Impact of opioid maintenance treatment during pregnancy on neonatal birth weight and head circumference

Abstract

BACKGROUND:

Pregnant mothers with opioid dependency commonly receive maintenance treatment of opioid (OMT), either as buprenorphine (BMT) or methadone maintenance treatment (MMT). We investigated, whether OMT adversely affects standardized neonatal anthropometric outcomes and whether BMT is potentially safer than MMT in this regard.

METHODS:

Retrospective chart review of mother infant dyad, with and without OMT. Infant’s absolute and standardized (z-score) anthropometric outcomes at birth were first compared, between OMT and control group (negative meconium drug screen), and then between BMT and MMT group. These outcomes were also compared between infants who did or did not require treatment after birth for neonatal abstinence syndrome (NAS).

RESULT:

A total of 1479 participants with MDS were included [Control = 1251; OMT = 228 (MMT = 181; BMT = 47)]. Both the z-scores of birth weight (BW) and head circumference (HC) was lower in OMT group (p < 0.001). Among the OMT group, GA at delivery was slightly higher in the BMT group (p = 0.05). There was an inverse correlation between maternal dose at the time of delivery and anthropometric z-scores in the BMT group, mainly in female infants (BW: p = 0.006; HC: p = 0.003). Furthermore, In BMT group, infants with lower HC were more likely to require treatment for NAS (p = 0.01).

CONCLUSION:

HC and BW when comparing Z-scores were not different between MMT and BMT. High maternal dosing of buprenorphine is associated with lower BW and HC Z-scores but dose effect is not seen with methadone. In addition, there seems to be an association between NAS severity and HC, especially in the BMT group.

Keywords

Birth anthropometry buprenorphine maintenance treatment opioid use in pregnancy methadone maintenance treatment

1 Introduction

The opioid epidemic in the United States continues to be a major public health concern, especially among pregnant mothers and newborns [1]. In utero opioid exposure has been associated with adverse neonatal outcomes such as increased risk of lower birth weight (BW), prematurity and neurodevelopmental problems [2, 3]. Opioid maintenance treatment (OMT), using either methadone (MMT) or buprenorphine (BMT), is currently the standard of care to stabilize and decrease the risk of relapse to illicit opioid use [4], and potentially help prevent several maternal and neonatal complications [5]. The overall safety of OMT during pregnancy on neonatal outcomes including birth anthropometry and rates of NAS remain a matter of concern [6, 7].

Previous studies comparing neonatal anthropometric measurements between infants exposed to the two commonly used OMTs during pregnancy (buprenorphine and methadone) have produced variable results. Comparison of birth weight in grams, has either shown lower birth weight [8, 9], higher birth weight [10 –13] or no such change [14] with BMT as compared to MMT. Recent studies including a meta-analysis of 3 randomized clinical trials including 223 infants concluded that BMT is associated with higher birth weight and head circumference, although the gestational age (GA) was also higher in the BMT group [10 , 16]. Thus, it is unclear which OMT is a preferred, safer choice. Further, previous studies have primarily reported data in the form of BW (g), HC (cm) and length (cm). These raw neonatal anthropometric measurements are significantly affected by GA at birth and sex. A Z-score is a numerical measurement that describes a value’s relationship to the mean of a group of values, such as each gender specific GA groups. If a Z-score is 0, it indicates that the data point’s score is identical to the mean score. Analyzing data without incorporating standardized measures of normalization (such as Z- score), for these variables can result in inaccurate interpretation [17]. In this study, we used both standardized and non-standardized metrics to compare neonatal anthropometric data among infants exposed to MMT, BMT, and those were not exposed to opioids.

The aims of this study were: a) to compare neonatal birth weight and head circumference with or without exposure to OMT using our practice-matched cohort, b) to evaluate the effect of increasing maternal prescribed doses of OMTs (BMT and MMT) on these outcomes and c) to determine whether neonatal BW and HC were different in infants who had severe symptoms and thus requiring pharmacological treatment for NAS.

