Objective
High altitude has been implicated in a variety of adverse pregnancy outcomes including preeclampsia and stillbirth. Smaller studies show conflicting data on the association between high altitude and preterm birth (PTB). The objective of this study was to assess the association between altitude and PTB.
Study Design
A retrospective cohort study was performed using data from the Perinatal Information System, which includes deliveries from 43 hospitals in Peru from 2000 through 2010. Altitude was classified into the following categories: low (0-1999 m), moderate (2000-2900 m), and high (3000-4340 m). The primary outcome was PTB (delivery <37 weeks). Secondary outcomes were cesarean delivery and small for gestational age (SGA). Deliveries less than 23 weeks are not included in the database. χ 2 analyses were performed to compare categorical variables, and a logistic regression was used to calculate the odds ratios and control for confounders. Clustering by hospital was accounted for using generalized estimating equations.
Results
A total of 550,166 women were included (68% low, 15% moderate, 17% high altitude). The overall PTB rate was 5.9%, with no difference in the PTB rate among the 3 altitudes (5.6%, 6.2%, 6.8%, P = .13). There was a significant difference in cesarean rates (28.0%, 26.6%, 20.6%, P < .001) with a 34% decreased risk at high vs low altitude adjusted for confounders (adjusted odds ratio, 0.66; 95% confidence interval, 0.51–0.85). There was a difference in SGA (3.3%, 3.6%, 5.0%, P = .02) with a 51% increased risk at high vs low altitude adjusted for confounders (adjusted odds ratio, 1.49; 95% confidence interval, 1.14–1.93).
Conclusion
High altitude is not associated with PTB. At high altitude, the cesarean rate was reduced and the SGA rate was increased.
Preterm birth (PTB) is a leading cause of perinatal morbidity and mortality worldwide. The reality of neonatal morbidity and health care costs associated with PTB are well known and are a major public health concern both nationwide and worldwide. In developing countries, PTB is a known contributor to neonatal mortality. In 2000, the United Nations held a summit to create goals for improving the world’s health and poverty. The fourth Millennium Development Goal is to reduce the child mortality rate by two thirds from 1990 to 2015. Among child mortality, neonatal deaths are a major contributor, with a large proportion of neonatal deaths being from complications of prematurity.
In developing countries, in which there are fewer resources, fewer hospitals, and fewer health care providers trained in caring for a preterm infant, the neonatal mortality rate (NMR) remains incredibly high. In Latin America, the PTB rate is estimated to be 6%, with an NMR of 15 per 1000 live births, which is 3 times as high as the United States. These rates are even higher in the country of Peru in which the PTB rate ranges from 6% to 18% and the NMR is 20 per 1000 live births, with large variations, depending on geographical location.
There are many identifiable risk factors for PTB ; however, to date, there are conflicting data on the association between high altitude and PTB. More than 140 million people live at high altitude in North, Central, and South America, East Africa, and Asia. Peru is a country of more than 30 million people. The country is divided into 3 regions: the coastal area at sea level, the Andean region at high altitudes, and the Amazonian jungle region at low altitude. Approximately 9 million people live at moderate or high altitude in the Andean regions.
High altitude has been associated with decreased uterine artery blood flow, increased uteroplacental resistance, alterations in the expression of placental factors, chronic hypoxia, and changes in vascularity and has been implicated in a variety of adverse pregnancy outcomes including intrauterine growth restriction, low birthweight infants, intrauterine fetal demise, and preeclampsia. Some of these same physiological changes have been observed and linked specifically with PTB. Previous studies that have evaluated the impact of high altitude on PTB have not been designed or powered to specifically evaluate the PTB outcome. Therefore, the objective of this study was to evaluate the association between PTB and high altitude in Peruvian pregnant women.
Materials and Methods
A retrospective cohort study was performed using data from the Perinatal Information System (PIS) database, which includes deliveries from 43 urban, public hospitals belonging to the Ministry of Health in Peru. Institutional Review Board approval was obtained from the University of Pennsylvania and the Universidad Peruana Cayetano Heredia prior to this study.
