|Year : 2023 | Volume
| Issue : 1 | Page : 10-15
Impact of medical conditions and medications received during pregnancy on adverse birth outcomes: A hospital-based prospective case–control study
Krishna Undela1, Parthasarathi Gurumurthy2, MS Sujatha3
1 Department of Pharmacy Practice, National Institute of Pharmaceutical Education and Research Guwahati, Kamrup, Assam; Department of Pharmacy Practice, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Mysuru, Karnataka, India
2 Department of Pharmacy Practice, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Mysuru, Karnataka, India; Pharmacovigilance and Clinical Trials, Botswana Medicines Regulatory Authority, Gaborone, Botswana
3 Department of Obstetrics and Gynaecology, JSS Medical College and Hospital, JSS Academy of Higher Education and Research, Mysuru, Karnataka, India
|Date of Submission||27-Jan-2021|
|Date of Decision||05-Mar-2021|
|Date of Acceptance||18-Mar-2021|
|Date of Web Publication||23-Oct-2021|
Director, Pharmacovigilance and Clinical Trials, Botswana Medicines Regulatory Authority, Gaborone, Botswana
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Purpose: In view of the raising rate of adverse birth outcomes (ABOs) across the globe, this study was conducted to assess the impact of medical conditions and medications received during pregnancy on ABOs.
Materials and Methods: A prospective case–control study was conducted at the Department of Obstetrics and Gynecology of a tertiary care hospital over a period of 3 years from July 2015 to June 2018. Liveborn and stillborn neonates included in the study were categorized into cases and controls based on the presence or absence of composite ABOs, respectively. Binary logistic regression analysis was used to identify the risk factors for ABOs among medical conditions and medications received by mothers during their current pregnancy.
Results: Among 1214 neonates included in the study, 556 (45.8%) were identified with composite ABOs, the majority were low birth weight (320 [26.4%]) and preterm birth 300 (24.7%). After adjusting for confounding factors, it was identified that hypertension (adjusted odds ratio [aOR] 7.3), oligohydramnios (aOR 3.9), anemia (aOR 3.2), nifedipine (aOR 10.0), nicardipine (aOR 5.3), and magnesium sulfate (aOR 5.3) were the risk factors for overall and specific ABOs like preterm birth and low birth weight. It was also identified that the early detection and management of hypertension with antihypertensives like labetalol and methyldopa can reduce the risk of preterm birth by 93% and 88%, respectively.
Conclusion: Medical conditions such as hypertension, oligohydramnios, and anemia and medications such as nifedipine, nicardipine, and magnesium sulfate during pregnancy were identified as the risk factors for overall and specific ABOs like preterm birth and low birth weight.
Keywords: Adverse birth outcomes, low birth weight, medical conditions, medications, pregnancy, preterm birth
|How to cite this article:|
Undela K, Gurumurthy P, Sujatha M S. Impact of medical conditions and medications received during pregnancy on adverse birth outcomes: A hospital-based prospective case–control study. Perspect Clin Res 2023;14:10-5
|How to cite this URL:|
Undela K, Gurumurthy P, Sujatha M S. Impact of medical conditions and medications received during pregnancy on adverse birth outcomes: A hospital-based prospective case–control study. Perspect Clin Res [serial online] 2023 [cited 2023 Mar 30];14:10-5. Available from: http://www.picronline.org/text.asp?2023/14/1/10/329044
| Introduction|| |
Adverse birth outcomes (ABOs) are described as any form of the unintended/undesired result of a pregnancy that can adversely affect the health of a newborn. The ABOs include miscarriage, stillbirth, preterm birth (before 37 weeks of gestation), low birth weight (<2500 g) or high birth weight (macrosomia >4000 g), small or large for gestational age (weight <10th or >90th percentile), congenital abnormalities, neurodevelopmental defects, and neonatal death. Preterm birth and low birth weight constitutes the highest rates of all ABOs, especially in developing countries, associated with increased infant morbidity and mortality.