2 Methods

2.1 Study design

This was a retrospective study approved by our local institutional review board, and was conducted in a level III neonatal intensive care unit (NICU) at Hurley Children’s Hospital, Flint, Michigan. Electronic charts were reviewed, from January 2012- December 2018, of infants born at gestational age of 34 week or more, with available meconium drug screen (MDS). At our institution MDS, is checked in all “at risk” babies, as determined by the maternal, social or prenatal history. MDS were available for 2611 infants. MDS with no documented exposure to opiate, methadone, buprenorphine, PCP, cocaine metabolite, amphetamine, benzodiazepine, or THC was defined as “negative”. Study participants included infants, not exposed to OMT in utero along with negative MDS (n = 1251), and infants, exposed to maternal OMT (MMT or BMT) in utero along with positive MDS (n = 228). We excluded infants with known congenital anomalies or who were delivered outside of Hurley Medical Center with no prenatal records.

2.2 Data collection

Our research team collected data from electronic medical records (EMR) for both mothers and infants. Maternal data included age, body mass index (BMI), marital status, number of prenatal visits, maternal maintenance dose at delivery, number of days mother received medication, prevalence of self-declared tobacco smoking, tetrahydrocannabinol use (THC), alcohol, and illicit substance use including methamphetamine, heroin, and cocaine. Data of illicit substance use was based on maternal urine drug screen. Neonatal data included mode of delivery, gender, gestational age at birth (GA), BW, length (L), HC, and treatment requirement for NAS. To minimize the variability in the anthropometric data and thus standardize the comparison among all the study participants, we calculated the associated Fenton Growth Chart (version 2013) [18, 19] percentile rankings and z-scores for each infant in addition to their absolute measurements. In order to compare the impact of the relative dosages of both the drugs prescribed at the time of delivery, we also calculated dosing percentile rank for each group and then correlated it with the anthropometric data.

2.3 NAS treatment protocol

At our center, we used the modified Finnegan scoring tool [20, 21] to manage infants born to opioid addicted mothers. All infants needing monitoring or treatment for NAS were admitted to the neonatal intensive care unit (NICU) for a minimum of 5 days. Neonates were scored every 3 hours, starting within 2 hours post-delivery. Any infants with a score of > 8 was rescored in an hour. Pharmacological treatment was started based on two consecutive scores > = 9. The pharmacological therapy was initially started with oral morphine. At our institution, morphine is initially prescribed as a flat dose of 0.02 mg PO every 3 hours and subsequently dosage is titrated up to maintain the scores below 9 for 48 hours, prior to initiating weaning of medications. Infants needing high doses of morphine (> 0.2 mg PO every 3 hourly) are treated with adjunctive treatment with clonidine. In severe cases, where symptoms were not controlled with escalating doses of morphine and addition of clonidine, phenobarbital was used as additional medical therapy.

2.4 Statistical analysis

Mother infant dyads were first categorized into two groups based on medication-assisted treatment used during current pregnancy and infant’s MDS: Control (mothers not on any OMT and infants with negative MDS) and OMT (mothers on OMT and infants with positive MDS). The OMT group were categorized into two groups based on medication-assisted treatment method used during current pregnancy: BMT or MMT. Infants were further subcategorized in each of the OMT group based on their requirement of pharmacological treatment post-delivery. Baseline characteristics were compared between the groups. In the first part our analysis we compared the anthropometric outcomes between the control and OMT group. Subsequently these outcomes were compared overall between BMT and MMT group, and then based on requirement of NAS treatment, and finally other additional exposures besides the medication-assisted treatments within each group. Continuous variables were compared by either t-test or Mann-Whitney test based on the normal distribution of the data. Categorical variables were compared by Chi-square test. A p-value < 0.012 was considered statistically significant after Bonferroni correction. In order to study the association of birth anthropometric data with the prescribed dosage, in each group, at the time of delivery, we calculated the percentile rank of dosing for each group. Linear regression analysis was subsequently performed to correlate it with the associated z-scores for infants at birth. Comparison of all statistical analysis was performed using MedCalc version 17.9 (MedCalc Software, Ostend, Belgium).

3 Results

3.1 Study population and demographics data

Of the total 1479 study cohort, 1251 were in the control group (negative MDS), and 228 were in OMT group [181 (79.4%) in the MMT group, and 47 (20.6%) in the BMT group]. Among the OMT group, the median daily dose, at the time of delivery, of buprenorphine was 8 mg (interquartile range (IQR): 4–16), and methadone was 96 mg (IQR: 65–135). Although in both groups the major indication of opioid maintenance therapy was addiction, in 18.8% it was used for both pain and addiction. Among the OMT group, 36% of the mothers used THC and 56.6% used other illicit substances. Eighty (80) % of mothers admitted of smoking tobacco during the pregnancy as opposed to 71.6% in the control group (p = 0.02).

