BMJ  2003;327:313 (9 August), doi:10.1136/bmj.327.7410.313

Paper

Interpregnancy interval and risk of preterm birth and neonatal death: retrospective cohort study

¹ Department of Obstetrics and Gynaecology, Cambridge University, Box 223, The Rosie Hospital, Cambridge CB2 2QQ, ² Department of Public Health, Greater Glasgow NHS Board, Glasgow, ³ Information and Statistics Division, Common Services Agency, Edinburgh

Abstract

Objective To determine whether a short interval between pregnancies is an independent risk factor for adverse obstetric outcome.

Design Retrospective cohort study.

Setting Scotland.

Subjects 89 143 women having second births in 1992-8 who conceived within five years of their first birth.

Main outcome measures Intrauterine growth restriction (birth weight less than the 5th centile for gestational age), extremely preterm birth (24-32 weeks), moderately preterm birth (33-36 weeks), and perinatal death.

Results Women whose subsequent interpregnancy interval was less than six months were more likely than other women to have had a first birth complicated by intrauterine growth restriction (odds ratio 1.3, 95% confidence interval 1.1 to 1.5), extremely preterm birth (4.1, 3.2 to 5.3), moderately preterm birth (1.5, 1.3 to 1.7), or perinatal death (24.4, 18.9 to 31.5). They were also shorter, less likely to be married, and more likely to be aged less than 20 years at the time of the second birth, to smoke, and to live in an area of high socioeconomic deprivation. When the outcome of the second birth was analysed in relation to the preceding interpregnancy interval and the analysis confined to women whose first birth was a term live birth (n = 69 055), no significant association occurred (adjusted for age, marital status, height, socioeconomic deprivation, smoking, previous birth weight vigesimal, and previous caesarean delivery) between interpregnancy interval and intrauterine growth restriction or stillbirth. However, a short interpregnancy interval (< 6 months) was an independent risk factor for extremely preterm birth (adjusted odds ratio 2.2, 1.3 to 3.6), moderately preterm birth (1.6, 1.3 to 2.0), and neonatal death unrelated to congenital abnormality (3.6, 1.2 to 10.7). The adjusted attributable fractions for these associations were 6.1%, 3.9%, and 13.8%. The associations were very similar when the analysis was confined to married non-smokers aged 25 and above.

Conclusions A short interpregnancy interval is an independent risk factor for preterm delivery and neonatal death in the second birth.

Introduction

Several studies have shown that women with a very short interval between pregnancies are at increased risk of complications such as preterm birth, neonatal death, and intrauterine growth restriction.^1-10 However, these studies do not clarify whether the associations are due to confounding effects of adverse obstetric history or to demographic factors. Many previous studies of the association between interpregnancy interval and the risk of adverse outcome have lacked information on maternal demographic factors and have had either no information on the outcome of previous pregnancies or minimal information. We report the relation between interpregnancy interval and the outcome of first and second births in a cohort of 89 143 women.

Methods

Data sources
The Scottish Morbidity Record collects information on clinical and demographic characteristics and outcomes for all patients discharged from Scottish maternity hospitals. The register is subjected to regular quality assurance checks and has been greater than 99% complete since the late 1970s.¹¹ We linked records from the register to records from the Scottish Stillbirth and Infant Death Enquiry, a national register that routinely classifies all perinatal deaths in Scotland. It is virtually 100% complete and has been described in detail elsewhere.^{12 13} We also linked the records from different pregnancies in the same women. All linkages were performed as previously described.¹⁴

Study cohort
The population studied consisted of all second births in Scotland in 1992-8. The study focused on births in 1992-8 as the Scottish Morbidity Record database included smoking status only from 1992 onwards. When studying the relation between interpregnancy interval and the outcome of the first pregnancy, we used exclusion criteria (both pregnancies) including multiple pregnancy, delivery outside the range 24-43 weeks' gestation, and birth weight less than 500 g.

We analysed the relation of interpregnancy interval to the outcome of the second birth in a subgroup of the main cohort. We defined this subgroup by excluding cases in which the first birth was outside the range 37-43 weeks, the first birth was a perinatal or infant death, or the birth weight of the first child was less than 1500 g.

Definitions
Maternal characteristics
In the comparison of risk of adverse obstetric outcome, we considered the following demographic factors as possible confounders: socioeconomic deprivation, smoking, maternal age, and maternal height; their classification has been defined elsewhere.¹⁵ We also included marital status.