Globally, about 15 million babies are born preterm in a year, which constitutes more than one in 10 babies. Above 60% of preterm births occurs in South Asia and Africa, India is in top place with 3,519,118 preterm births (23.6% of global preterm births). The United Nations Children's Fund (UNICEF) identified that nearly 22 million babies, an estimated 16% of all babies born globally, had low birth weight (28% in India). According to the WHO statistics, the frequency of low birth weight is 15.5% globally, and 96.5% of low birth weight neonates are born in developing countries. It was estimated that every fourth baby born in India has a low birth weight. Stillbirth rate has declined worldwide by 19.4% between 2000 and 2015. However, it remains higher in low- and middle-income countries with 98% of 2.6 million stillbirths in 2015 globally. Worldwide, an estimated 276,000 babies die every year from congenital abnormalities within 4 weeks of birth, which accounts for more than 20% of all neonatal deaths. In India, the prevalence of congenital abnormalities is estimated to be 231 per 10,000 births, and the majority were congenital heart defects (66 per 10,000 births) and neural tube defects (27 per 10,000 births).
Despite the recent advances in medicine, the rate of ABOs appears to be rising across the globe. A growing body of literature contends that ABOs are a result of harmful exposures. There are a vast array of risk factors such as the presence of chronic diseases/infectious diseases/genetic conditions, use of certain medications (e.g., isotretinoin, warfarin, anticonvulsants, etc.), alcohol and tobacco consumption, exposure to potentially infectious materials or toxic substances at work or home, overweight or obesity, and failure to receive adequate folic acid through multivitamins or diet and/or high-stress levels that can increase the odds of ABOs.
Even though there are studies conducted on various possible risk factors for the development of ABOs, there is a scantiness of information on ABOs due to medical conditions and medications received during pregnancy, especially in developing countries. Hence, a hospital-based prospective case–control study was conducted to identify the prevalence and impact of medical conditions and medications received during pregnancy on ABOs.
| Materials And Methods|| |
A prospective case–control study was conducted at the department of obstetrics and gynecology (OBG) of a South Indian tertiary care hospital over a period of 3 years from July 2015 to June 2018. The study protocol was reviewed and approved by the Institutional Human Ethics Committee during the meeting held on April 29, 2015.
Records of all deliveries taken place at the department of OBG were reviewed on a daily basis and included liveborn or stillborn babies in the study after obtaining informed consent from the parent/guardian. Demographic details, vital parameters, and details of physical surface examination of all included babies were collected from the medical records and/or interview of parents/guardians. Neonatologists were contacted as and when required for complete information on medical conditions of neonates and their management. The data collected regarding neonates was documented in a data collection form designed based on the WHO's pregnancy outcome data-sheet. Neonates with insufficient postnatal information were excluded from the study.
All included neonates were categorized into cases and controls based on the presence or absence of composite ABOs, respectively. A composite ABOs was defined as any one of the birth outcomes such as stillbirth, preterm birth, low birth weight or macrosomia, congenital abnormalities by physical surface examination, or neonatal death. Neonates with any of the complications of ABOs such as respiratory distress syndrome, respiratory retractions, or birth asphyxia were also considered as cases.
Irrespective of presence or absence of ABOs among neonates, mothers of all included neonates were enrolled in the study. Sociodemographic details, obstetric history, medical conditions, and medications received during current and previous pregnancies (if any) of mothers were collected by reviewing antenatal case records and/or interview of women/guardians. The data collected regarding mothers were documented in a data collection form designed based on the WHO's antenatal data-sheet cum questionnaire. Mothers and their neonates were excluded from the study when it was a multiple birth and/or lack of sufficient antenatal information of mothers.
Continuous variables were represented as mean with a standard deviation (SD) and categorical variables as the number with a percentage (%). An independent sample t-test and Chi-square or Fisher's exact test were used to identify the significance in differences between continuous and categorical variables, respectively. Binary logistic regression analysis was used to identify the independent risk factors for ABOs among medical conditions and medications received by mothers during the current pregnancy, after adjusting for cofounding variables such as sociodemographic characteristics, other medical conditions, and medications received. The strength of association between the risk factors and ABOs was ascertained by calculating odds ratio along with 95% confidence interval (CI). For all analyses, a probability value of <0.05 was considered statistically significant. All the statistical analyses were carried out using Statistical Package for Social Sciences (IBM Corp. Released 2012. IBM SPSS Statistics for Windows, Version 21.0. IBM Corp, Armonk, NY). The study was conducted as per the Strengthening the Reporting of Observational Studies in Epidemiology guidelines.
