Fetal Growth Outcomes in a Cohort of Polydrug- and Opioid-Dependent Patients

Abstract

Objectives

To evaluate the effects of prenatal polydrug and exclusive opioid use on fetal growth outcomes.

Methods

This analysis relied on the data obtained from two prospective cohorts at the University of New Mexico. For both cohorts, pregnant women were recruited during one of their prenatal care visits and followed up to delivery. The merged sample included 59 polydrug users, 22 exclusive opioid users, and 278 abstinent controls. Continuous growth measures (birth weight, height, occipital frontal circumference [OFC], and corresponding sex-specific percentiles) were compared by ANOVA and ANCOVA in bivariate and multivariable analyses, respectively. Categorical outcomes (prevalence of small-for-gestational age [SGA] for weight, length, and OFC) were compared among groups by Chi-square and multivariable logistic regression analyses..

Results

The sample included a large proportion of ethnic minorities (78.8% Hispanic) and patients with low educational attainment (68% ≤ high school). The risk of microcephaly (OFC<10^th percentile) was significantly greater in the polydrug (OR=4.7; 95% CI: 2.0; 10.8) and exclusive opioid (OR=2.8; 95% CI: 1.0; 8.1) groups compared to abstinent controls.

Conclusion

Given that microcephaly is often associated with serious neurocognitive and behavioral deficits later in life, our finding of 49.2% incidence of microcephaly among polydrug users is alarming and requires further investigation.

Introduction

Substance misuse during pregnancy has been recognized as a risk factor for multiple adverse birth outcomes, including intrauterine growth restriction (IUGR), preterm delivery, birth defects, and neurobehavioral and neuropsychological dysfunction with potential long-term effects on exposed children.^1–7 In the United States, unplanned pregnancies are a significant public health concern among populations who are also at high risk for substance misuse.⁸ In 2010–2011, the prevalence of substance use during pregnancy was estimated to be 20.9% among 15–17 year olds, 8.2% among 18–25 year olds, and 2.2% in 26–44 year old pregnant women.⁹ In 2008–2009, pregnant women between the ages of 15 and 17 had similar rates of illicit drug use (15.8%) as women of the same age who were not pregnant (13%).¹⁰

Unplanned pregnancy rates may be especially high among women who use opioids, thus increasing the risk for teratogenic exposure.¹¹ For opioid-dependent patients, opioid maintenance therapy (OMT) is a harm reduction strategy in clinical care that is associated with improved fetal and maternal outcomes. Currently, OMT is considered the ‘gold standard’ for managing opioid dependence among pregnant women. OMT is associated with improved prenatal care, decreased risk of maternal criminal involvement, and a more stable postnatal environment.^12–14 However, maternal opioid dependence and gestational use of OMT have also been associated with an increased risk for gestational polydrug use.^15,16

Polydrug use constitutes a disorder in which an individual uses more than one type of drug at the same time or sequentially. Polydrug use, as compared to single-substance use, has been associated with increased health and safety risks to the user, such as a greater number of traffic accidents, higher levels of psychomotor impairment, increase in toxicity, and greater mortality rates from overdose.^17–20 In 2009, the majority of emergency department visits that involved cocaine, marijuana, or heroin use were associated with polydrug use (68%, 73%, and 52%, respectively).²¹ Polydrug use is common among women with substance dependence problems, including those who receive OMT.²² Yet, there is a paucity of studies examining the contributing effects of polydrug use among pregnant OMT patients on perinatal outcomes.^23,24 The primary objective of this study was to compare fetal growth outcomes among women who used two or more classes of illicit drugs during pregnancy to those who exclusively used opioids and those who abstained from all drug use. We also consider the possible role that a high presence of concurrent OMT use in our polydrug group may have had on mediating severe growth restriction outcomes for this group.