Univariate analysis of other maternal confounders in the OMT subgroup showed a significantly higher use of any illicit substances other than THC (p = 0.001), in the MMT group. Among the other illicit substances, the major differences were due to heroin (p = 0.033) and cocaine (p = 0.002) use. There was no statistically significant difference between the two groups in the use of THC, benzodiazepines, SSRIs, or tobacco smoking (Table 2).

Table 1
Comparison of maternal and infant characteristics between Control (negative MDS) and OMT group

Variable Control OMT p-value

(n = 1251) (n = 228)

Maternal race (caucasian)^* 42.9% 90.8% 0.02

Maternal age (year)^|| 29.0±3.2 29.0±5.0 0.810

Maternal smoking^* 71.6% 80 0.02

Mode of delivery (vaginal)^* 45.6% 52.8% 0.05

Gestational age at birth (wks)^|| 38.3±1.8 37.6±1.7 < 0.001

Birth weight (grams)^|| 3127±558 2764±493 < 0.001

Birth weight z-score^|| –0.08±0.8 –0.56±0.8 < 0.001

Head circumference (cm)^|| 33.7±1.6 32.6±1.8 < 0.001

Head circumference z-score^|| –0.09±0.9 –0.57±1.1 < 0.001

Length (cm)^|| 47.2±2.3 46.4±3.1 0.155

Length z-score^|| –0.56±1.0 –0.66±1.1 0.610

Prematurity < 37 wks) ^* 18.3% 34.2% 0.001

Small for gestational age^* 7.9% 15.8% < 0.001

Sex (male)^* 47.6% 44.3% 0.429

Variable	Control	OMT	p-value
Maternal race (caucasian)^*	42.9%	90.8%	0.02
Maternal age (year)^\|\|	29.0±3.2	29.0±5.0	0.810
Maternal smoking^*	71.6%	80	0.02
Mode of delivery (vaginal)^*	45.6%	52.8%	0.05
Gestational age at birth (wks)^\|\|	38.3±1.8	37.6±1.7	< 0.001
Birth weight (grams)^\|\|	3127±558	2764±493	< 0.001
Birth weight z-score^\|\|	–0.08±0.8	–0.56±0.8	< 0.001
Head circumference (cm)^\|\|	33.7±1.6	32.6±1.8	< 0.001
Head circumference z-score^\|\|	–0.09±0.9	–0.57±1.1	< 0.001
Length (cm)^\|\|	47.2±2.3	46.4±3.1	0.155
Length z-score^\|\|	–0.56±1.0	–0.66±1.1	0.610
Prematurity < 37 wks) ^*	18.3%	34.2%	0.001
Small for gestational age^*	7.9%	15.8%	< 0.001
Sex (male)^*	47.6%	44.3%	0.429

^*Data represented as (%);p-value (t test). ^||Data represented as mean±SD; p-value (chi square-test).

Table 2

Comparison of maternal characteristics based on prenatal maintenance treatment

Variable	BMT (n 47)	MMT (n 181)	P-value
Race (caucasian)^*	89.4%	91.2%	0.704
Age (year)^\|\|	29.0±4.8	29.0±5.0	0.980
BMI^‡	27.9 (25–31)	29.8 (26–33)	0.075
First prenatal visit (week)^‡	16.5 (14–28)	21 (17–28)	0.052
Smoking^*	76.6%	82.3	0.372
SSRI use^*	19.6%	15.5%	0.502
Benzodiazepine use^*	10.6%	18.8%	0.187
THC^*	31.9%	34.3%	0.763
Illicit drug use (other than THC) ^*	36.2%	61.9%	0.001
Heroin^*	14.9%	30.4%	0.033
Cocaine^*	4.3%	23.8%	0.002
Methamphetamine^*	4.3%	6.1%	0.632
Alcohol^*	2.1%	5.5%	0.333
Mode of delivery (vaginal)^*	53.2%	54.7%	0.853
Medication exposure profile
Indication (addiction)^*	87.2%	79.6%	0.467
On treatment prior to pregnancy^*	74.5%	60.8%	0.082
GA at which t/t started	19 (13–27)	21 (14–30)	0.668
(if started during pregnancy)^‡
Duration of fetal exposure (wk)^‡	37.2 (29.3–39.0)	35.2 (20.5–38.0)	0.035
Prescribed dose at delivery (mg)^‡	8 (4–16)	96 (65–135)

^*Data represented as %; p-value (chi-square test). ^||Data represented as mean±s.d; p-value (t-test). ^‡Data represented as median (interquartile range); p-value (Mann Whitney test).