| Results|| |
A total of 1214 neonates comprising 630 (51.9%) boys were included in the study. Among the neonates included, 1204 (99.2%) were liveborn, six (0.5%) were stillborn, and four (0.3%) were dead. About 556 (45.8%) neonates were identified with composite ABOs, 320 (26.4%) were born low birth weight, 300 (24.7%) were born preterm, and 12 (1.0%) were macrosomic. Fifty-four (4.5%) neonates were identified with some form of congenital abnormalities. Majority of these abnormalities were related to hips and genitalia (18, 1.5%), followed by head and neck (16, 1.3%) and skin (12, 1.0%). Respiratory distress syndrome, respiratory retractions, and birth asphyxia were observed in 50 (4.1%), 24 (2.0%), and 14 (1.2%) neonates, respectively, as complications of ABOs. Mothers of all 1214 neonates were enrolled in the study. The mean (SD) age of mothers was 24.20 (4.2) years and the majority (51.2%) were in the age group of 19–23 years.
The prevalence of medical conditions among mothers during their current pregnancy was 50.25% and it was significantly higher among mothers of neonates with ABOs (WABOs) (65.5%) compared to mothers of neonates without ABOs (WoABOs) (37.4%). Anemia (37.9%) was the most prevalent medical condition, followed by hypertension (12.0%, including 142 (11.7%) mothers with gestational hypertension and four (0.3%) mothers with chronic hypertension), hypothyroidism (8.2%), and diabetes mellitus (7.7%, including 92 (7.6%) mothers with gestational diabetes mellitus and two (0.2%) mothers with type 2 diabetes mellitus) [Table 1].
The prevalence of medication use among mothers during their current pregnancy was 25.2% (other than regular supplements/medications during pregnancy), and it was significantly higher among mothers of neonates WABOs (34.2%) compared to mothers of neonates WoABOs (17.6%). Levothyroxine (7.6%), nifedipine (5.9%), labetalol (4.9%) and magnesium sulfate (3.6%) were the most common medications received by mothers for the management of medical conditions during their current pregnancy such as hypothyroidism, hypertension/pre-eclampsia, and as tocolytic agents [Table 2].
After adjusting for sociodemographic and obstetric characteristics and other medical conditions and medications received during the current pregnancy, the risk of giving birth to neonates WABOs was 6.3 times more when mothers had hypertension (adjusted odds ratio [aOR]: 7.3, 95% CI: 1.7–31.9; P = 0.008), 2.9 times more when mothers had oligohydramnios (aOR: 3.9, 95% CI: 1.2–20.6; P = 0.011), and 2.2 times more when mothers had anemia (aOR 3.2, 95% CI 1.1–8.7; P = 0.001) during their current pregnancy, compared to mothers without these conditions [Table 3].
|Table 3: Impact of medical conditions during pregnancy on adverse birth outcomes|
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After adjusting for sociodemographic and obstetric characteristics and medical conditions and other medications received during the current pregnancy, the risk of giving birth to neonates WABOs was 9.0 times more when mothers received nifedipine (aOR: 10.0, 95% CI: 2.9–21.9; P < 0.001), 4.3 times more when mothers received nicardipine (aOR: 5.3, 95% CI: 1.4–24.2; P = 0.026), and 4.3 times more when mothers received magnesium sulfate (aOR: 5.3, 95% CI: 1.9–11.7; P = 0.001) during their current pregnancy, compared to mothers who did not receive these medications [Table 4].
|Table 4: Impact of medications received during pregnancy on adverse birth outcomes|
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Upon subgroup analysis pertaining to the risk of preterm birth and low birth weight, it was identified that the risk of preterm birth was more when mothers had hypertension (aOR: 17.1, 95% CI: 4.1–72.2; P < 0.001), and the risk of low birth weight was more when mothers had hypertension (aOR: 8.9, 95% CI: 2.1–37.6; P = 0.003), oligohydramnios (aOR 4.7, 95% CI: 1.0–21.0; P = 0.046), and diabetes mellitus (aOR: 3.2, 95% CI: 1.2–8.5; P = 0.019), and when mothers received betamethasone (aOR: 11.6, 95% CI: 1.6–85.0; P = 0.016) and nifedipine (aOR: 8.8, 95% CI: 1.1–72.1; P = 0.044) during the current pregnancy. On the other side, the risk of preterm birth was 93% and 88% lower when mothers received labetalol (aOR: 0.1, 95% CI: 0.0–0.5; P = 0.008) and methyldopa (aOR: 0.1, 95% CI: 0.0–1.0; P = 0.049), respectively, during the current pregnancy, compared to mothers did not receive these medications.
| Discussion|| |
To the best of our knowledge, this is the first Indian data on the impact of overall medical conditions and medications received during pregnancy on ABOs. A total of 1214 neonates and their mothers were included in the study over a period of 3 years. More than 99% of neonates included in the study were liveborn, and the rate of stillbirth (0.5%) was half of the estimated stillbirth rate in India (1.0%, i.e., 10 per 1000 births). Around half of the neonates (45.8%) included in the study were identified with composite ABOs such as stillbirth, preterm birth, low birth weight or macrosomia, small or large for gestational age, congenital abnormalities, and neonatal death.
