0)	0.997
35–39	20(1.1)	1(2.0)	2(0.9)	12(1.6)	5(0.7)	0(0.0)	0.399
40-	8(2.3)	0(0.0)	1(5.3)	4(6.5)	1(0.7)	2(1.6)	0.109
a) Data are shown as n (%). P values were analyzed with χ² statistics. GDM, gestational diabetes mellitus; PROM, premature rupture of membrane.

The incidence of adverse delivery outcomes is shown in Table 4. Both the incidence of premature delivery and low birth weight were statistically significant across different IPI in the appropriate maternal age group (P < 0.05), but not in advanced and ultra-advanced maternal age groups. The highest rate of premature delivery was observed for the extra-long IPI category (13.3%), while the highest rate of low birth weight (6.9%) was noted for the 60–119 months category, and a decreased rate was observed for the extra-long IPI category (6.7%). There were no significant differences in the other outcomes across different IPI among the three maternal age groups.

Table 4

Rates of Adverse Delivery Outcomes
Outcome	Total	IPI (month) (n%)					P value
Outcome	Total	12–23	24–59	60–119	120–179	≥ 180	P value
Premature delivery
20–34	86(5.4)	19(4.6)	34(4.4)	30(8.3)	1(2.4)	2(13.3)	0.032
35–39	135(7.7)	5(10.2)	17(7.5)	50(6.8)	55(8.2)	8(9.1)	0.787
40-	35(9.9)	0(0.0)	0(0.0)	10(16.1)	12(8.5)	13(10.4)	0.227
Stillbirth
20–34	3(0.2)	0(0.0)	3(0.4)	0(0.0)	0(0.0)	0(0.0)	0.517
35–39	2(0.1)	0(0.0)	0(0.0)	0(0.0)	2(0.3)	0(0.0)	0.513
40-	1(0.3)	0(0.0)	0(0.0)	1(1.6)	0(0.0)	0(0.0)	0.321
Placenta retention
20–34	12(0.8)	4(1.0)	5(0.7)	2(0.6)	1(2.4)	0(0.0)	0.706
35–39	15(0.9)	0(0.0)	0(0.0)	6(0.8)	9(1.3)	0(0.0)	0.281
40-	5(1.4)	0(0.0)	0(0.0)	3(4.8)	1(0.7)	1(0.8)	0.173
The amniotic fluid is turbid
20–34	18(1.1)	3(0.7)	9(1.2)	5(1.4)	1(2.4)	0(0.0)	0.197
35–39	42(2.4)	1(2.0)	4(1.8)	21(2.9)	12(1.8)	4(4.5)	0.691
40-	6(1.7)	0(0.0)	0(0.0)	0(0.0)	3(2.1)	3(2.4)	0.618
Oligohydramnios
20–34	101(6.4)	24(5.9)	51(6.7)	21(50.9)	4(9.8)	1(6.7)	0.875
35–39	129(7.4)	5(10.2)	8(3.6)	56(7.8)	57(8.6)	3(3.4)	0.062