Although the majority of prenatal care for participants started in the second trimester, it was initiated relatively earlier in the BMT group (p = 0.052). A higher percentage of mothers in the BMT group (75% vs 61%) were already on medication-assisted treatment prior to pregnancy as compared to the MMT group (p = 0.08). In mothers not on maintenance therapy prior to conception, the median gestational week of initiating the treatment between the groups was not significantly different (19 weeks for BMT and 21 weeks for MMT). GA at delivery (if already on treatment) or the difference of GA from initiation of treatment to delivery was calculated, to estimate the total duration of fetal exposure. The median fetal exposure in weeks was higher in BMT group by 2 weeks (p = 0.035) (Table 2).

3.2 Anthropometric outcomes

First, we compared the OMT group with control group. Among the study subjects 45.6% of neonates were male in the OMT group (control 47%), and 90.8% were born to Caucasian mothers as opposed to 42.9% in control group (p = 0.02). Relatively more infants were delivered by cesarean section in the OMT group (52.8% vs 45.6%; p = 0.05). The mean±s.d GA in weeks at delivery (37.6±1.7 vs 38.3±1.8; p = 0.001), BW (2764±493 g vs 3127±558 g; p < 0.001) and HC (32.6±1.8 cm vs 33.7±1.6 cm; p < 0.001) was lower in the OMT group. More infants were premature (before 37 weeks GA) (34.2% vs 18.3%; p = 0.001) and small for gestational age (SGA) at birth (15.8% vs 7.9%; p < 0.001) in the OMT group (Table 1). In addition to the non-standardized data at birth, we also calculated the associated Fenton percentile rankings and z-scores for further comparison. Both the z-scores for BW (–0.56±0.8 vs –0.08±0.8; p < 0.001) and HC (–0.57±1.1 vs –0.09±0.9; p < 0.001) was lower in the OMT group (Fig. 1).

Fig. 1

Comparison of birth anthropometric z-score in infants with and without maternal OMT. 1a: Kernel density plot of birth weight z-score: The plot depicts the distribution pattern among infants in the control and OMT groups. Data representative of 1479 participants with MDS (Control = 1251; OMT = 228). 1b: Kernel density plot of birth head circumference z-score: The plot depicts the distribution pattern among infants in the control and OMT groups. Data representative of 1479 participants with MDS (Control = 1251; OMT = 228).

Among the OMT subgroups, although neonates in the BMT group were higher in BW (g) (p = 0.033) with a slightly higher trend in GA (p = 0.056) and HC (p = 0.083), the standardized anthropometric values (z-scores) were not significantly different between the two groups. There were also no significant differences in sex, prematurity and SGA at birth between the two maternal treatment groups (Table 3).

Table 3

Comparison of birth outcome based on prenatal maintenance treatment

Variable	BMT (n = 47)	MMT (n = 181)	p-value
Gestational age at birth (wks)^\|\|	38.0±1.7	37.4±1.7	0.056
Birth weight (grams)^\|\|	2870±561	2683±513	0.033
Birth weight z-score^\|\|	–0.36±0.82	–0.56±0.85	0.151
Head circumference (cm)^\|\|	32.8±1.8	32.3±1.7	0.083
Head circumference z-score^\|\|	–0.47±1.0	–0.60±0.9	0.393
Length (cm)^\|\|	47.2±2.3	46.4±3.1	0.155
Length z-score^\|\|	–0.56±1.0	–0.66±1.1	0.610
Prematurity (<37 wks) ^*	27.7%	35.9%	0.289
Small for gestational age^*	12.8%	16.6%	0.524
Sex (male)^*	40.4%	47.0%	0.423
Treated for NAS^*	46.8%	77.3%	< 0.0001

^*Data represented as n(%);p-value (t test). ^||Data represented as mean±SD; p-value (chi square-test).