Low birth weight and preterm birth were the two most common ABOs observed in our study, followed by congenital abnormalities. The rate of low birth weight in our study (26.4%) was similar to an estimated 28% in India by UNICEF, and the rate of preterm birth (24.7%) was higher than the reported 13% in India in 2010. The rate of congenital abnormalities observed in our study through physical surface examination was marginally higher (4.5%) than the previously reported 2.3% in India. The rate of macrosomia observed in our study (1.0%) was similar to the rate identified in a study conducted at 23 rural subcenters of Haryana state, India (1.3%). Other conditions such as respiratory distress syndrome (4.1%), respiratory retractions (2.0%), and birth asphyxia (1.2%) were observed as respiratory complications of preterm birth and low birth weight.
After adjusting for confounding factors, hypertension during pregnancy was identified as the important risk factor for overall ABOs, and also specifically for preterm birth and low birth weight. It was proved globally that hypertensive disorders in pregnancy can lead to ABOs like preterm birth and low birth weight. A recent study conducted in the USA identified that women with gestational hypertension or chronic hypertension had 3.4–11.6 times more risk of preterm birth compared to nonhypertensive women. Hypertension during pregnancy leads to preterm birth and low birth weight by decreasing blood supply to the placenta, thereby less oxygen and food supply to the fetus. As it was identified in our study, early detection and management of hypertension with labetalol or methyldopa can reduce the risk of ABOs like preterm birth and its complications.,
Oligohydramnios was identified as another important risk factor for ABOs, and specifically for low birth weight. Research conducted in international settings proved that oligohydramnios can increase the risk of spontaneous preterm delivery. We have also identified that anemia during pregnancy increases the risk of ABOs like preterm birth and low birth weight. A recently conducted systematic review and meta-analysis including 18 studies and 0.93 million pregnant women revealed that anemia during pregnancy increases the risk of preterm birth by 56% (relative risk [RR]: 1.6 [95% CI: 1.3–2.0]). Another systematic review conducted to determine the relationship between anemia during pregnancy and low birth weight revealed that maternal anemia, especially during the first trimester of pregnancy, can increase the risk of low birth weight by 26% (RR: 1.3, 95% CI: 1.0–1.6). Based on the subgroup analysis, we have identified that gestational diabetes mellitus leads to a twofold increase in the risk of low birth weight, which is similar to the study conducted in Italy.
Among the medications received by pregnant women, magnesium sulfate, nifedipine, and nicardipine were identified as reasons for ABOs. Specifically, betamethasone and nifedipine were identified as reasons for low birth weight. A prospective observational study conducted by the European Network of Teratology Information Services identified that the birth weight of neonates was significantly lower when mothers exposed to calcium channel blockers during the first trimester (study group) compared to mothers not exposed to potential teratogens (control group). The authors also identified more preterm births in the study group compared to the control group (23.8% vs. 6.5%). However, the authors contend that these ABOs are more likely due to the underlying medical conditions than to the medication.
The strength of the current study was recruiting more than 1200 neonates and their mothers over a period of 3 years in a nondatabase setting and gathering necessary information from the case records of neonates and their mothers. However, our study has some limitations. We could not assess the effect of duration and time (trimester) of exposure to medical conditions and medications during pregnancy, and effect of control measures of medical conditions on ABOs due to lack of information from all mothers recruited in the study. The medical conditions during pregnancy could have influenced the association identified between medications received during pregnancy and ABOs, as these medications are given for the management of medical conditions. Although we have adjusted for all medical conditions during the current pregnancy, confounding by indication bias cannot be ruled out completely on the association between the use of magnesium sulfate, nifedipine, nicardipine, and betamethasone on ABOs like preterm birth and low birth weight as these medications given to the pregnant women with threatened preterm delivery.
| Conclusion|| |
Medical conditions such as hypertension, oligohydramnios, and anemia and medications such as nifedipine, nicardipine, and magnesium sulfate during pregnancy were identified as the risk factors for overall and specific ABOs like preterm birth and low birth weight. It was also identified that the early detection and management of hypertension with antihypertensives like labetalol and methyldopa can reduce the risk of ABOs.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Weng YH, Yang CY, Chiu YW. Risk assessment of adverse birth outcomes in relation to maternal age. PLoS One 2014;9:e114843.