40-	26(7.5)	0(0.0)	0(0.0)	4(6.9)	9(6.5)	13(10.4)	0.453
Excessive amniotic fluid
20–34	22(1.5)	6(1.6)	9(1.3)	6(1.8)	1(2.6)	0(0.0)	0.909
35–39	20(1.2)	0(0.0)	1(0.5)	10(1.5)	8(1.3)	1(1.2)	0.735
40-	7(2.1)	0(0.0)	0(0.0)	4(6.9)	3(2.3)	0(0.0)	0.056
Postpartum haemorrhage
20–34	21(1.3)	4(1.0)	11(1.4)	6(1.7)	0(0.0)	0(0.0)	0.816
35–39	30(1.7)	1(2.0)	5(2.2)	10(1.4)	14(2.1)	0(0.0)	0.555
40-	12(3.4)	0(0.0)	2(10.5)	4(6.5)	4(2.8)	2(1.6)	0.183
Neonatal anemia
20–34	17(1.1)	8(1.9)	5(0.7)	4(1.1)	0(0.0)	0(0.0)	0.304
35–39	15(0.9)	1(2.0)	2(0.9)	5(0.7)	6(0.9)	1(1.1)	0.883
40-	6(1.7)	0(0.0)	0(0.0)	1(1.6)	2(1.4)	3(2.4)	0.932
Macrosomia
20–34	47(2.9)	12(2.9)	20(2.6)	15(4.2)	0(0.0)	0(0.0)	0.420
35–39	49(2.8)	2(4.1)	4(1.8)	20(2.7)	21(3.1)	2(2.3)	0.813
40-	18(5.1)	0(0.0)	2(10.5)	3(4.8)	7(5.0)	6(4.8)	0.834
LWB
20–34	62(3.9)	13(3.2)	23(3.0)	25(6.9)	0(0.0)	1(6.7)	0.010
35–39	107(6.1)	5(10.2)	15(6.6)	33(4.5)	50(7.5)	4(4.5)	0.115
40-	32(9.1)	0(0.0)	1(5.3)	7(11.3)	14(9.9)	10(8.0)	0.827
Neonatal malformation
20–34	11(0.7)	3(0.7)	6(0.8)	2(0.6)	0(0.0)	0(0.0)	0.963
35–39	20(1.1)	1(2.0)	2(0.9)	9(1.2)	7(1.0)	1(1.1)	0.964
40-	1(0.3)	0(0.0)	0(0.0)	1(1.6)	0(0.0)	0(0.0)	0.321
Fetal distress
20–34	7(0.4)	2(0.5)	4(0.5)	1(0.3)	0(0.0)	0(0.0)	0.962
35–39	10(0.6)	0(0.0)	1(0.4)	3(0.4)	6(0.9)	0(0.0)	0.651
40-	2(0.6)	0(0.0)	0(0.0)	0(0.0)	0(0.0)	2(1.6)	0.455
ABO hemolysis
20–34	5(0.3)	2(0.5)	3(0.4)	0(0.0)	0(0.0)	0(0.0)	0.763
35–39	5(0.3)	0(0.0)	2(0.9)	1(0.1)	1(0.1)	1(0.1)	0.180
40-	2(0.6)	0(0.0)	0(0.0)	0(0.0)	1(0.7)	1(0.8)	0.956
Neonatal asphyxia
20–34	7(0.4)	2(0.5)	3(0.4)	2(0.6)	0(0.0)	0(0.0)	0.981
35–39	13(0.7)	0(0.0)	0(0.0)	6(0.8)	7(1.0)	0(0.0)	0.456
40-	5(1.4)	0(0.0)	0(0.0)	3(4.8)	0(0.0)	2(1.6)	0.108
Respiratory distress syndrome
20–34	12(0.8)	3(0.7)	5(0.7)	4(1.1)	0(0.0)	0(0.0)	0.886
35–39	25(1.4)	1(2.0)	2(0.9)	8(1.1)	13(1.9)	1(1.1)	0.639
40-	5(1.4)	0(0.0)	0(0.0)	2(3.2)	0(0.0)	3(2.4)	0.322
a) Data are shown as n (%). P values were analyzed with χ² statistics. LWB, low birth weight.