Obstetric characteristics
We defined interpregnancy interval as the interval from the first birth until the estimated date of the last menstrual period before the second pregnancy. We defined very preterm delivery as live births between 24 and 32 weeks' gestation inclusive. We defined moderately preterm delivery as live births between 33 and 36 weeks' gestation inclusive. We defined intrauterine growth restriction as birth weight less than the 5th centile for gestational age. We defined neonatal death as death of a liveborn infant within the first four weeks of life.

Statistical analyses
We summarised continuous variables by the median and interquartile range and used the Mann-Whitney U test to make comparisons between groups. We made univariate comparisons of dichotomous data by using the ² test (> 5 observations in all cells) or Fisher's exact test ( 5 observations in one or more cells). We used multivariate logistic regression analysis to assess the risk of adverse obstetric outcome.

Results

Approximately 5.4% of the cohort had an interpregnancy interval of less than six months. Women who subsequently had a short interpregnancy interval were more likely to have experienced complications in their first pregnancy (table 1). Compared with women who had an interpregnancy interval of 18-23 months, those with an interval of less than six months had a 30-50% excess of intrauterine growth restriction and moderately preterm birth in their first pregnancy, a fourfold excess of extremely preterm birth, and a greater than 20-fold excess of perinatal deaths. An excess of extremely preterm first births existed among women whose subsequent interpregnancy interval was 2-5 years.

View this table: [in this window] [in a new window]   Table 1 Outcome of first pregnancy in relation to interval between first and second pregnancies (n=89 143)

 

All analyses of the outcome of the second birth were confined to the subgroup of women whose first birth was a term live birth. Even among this group, at the time of their second delivery, women with a short interval between their first and second pregnancy were more likely to be aged less than 20, to smoke, and to live in an area of high deprivation and were less likely to be married, to be aged greater than 35, and to live in an area of low socioeconomic deprivation.

On univariate analysis of obstetric outcome in the second birth, women with a short interpregnancy interval were more likely to have an extremely preterm birth, a moderately preterm birth, or a neonatal death (table 2). The strength of these associations was attenuated by adjustment for maternal age, marital status, height, socioeconomic deprivation category, smoking, previous birth weight vigesimal, and previous caesarean section, but significant associations persisted in multivariate analysis. An interpregnancy interval of less than six months was associated with an increased risk (compared with an interpregnancy interval of 18-23 months) of spontaneous preterm birth, both 24-32 weeks (adjusted odds ratio 2.2, 95% confidence interval 1.2 to 4.1) and 33-36 weeks (1.6, 1.2 to 2.2).

View this table: [in this window] [in a new window]   Table 2 Crude and adjusted odds ratios for interpregnancy interval and the outcome of the second pregnancy (n=69 055)

 

We explored the relations between interpregnancy interval, maternal age, and the outcome of the second birth in more detail. The attenuation of the association between interpregnancy interval and adverse outcome in multivariate analysis was principally due to the effect of adjustment for age. Maternal age less than 20 years at the time of the second birth was strongly associated with preterm birth and neonatal death. The association remained statistically significant in multivariate analysis but was attenuated by adjustment for both interpregnancy interval and other maternal factors. The strengths of the associations between interpregnancy interval and outcome of second births were virtually identical when confined to married non-smokers aged 25 or above: in this group an interpregnancy interval of less than six months was associated with an odds ratios of 2.8 (1.3 to 5.9) for extremely preterm birth and 1.7 (1.2 to 2.4) for moderately preterm birth.

Discussion

The main finding of this study is that in women having a second birth a short preceding interpregnancy interval was an independent risk factor for extremely preterm birth, moderately preterm birth, and neonatal death not due to congenital abnormality. The association occurred even among women whose first pregnancy was a term live birth and persisted after adjustment for maternal age, marital status, height, socioeconomic deprivation category, smoking, previous birth weight vigesimal, and previous caesarean section. The association was specific to preterm birth and neonatal death, as no association existed between a short interpregnancy interval and the risk of delivering a growth restricted infant.

When we examined the outcome of all first births in relation to the subsequent interpregnancy interval, women with a short interpregnancy interval had a significant excess of intrauterine growth restriction, preterm birth, and perinatal deaths in their first births. Indeed, approximately 10% of women with an interval of less than six months had a first birth that had ended in perinatal death, compared with less than 1% of women with an interval of 18-23 months. These observations are consistent with previous studies and underline the importance of excluding women with complications in their first birth when examining associations between interpregnancy interval and the outcome of the second birth.¹⁶

It is unlikely that the associations between interpregnancy interval and the outcome of the second birth were due to unmeasured or residual confounding. Firstly, after adjustment for maternal age, adjustment for other maternal factors had very little effect. Secondly, the strength of the association was virtually unchanged when we confined the analysis to married, non-smoking women aged 25 and above. Thirdly, no statistically significant first order interactions occurred between a short interpregnancy interval and other maternal factors. Finally, the association was specific for preterm birth and neonatal death. No association existed between a short interpregnancy interval and delivering a small for gestational age baby. In contrast, a high socioeconomic deprivation category (that is, more deprived) was significantly associated with delivering a small for gestational age baby in multivariate analysis (data not shown).