The PIS database was developed by the Latin American Centre for Perinatology/Women and Reproductive Health (CLAP/SMR) in Uruguay and has become a well-established national Peruvian database in which individual hospitals report information on all obstetric patients. The database includes maternal demographic information, medical history, and labor and delivery information from the 43 hospitals included. The altitude of these hospitals ranges from 29 m to 4340 m above sea level.
Data were collected from 2000 through 2010. The hospitals included health centers, community hospitals, and tertiary care referral hospitals. A quality assessment of the PIS database has been previously performed. During this assessment, Gonzales et al validated the database in 3 ways: (1) computer checks to reduce the risk of typing errors, (2) computer review of records for missing or aberrant data, and (3) review of a random sample of records to compare with other sources of information. For the record review, records were randomly sampled and compared with other sources of information (ie, a birth registry in a delivery room or records of neonatal services provided along with a review of the clinical record) to assure the reliability of the information in the database.
Data are grouped according to altitude of residency: low altitude (0-1999 m), moderate altitude (2000-2999 m), and high altitude (3000-4340 m). The unexposed patients are those living at low altitude and include 22 hospitals. The exposed patients are those living at moderate altitude (8 hospitals) and high altitude (13 hospitals). The altitude at the hospital site of delivery was used to define the altitude of residency. Almost all women deliver in close proximity to their place of residency, thereby making the hospital site altitude an acceptable way to classify this exposure.
Our primary outcome was PTB, which was defined by delivery less than 37 weeks’ gestation and included both spontaneous PTB (sPTB) and medically indicated PTB. Our secondary outcomes were PTB less than 34 weeks’ gestation, sPTB less than 37 weeks, preeclampsia/eclampsia, small for gestational age (SGA), stillbirth, Apgar less than 6 at 5 minutes, and cesarean delivery rate. SGA was defined as birthweight below the 10th percentile for gestational age using the CLAP standard. The birthweights for Peru are similar to those derived by CLAP. Stillbirth was defined as birth of a fetus 22 weeks or longer with no signs of life after birth.
Gestational age of delivery was determined by the last menstrual period or ultrasound and confirmed by physical examination. Those who did not have 2 forms of gestational age and those with incongruent data (for example, listed a gestational age of 24 weeks and birthweight of 4000 kg) were not included in the analysis (0.5% of cases) because of possible inaccuracies when sites input that data. Deliveries less than 23 weeks are not included in the database. Multiple gestations and women with fetal anomalies were excluded from the analysis.
Analysis occurred in 2 stages. First, we compared demographic and outcome data among the 3 groups. Next, we used bivariate comparisons to assess for potential confounders or risk factors for both the exposure, altitude, and the outcome, PTB. We included risk factors in our multivariable model that had an association at a significance level of P < .10. We then created our multivariable model and used a backward stepwise elimination strategy to obtain a parsimonious model.
Confounders retained in the model were those that had an impact on the effect size of greater than 15%. The confounders included in the final model were maternal age, parity, maternal weight, education, and type of hospital (health centers, community hospitals, and academic hospitals) and year (2000-2010). Clustering by hospital was accounted for in all analyses using generalized estimating equations to account for nonindependent data within each hospital.
Data analyses were performed using STATA 12.0 for Windows (STATA Corp, College Station, TX) logistic procedure including vce(cluster) option to estimate the robust variances. Statistical significance was set at P < .05. A post-hoc power analysis was performed, which showed greater than 80% power to detect an odds ratio of 1.16 for the association between altitude and PTB. To be conservative with this calculation, we assumed 1 year’s worth of data. A preterm birth rate of 5.6% in the low-altitude group was used and a ratio of 4:1 was used, given 4 times as many patients in the low altitude compared with high altitude. The actual power is greater than 80%, given 10 years of data.