3.3 Association with maternal medication exposure profile

Neonatal BW was higher if mothers were already receiving treatment prior to pregnancy [mean difference in z-score: 0.36 (OMT, p = 0.009); 0.57 (BMT, p = 0.03); 0.31 (MMT, p = 0.05)], along with a favorable trend in z-scores of HC [mean difference in z-score: 0.27 (OMT, p = 0.05); 0.69 (BMT, p = 0.05); 0.30 (MMT, p = 0.05)]. In the BMT group we also observed that early prenatal care was positively correlated with both BW z-score (β= 0.40, p = 0.02) and HC z-score (β= 0.36, p = 0.04).

3.4 Association with maternal dose at the time of delivery

Prescribed dosage percentiles for each were correlated with associated z-scores for infants at birth (Table 4). In the BMT group higher maternal dose was significantly associated with lower BW (p = 0.007) and a trend towards lower HC (p = 0.05). This correlation was more significant in female infants for both BW (p = 0.006) (Fig. 2a) and HC (p = 0.003) (Fig. 2b). No such correlation was found with MMT group (Table 4).

Table 4
Relationship between relative dose and neonatal anthropometric profile

BMT (n = 47; Dose range 1–24 mg)

Variable Group B coefficient Std error p -value

BW (z-score) Overall –0.40 0.00 0.007

Female –0.52 0.005 0.006

Male –0.245 0.006 0.342

HC (z-score) Overall –0.279 0.005 0.050

Female –0.421 0.007 0.003

Male –0.103 0.008 0.693

Length (z-score) Overall –0.261 0.005 0.094

Female –0.526 0.005 0.077

Male 0.055 0.008 0.833

MMT (n = 180; Dose range 5–268 mg)

Variable Group B coefficient Std error p -value

BW (z-score) Overall 0.14 0.00 0.063

Female 0.037 0.003 0.720

Male 0.250 0.004 0.061

HC (z-score) Overall 0.062 0.002 0.413

Female 0.075 0.003 0.473

Male 0.059 0.004 0.595

Length (z-score) Overall –0.040 0.003 0.596

Female –0.123 0.004 0.234

Male 0.037 0.005 0.737

BMT (n = 47; Dose range 1–24 mg)
Variable	Group	B coefficient	Std error	p -value
BW (z-score)	Overall	–0.40	0.00	0.007
	Female	–0.52	0.005	0.006
	Male	–0.245	0.006	0.342
HC (z-score)	Overall	–0.279	0.005	0.050
	Female	–0.421	0.007	0.003
	Male	–0.103	0.008	0.693
Length (z-score)	Overall	–0.261	0.005	0.094
	Female	–0.526	0.005	0.077
	Male	0.055	0.008	0.833
MMT (n = 180; Dose range 5–268 mg)
Variable	Group	B coefficient	Std error	p -value
BW (z-score)	Overall	0.14	0.00	0.063
	Female	0.037	0.003	0.720
	Male	0.250	0.004	0.061
HC (z-score)	Overall	0.062	0.002	0.413
	Female	0.075	0.003	0.473
	Male	0.059	0.004	0.595
Length (z-score)	Overall	–0.040	0.003	0.596
	Female	–0.123	0.004	0.234
	Male	0.037	0.005	0.737

Fig. 2

Relationship between birth anthropometric z-score and relative maternal dose percentile prescribed at the time of delivery. 1a: The plot depicts the pattern of birth weight z-scores for each infant and the fitted line by the group. The relative maternal prescribed dose was calculated as percentile rank of dosing in each group and then correlated it with associated z-scores for infants at birth. Data representative of 228 patients (BMT: 47; MMT: 181). 1b: The plot depicts the pattern of birth head circumference z-scores for each infant and the fitted line by the group. The relative maternal prescribed dose was calculated as percentile rank of dosing in each group and then correlated it with associated z-scores for infants at birth. Data representative of 228 patients (BMT: 47; MMT: 181).

3.5 Association with neonatal treatment for NAS

We also compared these outcomes in infants who did or did not receive treatment for NAS (Table 5). Overall the risk of infant withdrawal varied by dose of methadone but risk of infant NAS with BMT did not vary by dose (Table 5). Infants who were treated for NAS were more mature (p = 0.01), especially in the BMT group (p = 0.009). Although the BW was higher in the treatment group (p = 0.03), the mean difference in BW z-score was not statistically significant (mean difference 0.13; p = 0.292). We did find a significantly lower HC z-score (mean difference 0.35; p = 0.009) in infants who needed treatment, with a significant shift in the distribution curve especially in the BMT group (Fig. 3).