The predicted probability of adverse perinatal outcomes is shown in Fig. 3. The predicted probability of pregnant eclampsia increased with age, but no statistical significance was observed across the different groups, as shown in Fig. 3A. The predicted probability of premature rupture of membranes increased with IPI and decreased with age, as shown in Fig. 3B. The predicted probability of premature delivery and low birth weight both increased with IPI and age, as shown in Fig. 3C and Fig. 3D.

The results of multivariate logistic regression analysis of the relationship between IPI and adverse perinatal outcomes are shown in Table 5. The rate of premature rupture of membranes increased with increasing IPI in all maternity groups, among them IPI 24–59 months (aOR 1.43, 95% CI 1.00–2.05), IPI 120–179 months (aOR 1.68, 95% CI 1.13–2.53), and IPI 180 months (aOR 2.09, 95% CI 1.25–3.49). The rates of premature rupture of membranes increased with an increasing IPI in women with age-appropriate maternity, among them IPI 60–119 months (aOR 1.83, 95% CI 1.13–2.97) and IPI 120–179 months (aOR 3.30, 95% CI 1.40–7.74). However, the effects of IPI on adverse perinatal outcomes did not differ significantly among women of advanced maternal age.

Table 5

Adjusted Risks Ratios for Adverse Perinatal Outcomes
Outcome	Pregnancy interval, aOR^c(95%CI)
Outcome	180-	120–179	60–119	24–59	12–23
Eclampsia
All women	Suppressed^b	Suppressed^b	Suppressed^b	Suppressed^b	1
Age at preinterval birth, y
20–34	Suppressed^b	Suppressed^b	Suppressed^b	Suppressed^b	1
≥ 35	Suppressed^b	Suppressed^b	Suppressed^b	Suppressed^b	1
PROM
All women	2.09(1.25–3.49)**	1.68(1.13–2.53)*	1.43(0.98–2.08)	1.43(1.00-2.05)*	1
Age at preinterval birth, y
20–34	1.55(0.32–7.46)	3.30(1.40–7.74)**	1.83(1.13–2.97)*	1.50 (0.99–2.28)	1
≥ 35	0.98(0.46–2.08)	0.72(0.36–1.41)	0.58(0.29–1.14)	0.70(0.34–1.46)	1
Premature delivery
All women	1.48(0.72–3.06)	1.24(0.70–2.20)	1.34(0.79–2.28)	0.91(0.53–1.55)	1
Age at preinterval birth, y
20–34	4.37(0.85–22.45)	Suppressed^b	1.66(0.82–3.34)	0.82(0.43–1.55)	1
≥ 35	0.92(0.32–2.64)	0.85(0.33–2.21)	0.81(0.31–2.13)	0.76(0.27–2.15)	1
LBW
All women	1.27(0.53–3.02)	1.64(0.83–3.23)	1.33(0.70–2.57)	1.07(0.56–2.06)	1
Age at preinterval birth, y
20–34	3.07 (0.34–27.93)	Suppressed^b	2.39 (0.99–5.81)	0.99(0.42–2.328)	1
≥ 35	0.55(0.18–1.65)	0.80(0.31–2.10)	0.54(0.20–1.43)	0.71(0.25–2.04)	1
a) , P < 0.05, *, P < 0.01. aOR, adjusted odds ratios; CI, confidence interval; PROM, premature rupture of membrane; LWB, low birth weight. b) The No. (%) was suppressed if cell counts were less than 5. c) Adjusted for age, occupation, marital status, educational level, number of pregnancies, history of induced abortion and history of cesarean section.

To maintain sufficient accuracy in assessing the correlation of exposure results, hierarchical analysis of the classified age groups allowed us to explore the effects of different IPI^16,35, categorized as 12–23 months, 24–59 months, 60–119 months, 120–179 months, and ≥ 180 months. Our study found that perinatal outcomes in different maternal age groups were different across different IPI. After adjusting for all possible confounding factors, an increased risk of premature rupture of membranes (aOR 1.43, 95% CI 1.00–2.05; aOR 1.68, 95% CI 1.13–2.53; and aOR 2.09, 95% CI 1.25–3.49) were found at IPI 24–59 months, 120–179 months, and 180 months among all women. An increased risk of premature rupture of membranes (aOR 1.83, 95% CI 1.13–2.97; aOR 3.30, 95% CI 1.40–7.74) were also found at IPI 60–119 months and 120–179 months among women of age-appropriate maternity. However, we failed to find a similar association in women of advanced maternal age. In addition, the effects of extra-long IPI on adverse perinatal outcomes did not differ significantly among women of advanced maternal age.

For long intervals, a woman’s reproductive capacity may decline and return to the primiparous state if birth intervals are overly long³⁵. This hypothesis, which explains the association between long IPI and adverse outcomes, is known as the “physiological regression hypothesis”²², and it suggests that pregnancy helps mothers gain growth-supporting capacities such as increased uterine blood flow, as well as other physiological and anatomical reproductive system changes³⁷. After delivery, this capacity may gradually weaken³⁸, and if there is no pregnancy after a long IPI, then the physiological characteristics of women are likely to become those of primiparous women.

Several studies have reported inconsistent findings. These studies focus on long IPI and fail to distinguish long IPI from extra-long IPI (≥ 180 months). Previous studies have reported that women with longer IPI have higher obstetric risks^12–17, and long IPI (≥ 60 months) was associated with a greater risk of premature rupture of membranes compared to IPI 18–23 months¹⁴. In the current study, women with a second baby mostly benefited from the two-child policy, and confounding factors, such as age, occupation, marital status, educational level, number of pregnancies, history of induced abortion, and history of cesarean section, were adjusted. Our stratified analysis was consistent, suggesting that the risk of premature rupture of membranes may be highest among women of age-appropriate maternity with IPI 120–179 months. However, the effects of extra-long IPI (≥ 180 months) on adverse perinatal outcomes did not differ significantly among women of advanced maternal age, which may be attributed to the "physiological regression" theory.