Results
There were 569,667 patients in the database and 550,166 were included in our analysis. Of those, 68% (n = 371,402) resided at low altitude, 15% (n = 83,202) at moderate altitude, and 17% (n = 95,562) at high altitude ( Figure 1 ). The average number of patients per hospital was 11,960 and ranged from 440 to 55,775. Table 1 lists the maternal demographics for low, moderate, and high altitude. Maternal age, maternal weight, level of education, and type of hospital were significantly different among groups.
| Demographic | Low altitude (n = 371,402; 68%) (22 hospitals) | Moderate altitude (n = 83,202; 15%) (8 hospitals) | High altitude (n = 95,562; 17%) (13 hospitals) | P value a |
|---|---|---|---|---|
| Maternal age, y b | 25.3 (6.6) | 25.9 (6.8) | 25.7 (6.6) | .04 |
| Maternal age category, y | ||||
| <18 | 10 | 9 | 8 | .0002 |
| 18-34 | 79 | 78 | 80 | |
| ≥35 | 11 | 13 | 12 | |
| Parity b | 1.7 (1.4) | 1.9 (1.7) | 1.9 (1.7) | .09 |
| Prenatal care visits | ||||
| None | 20 | 21 | 21 | .71 |
| 1-5 | 32 | 35 | 36 | |
| >5 | 47 | 44 | 43 | |
| Marital status | ||||
| Married | 18 | 20 | 18 | |
| Living together | 67 | 61 | 65 | .13 |
| Single | 14 | 16 | 15 | |
| Other | 1 | 3 | 1 | |
| Education | ||||
| Primary | 17 | 24 | 18 | .02 |
| Secondary | 67 | 53 | 56 | |
| Advanced with university | 11 | 15 | 17 | |
| Technical school | 5 | 8 | 9 | |
| Maternal weight at delivery, kg b | 56.0 (9.6) | 55.4 (8.7) | 54.3 (7.9) | .03 |
| Type of labor | ||||
| Spontaneous | 81 | 82 | 85 | .14 |
| Induction | 4 | 3 | 3 | |
| Scheduled cesarean | 15 | 15 | 12 | |
| Level of hospital | ||||
| Community hospital | 9 | 7 | 11 | .002 |
| Health center | <1 | 1 | 2 | |
| Tertiary care referral hospital | 91 | 92 | 87 | |
| Gestational age of delivery, wks b | 38.8 (1.9) | 38.9 (2.1) | 38.7 (2.1) | .46 |
| Year | ||||
| 2000 | 79 | 10 | 11 | < .001 |
| 2001 | 72 | 14 | 15 | |
| 2002 | 77 | 10 | 13 | |
| 2003 | 76 | 11 | 13 | |
| 2004 | 71 | 15 | 14 | |
| 2005 | 65 | 18 | 18 | |
| 2006 | 66 | 13 | 21 | |
| 2007 | 64 | 15 | 21 | |
| 2008 | 58 | 21 | 22 | |
| 2009 | 61 | 18 | 21 | |
| 2010 | 74 | 17 | 9 | |
a Tests of significance were adjusted for clustering by hospital using generalized estimating equations
Table 2 displays the primary and secondary outcomes among the 3 altitudes. The overall PTB rate, our primary outcome, was 5.9% with no difference in the rate of PTB among the 3 altitudes (5.6%, 6.2%, and 6.8%, P = .13) ( Figure 2 ). Although there was no association between altitude and PTB, pairwise comparisons showed a modest elevated risk of PTB when comparing high altitude with low altitude (odds ratio [OR], 1.23; 95% confidence interval [CI], 1.01–1.50). The values for the odds ratios for the entire multivariable model, after adjusting for confounders, can be found in Table 3 . Similarly, there was no difference in the sPTB rate ( P = .10) or PTB rate less than 34 weeks’ gestation ( P = .14) among groups.