Table 5
Anthropometric profile at birth in relation to NAS treatment

Variable Groups No treatment Treatment p-value

GA (wks)^‡ Overall 37.1 (35.2–38.1) 38.1 (36.3–39.1) 0.01

BMT 37.3 (35.1–38.2) 39.1 (37.6–39.5) 0.009

MMT 37.0 (35.1–38.0) 38.0 (36.1–39.0) 0.06

BW (grams)^|| Overall 2580±589 2753±519 0.03

BMT 2622±669 3004±556 0.04

MMT 2555±541 2714±503 0.08

BW (z-score)^|| Overall –0.44±0.7 –0.53±0.9 0.456

BMT –0.30±0.7 –0.41±0.9 0.659

MMT –0.53±0.7 –0.55±0.9 0.852

HC (cm)^|| Overall 32.0±2.0 32.4±1.6 0.132

BMT 32.2±2.2 32.9±1.8 0.267

MMT 31.9±1.9 32.3±1.6 0.148

HC (z-score)^|| Overall –0.32±0.9 –0.67±0.84 0.009

BMT –0.16±1.0 –0.81±0.91 0.003

MMT –0.51±0.9 –0.69±0.84 0.245

Prescribed dose Overall (percentile) 38 (22–76) 54 (31–80) 0.02

at delivery^‡ Buprenorphine (mg) 8 (4–16) 8 (3–20) 0.92

Methadone (mg) 70 (45–115) 102 (70–140) 0.002

Variable	Groups	No treatment	Treatment	p-value
GA (wks)^‡	Overall	37.1 (35.2–38.1)	38.1 (36.3–39.1)	0.01
	BMT	37.3 (35.1–38.2)	39.1 (37.6–39.5)	0.009
	MMT	37.0 (35.1–38.0)	38.0 (36.1–39.0)	0.06
BW (grams)^\|\|	Overall	2580±589	2753±519	0.03
	BMT	2622±669	3004±556	0.04
	MMT	2555±541	2714±503	0.08
BW (z-score)^\|\|	Overall	–0.44±0.7	–0.53±0.9	0.456
	BMT	–0.30±0.7	–0.41±0.9	0.659
	MMT	–0.53±0.7	–0.55±0.9	0.852
HC (cm)^\|\|	Overall	32.0±2.0	32.4±1.6	0.132
	BMT	32.2±2.2	32.9±1.8	0.267
	MMT	31.9±1.9	32.3±1.6	0.148
HC (z-score)^\|\|	Overall	–0.32±0.9	–0.67±0.84	0.009
	BMT	–0.16±1.0	–0.81±0.91	0.003
	MMT	–0.51±0.9	–0.69±0.84	0.245
Prescribed dose	Overall (percentile)	38 (22–76)	54 (31–80)	0.02
at delivery^‡	Buprenorphine (mg)	8 (4–16)	8 (3–20)	0.92
	Methadone (mg)	70 (45–115)	102 (70–140)	0.002

^||Data represented as mean±s.d; p-value (t-test). ^‡Data represented as median (interquartile range); p-value (Mann Whitney test)

Fig. 3

Kernel density plot of birth head circumference z-score in relation to NAS treatment. The plot depicts the distribution pattern of birth head circumference z-scores between prenatal maintenance treatment groups based on the requirement of treatment for NAS. Data representative of 228 patients [BMT (No Treatment): 25; BMT (Treatment): 22; MMT (No Treatment): 41; MMT (Treatment): 140)].

3.6 Association with other maternal exposures

Finally, we analyzed the impact of other exposures in our population. BW z -score was not different in mothers who admitted to smoking tobacco as compared to mothers who did not, in the control group (mean difference in z-score 0.07; p = 0.916), as opposed to OMT group (mean difference in z-score 0.41; p = 0.005). Among the OMT population, the average decrease in BW z-score was 40% higher in the MMT group [mean difference 0.44 (MMT) vs 0.26 (BMT); p = 0.009]. This association was significant even after correcting for potential confounders (p = 0.003). The confounders included in our linear regression model were maternal age, race, marital status, THC use, illicit substance use, Benzodiazepine use and SSRI use.

4 Discussion

Both methadone and buprenorphine are commonly prescribed to mothers in the medication-assisted treatment programs. We investigated birth outcomes in neonates exposed to these opioid maintenance treatments in their fetal life. We found that overall OMT was associated with lower GA (week), BW and HC as compared to infants with no exposure. Among the infants exposed to OMT, BMT was associated with higher GA (week) and BW (gm). However, BW z-score was not different in BMT group as compared to MMT group. Our data also shows that among the BMT group, higher dosage at the time of birth was associated with lower BW and HC, especially in female infants. Finally, we also noted that the HC was smaller in infants who required treatment for NAS, more so in the BMT group.