Ra A, Tb E. Prevalence and associated factors of adverse birth outcomes among women attended maternity ward at negest elene mohammed memorial general hospital in Hosanna Town, SNNPR, Ethiopia. J Womens Health Care 2016;5:1-5.
Liu L, Oza S, Hogan D, Chu Y, Perin J, Zhu J, et al
. Global, regional, and national causes of under-5 mortality in 2000-15: An updated systematic analysis with implications for the Sustainable Development Goals. Lancet 2016;388:3027-35.
Blencowe H, Cousens S, Oestergaard MZ, Chou D, Moller AB, Narwal R, et al
. National, regional, and worldwide estimates of preterm birth rates in the year 2010 with time trends since 1990 for selected countries: A systematic analysis and implications. Lancet 2012;379:2162-72.
Wataganara T, Grunebaum A, Chervenak F, Wielgos M. Delivery modes in case of fetal malformations. J Perinat Med 2017;45:273-9.
Bhide P, Gund P, Kar A. Prevalence of congenital anomalies in an Indian maternal cohort: healthcare, prevention, and surveillance implications. PLoS One 2016;11:e0166408.
Mehta U, Clerk C, Allen E, Yore M, Sevene E, Singlovic J, et al
. Protocol for a drugs exposure pregnancy registry for implementation in resource-limited settings. BMC Pregnancy Childbirth 2012;12:89.
Altijani N, Carson C, Choudhury SS, Rani A, Sarma UC, Knight M, et al
. Stillbirth among women in nine states in India: Rate and risk factors in study of 886,505 women from the annual health survey. BMJ Open 2018;8:e022583.
Malik M, Khanna P, Verma R. The association of maternal risk factors to macrosomia in rural areas of Haryana, India: A community based study. Int J Community Med Public Health 2018;5:3842.
Premkumar A, Baer RJ, Jelliffe-Pawlowski LL, Norton ME. Hypertensive disorders of pregnancy and preterm birth rates among black women. Am J Perinatol 2019;36:148-54.
Ray JG, Vermeulen MJ, Burrows EA, Burrows RF. Use of antihypertensive medications in pregnancy and the risk of adverse perinatal outcomes: McMaster Outcome Study of Hypertension In Pregnancy 2 (MOS HIP 2). BMC Pregnancy Childbirth 2001;1:6.
National Collaborating Centre for Women's and Children's Health (UK). Hypertension in Pregnancy: The Management of Hypertensive Disorders during Pregnancy. Available from: https://www.ncbi.nlm.nih.gov/books/NBK62654/
. [Last accessed on 2021 Jan 27].
Park JS, Yoon BH, Romero R, Moon JB, Oh SY, Kim JC, et al
. The relationship between oligohydramnios and the onset of preterm labor in preterm premature rupture of membranes. Am J Obstet Gynecol 2001;184:459-62.
Rahmati S, Azami M, Badfar G, Parizad N, Sayehmiri K. The relationship between maternal anemia during pregnancy with preterm birth: A systematic review and meta-analysis. J Matern Fetal Neonatal Med 2020;33:2679-89.
Rahmati S, Delpishe A, Azami M, Hafezi Ahmadi MR, Sayehmiri K. Maternal Anemia during pregnancy and infant low birth weight: A systematic review and Meta-analysis. Int J Reprod Biomed 2017;15:125-34.
Seghieri G, Anichini R, De Bellis A, Alviggi L, Franconi F, Breschi MC. Relationship between gestational diabetes mellitus and low maternal birth weight. Diabetes Care 2002;25:1761-5.
Weber-Schoendorfer C, Hannemann D, Meister R, Eléfant E, Cuppers-Maarschalkerweerd B, Arnon J, et al
. The safety of calcium channel blockers during pregnancy: A prospective, multicenter, observational study. Reprod Toxicol 2008;26:24-30.
[Table 1], [Table 2], [Table 3], [Table 4]