Methods

Study design and population

This analysis relied on data obtained from 359 mother-infant dyads enrolled in two University of New Mexico (UNM) prospective studies, called the “Biomarkers in Pregnancy Study” (BIPS), and “Safety of Medications during Pregnancy and Women's Perception of Teratogenicity” (SMART). Patients for both studies were recruited by the same UNM faculty and from UNM-affiliated prenatal care clinics in Albuquerque, NM. For the purpose of this analysis, enrolled mother-infant pairs were assigned to one of three study groups based on their substance use/nonuse behaviors throughout pregnancy: 1) polydrug users; 2) exclusive opioid users; and 3) abstinent controls. Both parent studies were approved by the UNM Human Research Review Committee (HRRC) and informed consent was obtained from all participants. The detailed methodologies of both studies have been described elsewhere.^25–27

In brief, BIPS was conducted in 2011–2013 to assess the validity of ethanol biomarkers among pregnant women and newborn children for identification of prenatal alcohol exposure. Patients attending a UNM specialized prenatal care clinic for women with current or past substance use history were enrolled during one of their prenatal visits and were followed up to delivery. The majority of these patients had opioid dependency and received OMT. To be eligible for BIPS, women had to be able to give consent in either English or Spanish, be at least 18-years old, have an ultrasound-confirmed singleton pregnancy, and be less than 35 weeks’ gestational age at the time of enrollment. A structured interview was administered, first, at the time of enrollment, and second, during the hospital stay following delivery. Patients were asked to report on their use of major classes of illicit drugs, such as cocaine, marijuana, heroin, prescription opioids, MDMA (4-methylenedioxymethamphetamine, or “ecstasy”), benzodiazepines, and amphetamines specifically during the periconceptional period and throughout their pregnancy up to the time of delivery. Alcohol and nicotine use behaviors were similarly ascertained during the interviews.

Out of 103 pregnant women recruited into BIPS, 13 were lost to follow-up or had a pregnancy loss; an additional 3 were missing fetal growth measures from their medical records; and 6 others did not meet criteria for either polydrug or exclusive opioid use (e.g., had single-substance use of a non-opioid). For these reasons, 22 BIPS participants were excluded from the current analysis. The 81 participants included were classified as either polydrug users (n=59) or exclusive opioid users (n=22). Exclusive opioid users were patients on OMT whose substance use during pregnancy may or may not have included other opioids (i.e., heroin, opioid analgesics), but excluded all other classes of illicit drugs. The polydrug group was comprised of patients who used two or more classes of illicit drugs at any time during pregnancy, such as opioids/OMT, cocaine, marijuana, amphetamines, MDMA, and benzodiazepines.

Overall, 404 patients were recruited for the SMART study. For purposes of the current analyses, this sample was restricted to SMART study patients who had complete sets of data for both fetal growth measurements and substance use variables, and who also reported abstinence from any drug use (including OMT) during pregnancy (n=278). The primary objective of the parent SMART study, conducted during 2007–2011 at UNM, was to evaluate patients’ knowledge of and attitudes towards medication use in pregnancy, the sources of information about medication safety, and key barriers to effective patient-provider communication regarding gestational medication use.²⁵ Pregnant women who were ≥18 years old and had no prenatal diagnosis indicating an abnormal pregnancy were recruited from the UNM main hospital and its five satellite clinics throughout the city of Albuquerque. In addition to the use of medications, patients were asked to report on their substance use during pregnancy.

Data collection

Demographic and lifestyle characteristics

Maternal demographic and reproductive health characteristics, such as maternal age, gestational age at enrollment, race, ethnicity, education level, gravidity, parity, and complications during pregnancy were ascertained in both studies during the enrollment interviews, which were then verified by a review of medical records. Maternal lifestyle characteristics assessed in this analysis included maternal smoking status and alcohol consumption patterns. In both studies, episodes of binge drinking were measured for the periconceptional period (two weeks prior to and two weeks following the first date of last menstrual period [LMP]). In the periconceptional period, one binge drinking episode consisted of consuming ≥ 4 drinks per occasion. Studies have demonstrated that periconceptional binge drinking data is an effective predictor of continued drinking later in pregnancy.^28,29