Neonatal anthropometric outcomes, in relation to maternal OMT, has been studied in the past [8 –14]. Majority of these previous studies have used non-standardized data, such as birth weight in grams and head circumference in centimeters, for the comparison. In our study, in order to minimize the variability, and therefore standardize the comparison among all the study participants, we also calculated and analyzed z-scores (specific for GA and gender) of each infant in addition to their absolute measurements. Recent studies including a systematic review and meta-analysis have suggested an association of greater BW (g) and HC (cm) with buprenorphine treatment [10, 15]. Although our data also showed that buprenorphine exposed infants had higher birth weight in grams, and a positive trend in head circumferences in cm, we did not find this association when we used their birth z-scores similar to the recent observations by Myers et al. [22].These higher non-standardized anthropometric values in the BMT groups may be due to the slightly higher GA at birth in this group.

We also observed a higher neonatal BW if the mothers were already on treatment prior to pregnancy. We speculate that his may be reflective of either both better and early prenatal care or uncontrolled opioid use in early pregnancy may negatively impact fetal growth. In addition, we looked at the relationship between increasing maternal dosage at the time of birth in each group and neonatal anthropometric outcomes. In contrast to the secondary data from the MOTHER trial and a retrospective cohort study by O’Connor et al., which used non-standardized values [23, 24], our data suggest a negative correlation between higher buprenorphine doses and standardized BW and HC z-scores. This higher dose response may imply that either BMT affect neonatal outcomes or higher required dosing may reflect more/continued use of illicit drugs. Furthermore, we found that this correlation was even more significant in female infants. One of the limitations of our study is the relatively smaller sample in this group. Future studies with a relatively larger sample size will be required to better understand the neonatal gender specific differences in these outcomes.

We also observed that infants who were treated for NAS had significantly lower HC with an overall shift in the HC z-score distribution curve, especially in the buprenorphine group. Recently Visconti et al. and Towers et al. in their prospective studies found that chronic opioid exposure during pregnancy was associated with smaller HC in infants who were treated for NAS [25, 26]. Interestingly, close to two thirds of the population in Towers study consisted of buprenorphine group. These findings suggest that BMT may have a negative impact on the head growth, and that this effect is influenced by both maternal dose and neonatal sex. We did not have data on long-term neurological outcomes, which would have been able to determine the impact of decreased HC on psychomotor development. Although these were priori hypotheses in our study, there is a potential possibility of random association of these anthropometric outcomes with BMT group due to the multiple comparisons done. Therefore, we applied the conservative Bonferroni approach to correct for multiple comparisons.

Another potential confounder was self-reported maternal tobacco smoking, which is a well-known risk factor for lower birth weight (LBW) [6 , 28]. We found that tobacco smoking was associated with an overall decrease in the BW z-scores, and this drop was 40% larger among methadone users. The association of lower BW z-scores in the MMT group with smoking was still significant after correcting for potential confounders including other substance exposure including heroin and cocaine use. Similar observations were also made recently made by Nørgaard et al. showing that in mothers who smoked during pregnancy, methadone exposure was associated with more than a two-fold higher prevalence in LBW [6]. These findings suggest that methadone exposure may increase the negative impact of maternal smoking on birth weight.

5 Conclusion

In our study, we found a favorable anthropometric outcome in neonates, if mothers received treatment prior to conception, had early prenatal care, and did not smoke. Although both the OMT groups showed lower HC, there seems to be a dose correlation in the BMT group which is dependent on neonatal gender. Furthermore, in the BMT group, infants who received pharmacologic treatment for NAS had lower HC. One of the major limitations of our study is its retrospective nature and relatively few numbers of infants in the BMT group. The differences between MMT and BMT could be due to maternal socioeconomic class differences or noted differences in usage of recreational drugs. In view of this, our results should be considered to be hypothesis-generating, and as such does not warrant changes in current treatment practices. However, if our results are replicated in future prospective studies, it might warrant a further investigation of the use of OMT in expectant mothers especially from neonatal anthropometric point of view.

Disclosure statements

The authors declare no conflict of interest.

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