A recent retrospective study conducted in Chinese reported that women with long IPI (≥ 75 months) had higher risks of preterm birth and low birth weight^15,17. However, we could not rule out possible selection bias because the attributes of women, usually working in the private sector or residing in rural areas, who had a second child before the implementation of the two-child policy may have generated this pattern of associations, especially through their geographic setting and socioeconomic status. In the present study, after adjusting for possible confounding factors, we found that long IPI, especially extra-long IPI, did not increase the risk of pregnancy eclampsia, premature delivery, and low birth weight in women of advanced maternal age. Previous studies have shown that long IPI increases the risk of adverse perinatal outcomes^12–16, which may have been related to the lack of extra-long IPI and combined age cases. The effect of IPI is masked by the effect of different ages, and the risk of adverse perinatal outcomes is higher if long IPI and advanced age exist at the same time.

Longer birth intervals may indicate other benefits. For example, a study reported that birth intervals with ≥ 60 months had lower odds of under-5 mortality than reference intervals (OR 0.59, 95% CI 0.52–0.67), which offered a strong protective effect for high fertility mothers³⁹. Although puerpera with extra-long IPI may tend to be primipara according to the "physiological regression" theory, it is worth noting that the existence of extra-long IPI is usually accompanied by advanced age, a well-known and recognized obstetric risk factor^25,26,40. Furthermore, maternal factors, such as socioeconomic and lifestyle factors, are not easy to measure or model^33,41, which may increase the difficulty of exploring the association between birth intervals and postpartum outcomes. Therefore, although there is no statistically significant association between extra-long IPI and adverse perinatal outcomes in women at advanced age, we do not recommend clinicians to treat women with extra-long IPI as primipara. We should be alert to potential maternal risk factors that may accompany the presentation of extra-long IPI.

Some limitations should be taken into consideration. Firstly, although more than one-third of the women aged 40 years or older (35.5%) showed an extra-long IPI, data were collected from a single hospital, and therefore, the results may not be representative of China as a whole²². Secondly, although we were able to adjust for some potential confounders, residual and unmeasured confounders, such as maternal obesity, prior gestational diabetes, and other pregnancy complications, could not be completely ruled out. We were also unable to perform analyses by prior obstetric outcomes⁴². Thirdly, the effects of IPI may differ depending on whether the previous pregnancy resulted in a loss (i.e., miscarriage) versus a live birth, which means selective fertility may have played a role⁴³. We were unable to collect a comprehensive list of sociodemographic and clinical variables.

In the present study, we found long IPI (60–179 months) is an independent risk factor for premature rupture of membranes in age-appropriate women. Extra-long IPI (≥ 180 months) was not associated with an increase in major morbidity. Although a women’s reproductive capacity seems to return to the primiparous state with an extra-long IPI, great attention should be given to these women because of their advanced age, which is a confirmed risk. With the universal introduction of the two-child policy in China, an increasing proportion of women will choose to have a second child. Development of clinical guidelines on birth intervals between two pregnancies are urgently needed.

GDM, gestational diabetes mellitus; PROM, premature rupture of membrane; LWB, low birth weight; aOR, adjusted odds ratios; CI, confidence interval.

Ethics approval and consent to participate

The study was approved by the Ethics Committee of the Shunde Maternal and Child Health Hospital affiliated with Guangdong Medical University. All participants gave signed informed consent for participation in research and provided signed authorization for complete medical record review. All methods were carried out in accordance with the relevant guidelines and regulations. Declaration of helsinki.

Consent for publication

Not applicable.

Availability of data and material

The datasets generated and/or analysed during the current study are not publicly available due [REASON WHY DATA ARE NOT PUBLIC] but are available from the corresponding author on reasonable request.

Competing interests

The authors declare that they have no competing interests in this section.

Funding

This work was supported by the Major Program of Natural Science Foundation of Guangdong Province, China (2021A1515011038) and Discipline construction project of Guangdong Medical University (4SG21001G).

Authors' contributions

JDN, RLC designed this study. DML , XYM, XWL , XYP , JL , LZ collected inpatient medical record data on pregnant women. TYL, MJY analyzed and interpreted the relevant data. JMZ, JYH, XYZ and JDN drafted and revised the manuscript. All authors read and approved the final manuscript.

Acknowledgements

We thank International Science Editing (http://www.internationalscienceediting.com) for editing this manuscript.

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No competing interests reported.

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Relationship Between Extra-Long Interpregnancy Interval and Adverse Perinatal Outcomes in Chinese Women

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