Fetal growth outcome measures

Birth outcomes examined in this analysis included mean absolute and percentile anthropometric measures (birth weight, length and occipital frontal circumference [OFC]), and proportion of infants small-for-gestational-age (SGA) for weight, length, and OFC across the three study groups. Birth growth measures and gestational age at delivery were abstracted from the electronic medical records of study participants. For each growth measure, sex-specific percentiles for full-term infants were estimated using the 2000 Centers of Disease Control and Prevention (CDC) growth charts for the U.S.³⁰ Infants who scored lower than the 10th percentile were classified as SGA for each growth measure. While narrower criteria for diagnosing microcephaly (e.g., OFC <3^rd percentile) is favored in many clinical settings, OFC <10^th percentile remains a widely-used standard for detecting neurocognitive deficit risks associated with small head size by epidemiologists,³¹ and is thus used for this analysis. Finally, in addition to assessing each growth measure individually, we also ascertained symmetrical versus asymmetrical growth deficiency, where asymmetrical growth deficiency was defined as microcephaly (head circumference <10^th percentile) in the presence of normal-for-gestational age weight and length.

Statistical Analyses

Descriptive statistics (means, frequencies) were estimated for the study population. Maternal socio-demographic and lifestyle characteristics were compared across the three study groups using Chi-square and one-way analysis of variance for categorical and continuous variables, respectively. Categorical outcome measures, including the proportion of infants SGA for each growth measure, were compared among the study groups by a Chi-square test. Mean absolute and percentile growth measures were first compared in a bivariate analysis using ANOVA. In the multivariable analysis, analysis of covariance (ANCOVA) was used to compare the growth outcomes across the three groups after adjusting for maternal age, smoking status, binge drinking episodes, and education level. If an overall test comparing the three study groups was statistically significant (p<0.05), pairwise comparisons were conducted between the groups. For binary outcomes (i.e., SGA for each growth measure), multiple logistic regression analysis was conducted to adjust for the same covariates. All analyses were conducted in SAS version 9.3 for Windows (SAS Institute, Cary, NC).

Results

Maternal socio-demographic and lifestyle characteristics are presented in Table I. The mean maternal age of the study population was 27.4±5.8 years and included a large proportion of Hispanic/Latina women (78.8%) and women with high school or lower education level (68%). There were no significant differences in maternal age, gravidity, and binge drinking in the periconceptional period across the three groups (all p-values >0.05). However, the percentage of current smokers was significantly higher in the exclusive opioid (54.6%) and polydrug (66.1%) groups compared to the abstinent control group (2.5%; p<0.01). Moreover, gestational age at enrollment was significantly different for exclusive opioid and polydrug use groups compared to abstinent controls (p<0.01).

Table I.

Description of the study sample (N=359)

Maternal characteristics	Exclusive opioid users (n=22)	Polydrug users (n=59)	Abstinent controls (n=278)	Overall p-value
	Mean±s.d.	Mean±s.d.	Mean±s.d.
Maternal age (years)	27.0±4.8	25.9±4.9	27.7±6.0	0.10
Gestational age at enrollment (weeks)	22.7± 9.5†	21.0±7.5†	31.4± 7.6	<0.01
	%	%	%
Alcohol use: binge drinking around LMP	31.8	39.0	29.9	0.39
Ethnicity: Hispanic	77.3	81.4	78.4	0.87
Race: White	86.4	88.1	71.9	0.02
Education:				0.02
Less than high school	50.0	54.2	33.5
High school or GED	31.8	22.0	33.7
College, vocational or higher	18.2	23.7	34.9
Primigravida	13.6	17.0	22.3	0.45
Any tobacco use in pregnancy	54.6	66.1	2.5	<0.01

LMP, last menstrual period.

^†p<0.05 for pairwise comparisons using abstinent controls as a reference group

Table II presents the prevalence of drug classes for the exclusive opioid and polydrug groups. Among exclusive opioid participants, methadone (68.2%), heroin (59.1%), and buprenorphine (36.4%) were the most prevalent. Among polydrug users, marijuana (69.5%) and cocaine (45.8%) were the most prevalent non-opioid drugs of abuse, followed by benzodiazepines (33.9%), amphetamines (27.1%), and MDMA (3.4%). Additionally, use of methadone (72.9%) and buprenorphine (25.4%), heroin (57.6%), and prescription opioids (40.7%) were highly prevalent in the polydrug group.