| Variable | Low altitude (n = 371,402; 68%) (22 hospitals) | Moderate altitude (n = 83,202; 15%) (8 hospitals) | High altitude (n = 95,562; 17%) (13 hospitals) | P value a |
|---|---|---|---|---|
| Overall PTB | 5.6 | 6.2 | 6.8 | .13 |
| Spontaneous PTB | 3.7 | 4.4 | 4.5 | .10 |
| PTB <34 wks | 2.8 | 3.4 | 3.6 | .14 |
| Preeclampsia | 4.6 | 2.8 | 2.9 | .09 |
| SGA | 3.3 | 3.6 | 5.0 | .02 |
| Birthweight, g b | 3218 (575) | 3159 (569) | 3041 (532) | < .001 |
| Stillbirth | 1.3 | 1.5 | 1.7 | .11 |
| Apgar <6 at 5 min | 0.8 | 1.1 | 1.3 | .004 |
| Cesarean delivery | 28.0 | 26.6 | 20.6 | < .001 |
a Tests of significance were adjusted for clustering by hospital using generalized estimating equations
| Variable | Preterm birth | Cesarean delivery | Small for gestational age |
|---|---|---|---|
| Low altitude | 1.00 | 1.00 | 1.00 |
| Moderate altitude | 1.06 [0.78–1.41] | 0.86 [0.69–1.08] | 1.01 [0.70–1.46] |
| High altitude | 1.21 [1.00–1.47] | 0.62 [0.47–0.81] a | 1.50 [1.16–1.95] a |
| Maternal age <18 y | 1.00 | 1.00 | 1.00 |
| Maternal age 18-34 y | 0.79 [0.74–0.84] a | 1.05 [1.00–1.10] a | 0.83 [0.75–0.91] a |
| Maternal age ≥35 y o | 1.01 [0.94–1.08] | 1.46 [1.33–1.59] a | 0.98 [0.89–1.08] |
| Community hospital | 1.00 | 1.00 | 1.00 |
| Health center | 1.44 [1.13–1.83] a | 2.54 [1.62–3.97] a | 0.81 [0.60–1.10] |
| Tertiary care referral hospital | 1.24 [1.00–1.54] a | 1.77 [1.26–2.49] a | 0.81 [0.59–1.12] |
| Primary education | 1.00 | 1.00 | 1.00 |
| Secondary education | 0.82 [0.77–0.88] a | 1.02 [0.94–1.12] | 0.80 [0.75–0.85] a |
| University | 0.80 [0.73–0.88] a | 1.27 [1.10–1.45] a | 0.69 [0.64–0.75] a |
| Technical school | 0.79 [0.73–0.85] a | 1.48 [1.28–1.71] a | 0.71 [0.65–0.77] a |
| Multiparous | 1.03 [0.97–1.08] | 0.78 [0.73–0.82] a | 1.00 [0.93–1.07] |
| Delivery year 2000 | 1.00 | 1.00 | 1.00 |
| Delivery year 2001 | 0.97 [0.88–1.07] | 0.96 [0.79–1.17] | 1.06 [0.89–1.23] |
| Delivery year 2002 | 1.02 [0.89–1.16] | 0.96 [0.75–1.12] | 1.10 [0.92–1.32] |
| Delivery year 2003 | 0.97 [0.85–1.11] | 0.93 [0.76–1.14] | 1.16 [0.94–1.44] |
| Delivery year 2004 | 1.05 [0.93–1.18] | 0.99 [0.82–1.19] | 1.11 [0.91–1.36] |
| Delivery year 2005 | 1.02 [0.90–1.16] | 1.08 [0.91–1.28] | 1.10 [0.89–1.33] |
| Delivery year 2006 | 1.04 [0.92–1.17] | 1.19 [1.00–1.41] a | 1.08 [0.88–1.32] |
| Delivery year 2007 | 0.99 [0.85–1.15] | 1.24 [1.03–1.47] a | 1.05 [0.87–1.26] |
| Delivery year 2008 | 1.04 [0.88–1.23] | 1.35 [1.15–1.59] a | 1.12 [0.91–1.36] |
| Delivery year 2009 | 1.02 [0.86–1.21] | 1.38 [1.15–1.65] a | 1.04 [0.84–1.28] |
| Delivery year 2010 | 1.10 [0.92–1.32] | 1.36 [1.04–1.76] a | 1.10 [0.83–1.44] |
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