The lack of association between interpregnancy interval and growth restriction also suggests that the relation between a short interpregnancy interval and other adverse outcomes is unlikely to be due to depletion of maternal nutritional reserves. A specific association between a short interpregnancy interval and preterm birth is biologically plausible. The control of parturition is thought to be mediated by a two step process of activation and stimulation.¹⁷ Activation is defined as the up regulation of expression of a range of contraction associated proteins, such as G protein coupled receptors, in the weeks leading up to term. Stimulation is defined as the process by which synthesis and release of natural agonists for these receptors, such as prostaglandins, initiates uterine contraction. We hypothesise that failure to allow expression of contraction associated proteins to return to prepregnancy levels may be the mechanism by which a short interpregnancy interval predisposes to preterm birth.

We propose that women should be informed of a small but significantly elevated risk of preterm birth and perinatal death when they conceive shortly after a birth. Contraceptive advice should be targeted towards women who are most likely to have a subsequent short interpregnancy interval—namely, teenagers and women who have just experienced a perinatal loss.

What is already known on this topic Women with a short interval between pregnancies are at increased risk of obstetric complications These women also differ in their previous obstetric complications and demographic characteristics Whether the increased risk of adverse outcome after a short interpregnancy interval is merely due to confounding by obstetric and demographic associations is unclear What this study adds Women with short intervals between pregnancies are much more likely to have had complicated first births and to have demographic risk factors for obstetric complications Even among women with an uncomplicated first birth and after adjustment for maternal demographics, a short interpregnancy interval was associated an increased risk of preterm birth and neonatal death

---

This is an abridged version; the full version is on bmj.com

Contributors: See bmj.com

Funding: None.

Competing interests: None declared.

References

1. Brody DJ, Bracken MB. Short interpregnancy interval: a risk factor for low birthweight. Am J Perinatol 1987;4: 50-4.[Web of Science][Medline]
2. Lieberman E, Lang JM, Ryan KJ, Monson RR, Schoenbaum SC. The association of inter-pregnancy interval with small for gestational age births. Obstet Gynecol 1989;74: 1-5.[Web of Science][Medline]
3. Rawlings JS, Rawlings VB, Read JA. Prevalence of low birth weight and preterm delivery in relation to the interval between pregnancies among white and black women. N Engl J Med 1995;332: 69-74.[Abstract/Free Full Text]
4. Adams MM, Delaney KM, Stupp PW, McCarthy BJ, Rawlings JS. The relationship of interpregnancy interval to infant birthweight and length of gestation among low-risk women, Georgia. Paediatr Perinat Epidemiol 1997;11(suppl 1): 48-62.
5. Basso O, Olsen J, Knudsen LB, Christensen K. Low birth weight and preterm birth after short interpregnancy intervals. Am J Obstet Gynecol 1998;178: 259-63.[CrossRef][Web of Science][Medline]
6. Khoshnood B, Lee KS, Wall S, Hsieh HL, Mittendorf R. Short interpregnancy intervals and the risk of adverse birth outcomes among five racial/ethnic groups in the United States. Am J Epidemiol 1998;148: 798-805.[Abstract/Free Full Text]
7. Zhu BP, Rolfs RT, Nangle BE, Horan JM. Effect of the interval between pregnancies on perinatal outcomes. N Engl J Med 1999;340: 589-94.[Abstract/Free Full Text]
8. Shults RA, Arndt V, Olshan AF, Martin CF, Royce RA. Effects of short interpregnancy intervals on small-for-gestational age and preterm births. Epidemiology 1999;10: 250-4.[Web of Science][Medline]
9. Fuentes-Afflick E, Hessol NA. Interpregnancy interval and the risk of premature infants. Obstet Gynecol. 2000;95: 383-90.[CrossRef][Web of Science][Medline]
10. Zhu BP, Haines KM, Le T, McGrath-Miller K, Boulton ML. Effect of the interval between pregnancies on perinatal outcomes among white and black women. Am J Obstet Gynecol 2001;185: 1403-10.[CrossRef][Web of Science][Medline]
11. Cole SK. Scottish maternity and neonatal records. In: Chalmers I, McIlwaine GM, eds. Perinatal audit and surveillance. London: Royal College of Obstetricians and Gynaecologists, 1980: 39-51.
12. McIlwaine GM, Dunn FH, Howat RC, Smalls M, Wyllie MM, MacNaughton MC. A routine system for monitoring perinatal deaths in Scotland. Br J Obstet Gynaecol 1985;92: 9-13.[Web of Science][Medline]
13. Information and Statistics Division NHS Scotland. Scottish perinatal and infant mortality and morbidity report 2001. Edinburgh: Common Services Agency, 2002 (available at www.show.scot.nhs.uk/isd/sexual_health/spimmr/SPIMMR-_2001.pdf).
14. Kendrick S, Clarke J. The Scottish record linkage system. Health Bull (Edinb) 1993;51: 72-9.
15. Smith GCS, Pell JP, Cameron AD, Dobbie R. Risk of perinatal death associated with delivery after previous caesarean section. JAMA 2002;287: 2684-90.[Abstract/Free Full Text]
16. Erickson JD, Bjerkedal T. Interpregnancy interval: association with birth weight, stillbirth, and neonatal death. J Epidemiol Community Health 1978;32: 124-30.[Abstract/Free Full Text]
17. Norwitz ER, Robinson JN, Challis JR. The control of labor. N Engl J Med 1999;341: 660-6.[Free Full Text]