Table II.

Prevalence of substance use among the Exclusive Opioid and Polydrug Groups

Drug class	Exclusive opioid users (n=22) (%)	Polydrug users (n=59) (%)
Methadone	68.2	72.9
Buprenorphine	36.4	25.4
Heroin	59.1	57.6
Prescription opioids	31.8	40.7
Marijuana	--	69.5
Crack/Cocaine	--	45.8
Benzodiazepines	--	33.9
Amphetamines	--	27.1
MDMA (ecstasy)	--	3.4

As shown in Table III, in the bivariate analysis of mean absolute and percentile growth measures, all differences were statistically significant among the three study groups (all p<0.05). Pairwise comparisons revealed that both the exclusive opioid and polydrug groups had significantly lower mean absolute and percentile weight and length measures compared to abstinent controls. While mean OFC percentiles were significantly lower among both exclusive opioid and polydrug groups compared to abstinent controls (p<0.05), absolute OFC was significantly lower only for the polydrug group in bivariate analyses. No significant differences were observed between exclusive opioid and polydrug participants in the pairwise comparisons (all p >0.05). In the multivariable analyses, after adjusting for maternal age, tobacco use, binge drinking around LMP, and maternal education level, the overall significant differences among the three study groups persisted for all three mean percentile growth measures. In the adjusted analyses, only the polydrug participants had significantly lower absolute OFC measures compared to abstinent controls. The mean gestational age at delivery was not significantly different across the three groups in either bivariate or multivariable analyses (p >0.05).

Table III.

Newborn Outcomes by Study Group (n=359)

Outcome variables		Exclusive opioid users (n=22)	Polydrug users (n=59)	Abstinent controls (n=278)	p value
		Birth weight
Weight (grams)	unadjusted	2925.2±313.0‡	2868.2±347.3‡	3302.7±420.7	<0.01
	adjusted§	2895.7±105.8‡	2873.5±78.3‡	3222.6±69.7	<0.01
Weight percentile	unadjusted	18.9±15.4†	19.1±19.8‡	40.3±24.8	<0.01
	adjusted§	17.8±6.0‡	19.2±4.4‡	36.7±3.9	<0.01
SGA for weight (<10th percentile)		36.4%	37.3%	10.4%	<0.01
		Birth length
Length (cm)	unadjusted	47.8±3.6†	48.2±2.8‡	49.9±3.7	<0.01
	adjusted§	47.7±0.9‡	48.3±0.7‡	49.7±0.6	<0.01
Length percentile	unadjusted	29.5±23.8‡	34.1±24.9‡	56.4±27.8	<0.01
	adjusted§	26.4±6.9‡	31.8±5.1‡	53.1±4.5	<0.01
SGA for length (<10th percentile)		27.3%	17.0%	8.3%	<0.01
		Head circumference
OFC (cm)	unadjusted	34.0±3.7	33.4±2.5†	34.8±3.6	0.03
	adjusted§	33.5±0.9	32.9±0.7†	34.6±0.6	0.03
OFC percentile	unadjusted	21.1±25.4‡	19.0±21.9‡	38.5±27.0	<0.01
	adjusted§	17.2±6.6‡	14.9±4.9‡	36.4±4.3	<0.01
SGA for OFC (<10th percentile)		36.4%	49.2%	15.8%	<0.01
		Gestational age at delivery
Gestational age at delivery	unadjusted	38.6±1.7	38.4±2.5	38.6±1.7	0.69
	adjusted§	38.6±0.4	38.5±0.2	38.2± 0.2	0.64

SGA, small for gestational age (<10^th percentile)

OFC, occipital-frontal circumference.

^†p<0.05;

^‡p<0.01 for pairwise comparisons using the abstinent control group as a reference

^§Adjusted for maternal age, tobacco use, binge drinking around LMP, and education level.

There were significant differences among groups with respect to the incidence of SGA for weight, height, and OFC (all p<0.01). The proportion of infants with microcephaly (OFC <10^th percentile) was much higher in the polydrug group (49.2%) compared to the exclusive opioid (36.4%) and abstinent control groups (15.8%; overall p<0.01). After adjusting for maternal age, smoking, education, and binge drinking around LMP, the exclusive opioid (OR=3.9: 95% CI: 1.3; 11.9) and polydrug group (OR=3.7; 95% CI: 1.4; 9.4) participants had significantly higher odds of having infants SGA for weight compared to abstinent controls (Table IV). While the odds of microcephaly (OFC <10^th percentile) was slightly higher among the exclusive opioid group (OR=2.8; 95% CI: 1.0; 8.1) compared to the abstinent control group, polydrug group participants had almost 5-fold (OR=4.7; 95% CI: 2.0; 10.8) higher odds of having an infant with microcephaly compared to abstinent controls after adjusting for maternal education, smoking, and alcohol use.

Table IV.

Predictors of SGA for Birth Weight, Length, and OFC

Predictors	SGA for weight		SGA for length		SGA for OFC
	OR§	95% CI	OR§	95% CI	OR§	95% CI
Drug use:
Abstinent controls	1.0	--	1.0	--	1.0	--
Exclusive opioid users	3.9	1.3; 11.9	2.4	0.7; 8.5	2.8	1.0; 8.1
Polydrug users	3.7	1.4; 9.4	1.2	0.4; 3.8	4.7	2.0; 10.8
Maternal age (years)	1.0	1.0; 1.1	1.0	1.0; 1.1	1.0	1.0; 1.1
Smoking status:
Non-smokers	1.0	--	1.0	--	1.0	--
Any smoking in pregnancy	2.3	0.9; 5.7	2.8	0.9; 8.3	1.2	0.5; 2.3
Maternal education:
Less than high school	1.0	--	1.0	--	1.0	--
High school of GED	1.5	0.7; 3.3	1.0	0.4; 2.3	0.6	0.3; 1.1
Vocational, college of higher	2.4	1.1; 5.0	1.0	0.4; 2.4	0.9	0.5; 1.7
Alcohol use around LMP‡
No	1.0	--	1.0	--	1.0	--
Yes	0.8	0.4; 1.5	1.0	0.5; 2.0	0.8	0.5; 1.5

SGA, small for gestational age (<10^th percentile)

OFC, occipital-frontal circumference

LMP, last menstrual period

^§All ORs are adjusted for all variables in the table

^‡At least one binge drinking episode (≥4 drinks/occasion) a month around LMP

Finally, both exclusive opioid and polydrug groups had very similar prevalence of asymmetrical growth deficiency, wherein microcephaly (OFC<10^th percentile) was present in conjunction with normal for gestational age weight and length (>10^th percentile). However, the prevalence of isolated microcephaly with normal weight and height in these two groups (22.7% and 22.0%, respectively) was twice as high compared to abstinent controls (10.1%; p=0.02).

Discussion

This study demonstrated significant differences in mean absolute and percentile birth weight and length across the three study groups. In pairwise comparison, both the exclusive opioid and polydrug groups demonstrated lower growth measures for absolute and percentile weight and length, as well as percentile OFC, when compared to the abstinent control group. However, for absolute OFC, no significant differences were found between exclusive opioid participants and abstinent controls; only the polydrug group demonstrated significantly lower absolute OFC measures. Strikingly, polydrug group participants were almost 5-times more likely to have an infant with microcephaly compared to abstinent controls, even after controlling for other risk factors.

Microcephaly has a heterogeneous etiology and might stem from an array of genetic disorders and in utero environmental exposures. While some prior studies suggest that prenatal exposure to opioids, in particular, may result in lower infant and child head circumference measurements,^32–34 others indicate that restricted growth measurements, including microcephaly, may be more strongly associated with polysubstance exposure, and particularly correlated to the number of different exposures.^16,35 It should be noted that, while microcephaly is an important measure of brain volume, it is only a symptom, rather than a clinical diagnosis by itself. Microcephaly is often associated with serious neurocognitive and behavioral deficits later in life, such as lower IQ, impaired executive function, and emotional dysregulation in some children.^36,37 As such, a very high prevalence of microcephaly among the polydrug group in our study is alarming due to potential neurocognitive deficits in children born to this population.