(Accepted June 18, 2003)

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    StumbleUpon    Technorati    What's this?

Relevant Article

Short interpregnancy interval is associated with adverse outcome
BMJ 2003 327: 0. [Full Text]

This article has been cited by other articles:

• Kramer, M. R., Hogue, C. R. (2009). What Causes Racial Disparities in Very Preterm Birth? A Biosocial Perspective. Epidemiol Rev 31: 84-98 [Abstract] [Full text]  
• Cetin, I., Berti, C., Calabrese, S. (2009). Role of micronutrients in the periconceptional period. Hum Reprod Update 0: dmp025v1-dmp025 [Abstract] [Full text]  
• Conde-Agudelo, A., Rosas-Bermudez, A., Kafury-Goeta, A. C. (2006). Birth spacing and risk of adverse perinatal outcomes: a meta-analysis.. JAMA 295: 1809-1823 [Abstract] [Full text]  
• Fairley, L, Leyland, A H (2006). Social class inequalities in perinatal outcomes: Scotland 1980-2000. J. Epidemiol. Community Health 60: 31-36 [Abstract] [Full text]  
• Pallitto, C. C., Campbell, J. C., O'Campo, P. (2005). Is Intimate Partner Violence Associated with Unintended Pregnancy? A Review of the Literature. Trauma Violence Abuse 6: 217-235 [Abstract]  
• Hsieh, T.-T., Chen, S.-F., Shau, W.-Y., Hsieh, C.-C., Hsu, J.-J., Hung, T.-H. (2005). The Impact of Interpregnancy Interval and Previous Preterm Birth on the Subsequent Risk of Preterm Birth. Reproductive Sciences 12: 202-207 [Abstract]  
• (2004). Other articles noted: 25 Jul 03 to 7 Nov 03. Evid. Based Nurs. 7: e1-1 [Full text]  
• (2003). Short Interpregnancy Intervals Could Put Infants at Risk. JWatch General 2003: 3-3 [Full text]  

Rapid Responses:

Read all Rapid Responses

parturition

william s. craig
bmj.com, 9 Aug 2003 [Full text]

Poor maternal and perinatal outcome with short interpregnancy interval

Jai B Sharma, et al.
bmj.com, 10 Aug 2003 [Full text]

Interpregnancy interval and breast feeding

angela m hamon
bmj.com, 11 Aug 2003 [Full text]

Residual confounding and biased odds ratios

Adam Jacobs
bmj.com, 13 Aug 2003 [Full text]

too little DHEA

James M. Howard
bmj.com, 23 Nov 2003 [Full text]

Re: too little DHEA FULL VERSION

James M. Howard
bmj.com, 24 Nov 2003 [Full text]

Re: Re: too little DHEA New Support: Magnesium: JAMA. 2003; 290: 2669-2676

James M. Howard
bmj.com, 27 Nov 2003 [Full text]

Re: Re: Re: too little DHEA New Support: Caesarean section: Lancet 2003; 362: 1779-84

James M. Howard
bmj.com, 30 Nov 2003 [Full text]

Online poll

Find out more here>> and here>>