Our finding that prenatal drug exposure is associated with growth impairment is consistent with the previous literature. Studies have reported decreased birth weight, height, and head circumference among infants exposed to illicit drugs prenatally.^7,32,38–43 However, to the best of our knowledge, our finding that microcephaly was significantly more prevalent among polydrug users, the majority of whom received OMT and/or concurrently used opioids, has not previously been described in comparison to exclusive opioid users from the same cohort. Our finding strengthens what prior studies have suggested regarding possible correlation between reduced fetal growth measurements and multiple drug exposures in utero.^16,35

The few existing studies that have examined differences in fetal growth and development between pregnant women with polysubstance use, single-substance use, and no substance use have produced conflicting results.^45–47 These studies suffered from limitations related to the absence of a control group comprised of women who remained abstinent throughout the duration of their pregnancy, and a direct comparison between exclusive opioid and polydrug users in the same cohort. Additional studies examining neonatal outcomes among substance-using pregnant women have not distinguished between different subtypes of polysubstance users (e.g., concurrent marijuana and alcohol users versus concurrent opioid and methamphetamine users), or have lacked an abstinent control group.^42,44,48

An important limitation of our study that needs to be acknowledged is a lack of objective measure, such as biomarker testing through urine toxicology screening, to confirm accuracy of self-reported substance use behaviors. While the shortcomings of reliance on self-reported data in epidemiological research are well-known, so are the strengths of self-reported data, particularly in the setting of substance use treatment clinics.^49,50 That is, patients of substance use treatment clinics have been found to self-report more accurately due to perceptions that their reason for being in the clinic is already known by interviewers, thereby minimizing possible concerns about stigmatization. However, patients in the abstinent control group had no known history of substance misuse, and they were not in a substance use treatment program that could minimize fears of perceived stigmatization. Therefore, the possibility of misclassification due to inaccurate self-reporting cannot be completely ruled out.⁵¹ Misclassification due to underreporting by study participants could have resulted in biases towards the null (lack of association). Thus, it is possible that differences observed between the polydrug and exclusive opioid participants and abstinent controls in our study may be an underestimation of a true larger effect size.

It should be acknowledged that we defined microcephaly as <10^th OFC percentile in this study to be consistent with birth weight and height SGA measures also defined as <10^th percentile. However, we are aware that microcephaly can be defined as < 3^rd OFC percentile to represent the most severe care of growth restriction. Interestingly, the prevalence of OFC<10^th percentile was somewhat higher than expected among abstinent controls (15.8%). Lower maternal education (67% ≤ high school education among abstinent controls in our study) is a surrogate measure of lower socio-economic status and a known risk factor for microcephaly.⁵² Additionally, isolated SGA for OFC (with normal birth weight and length percentiles) affected only 10% of abstinent controls in this population.

To our knowledge, this is the first study to evaluate the effect of polydrug use in pregnancy on fetal growth in a predominantly Hispanic population. Moreover, the inclusion of a polydrug use group with a high prevalence of OMT use, which we were able to compare to an exclusive opioid use group, was a unique strength of our study. While a great deal of prior research has identified risks of prenatal exposure to illicit substances used in isolation, little is known about how gestational polydrug use concurrent with OMT could affect infant growth outcomes. Given the high rates of polysubstance use among patients receiving OMT during pregnancy, our research contributes to stronger understandings about the possible risks and particular needs of opioid-dependent pregnant women who concurrently use other classes of drugs.

In summary, our study underscores the importance of addressing concurrent substance use problems for women who are pregnant or might become pregnant. In particular, the alarmingly high prevalence of microcephaly (49.2%) among children born to polydrug-dependent patients observed in our study requires further investigation. For pregnant women with multiple substance dependence problems, OMT alone may not provide sufficient therapeutic benefits. Multi-dimensional and holistic approaches that address polysubstance use and dependence among pregnant women may reduce the risks for adverse fetal outcomes associated with prenatal polydrug exposure.

Synopsis.

Polysubstance use was associated with higher risk of microcephaly (OR=4.7; 95% CI: 2.0; 10.8) and SGA for weight (OR=3.7; 95% CI: 1.4; 9.4).