The association of electronic cigarettes use during pregnancy and its influence on birth weight. Protocol for a prospective cohort study.

Table of contents

1. INTRODUCTION                      3

1.1  Risks of tobacco        3

1.2  Risks of tobacco in pregnancy      3

1.3  Cessation techniques       3

1.4  Drugs in cessation       3

1.5  Electronic cigarettes       4

1.6  Electronic cigarette safety      5

1.7  Electronic cigarette safety in pregnancy     5

2. STUDY AIM         6 

3. METHODS         7

3.1  Study design        7

3.2  Setting         7

3.3 Participants        8

3.4  Variables             10

3.5  Data Sources/measurement      10

3.6  Bias         11

3.7  Study size        13

3.8  Quantitative variables       14

3.9  Participant recruitment       15

3.10  Participant characteristics      17

3.11 Main results        00 

4. ANALYSIS         15 

5. DISCUSSION                      20 

6. REFERENCES         22

Introduction

Tobacco products are one of the most common causes of preventable diseases globally.(1) Their use leads to many diseases of the heart and lungs, these include but are not limited to chronic obstructive pulmonary disease (COPD), stroke and lung cancer. (2) Maternal use of these products puts the fetus at increased risk of a number of adverse health outcomes such as low birth weight, congenital disorders, and stillbirth being reported from studies.(3) With these being preventable diseases and malformations it may motivate one to quit or use a cessation technique in order to improve their own health or put their fetus at less of risk during its development.(4, 5)

Even with all the health risks of smoking being known it still remains a major public health issue with ~20% of pregnant women in Ireland reporting to have smoked during their pregnancy.(6) Prenatal smoking and the use of smokeless tobacco use can have a negative effect on the fetus birth weight. From a study of 34,928 singleton births, it has been reported that smoking can cause a reduction of 129g (95% CI -170, -87) in birth weight among normal weight women.(7) Maternal smokeless tobacco use has also been examined by the WHO and in a report in 2003 of smokeless tobacco use in India, it stated that there was 2-3 times higher rate of stillbirth and 2-3 times higher rate of low birth weight compared to that of non-exposed to smokeless tobacco. (8)

Currently, there are several cessation techniques available – quitting altogether, behavioral therapy, use of nicotine replacement therapy (NRT), medication and combination therapy.(9) Pharmaceutical intervention through the use of NRT and medications such as varenicline and bupropion have been reported as more effective methods of cessation than placebo for quitting.(10) However, the use of NRT and these medications in pregnancy are not without risk.

With the use of NRT in pregnancy the fetus is exposed to nicotine and this can have an influence on brain development and may cause fetal harm.(11) From a Danish National Birth Cohort from 1997-2003, there was a suggested increase of congenital malformations risk with a relative prevalence rate ratio of 1.61 (95% CI, 1.01-2.58) in nonsmokers using nicotine substances compared to non-exposed children. Within this cohort, it was suggested that maternal use of NRT does not seriously affect birth weight, but there could be a negative effect on birth weight with the simultaneous use of more than one type of NRT product.(12) This posed the question that if there are high levels of maternal nicotine exposure is there an association with birth weight. The use of transdermal systems has appeared to show more positive results than chewing gum for cessation. However, there are concerns that transdermal patches can actually deliver more nicotine to the embryo/fetus as there are continuous blood levels of nicotine relative to episodic smoking or use of gums are available to cross the placenta. (13, 14)

According to Briggs’s Drug in Pregnancy and Lactation, there have been no reports describing the use of Varenicline in pregnancy and the benefit appears to outweigh the risk to the embryo and/or fetus. (15) However, there has been lack of studies in this area. The use of Bupropion has been suggested as low risk according to animal and human data. However, there has been a strong association between the use of Bupropion in pregnancy and attention-deficit/hyperactivity disorder (ADHD) in offspring, however, it was considered that cigarette smoking was a potential confounder. (16) It has been reported that there has been an increased rate of heart defects reported in two studies, however, this outcome has not been confirmed by other studies. (17, 18)

The use of electronic cigarettes has been proposed as an effective cessation technique for tobacco cigarette smokers. Electronic cigarettes are nicotine-delivery devices that vaporize a liquid also known as an e-liquid. This e-liquid contains nicotine that has been processed and purified from nicotine of tobacco leaves. This then is suspended within a mixture of glycerin or propylene glycerol with water and flavouring’s, and then vapourised. The nicotine is then inhaled into the respiratory tract and absorbed into the bloodstream.(19)

Electronic cigarettes and devices have now been showing an increase in use, especially among young people. There has been an 86% increase seen in users of electronic cigarettes or vaping devices from 2013 to 2015.(20, 21) Their use as a tobacco smoking cessation technique has been tested and was reported to have a potential for cessation, to have higher acceptability among smokers relative to NRT and seemed to have no greater risk of adverse effects.(22)

However, there are concerns that electronic cigarette use may be a gateway product for nicotine containing products such as tobacco cigarettes. The influence of its use in the younger generations is a worry of health institutions around the globe. Approaches of these companies to advertise their product to the masses has been observed through TV advertising, celebrity endorsement, and music festivals. There is worry that these companies are portraying claims that electronic cigarettes are safe and beneficial despite them containing nicotine and other unknown containing excipients.(23)

The World Health Organization (WHO) also has expressed their concern about the safety of electronic cigarettes. Especially as it contains nicotine and this can have an adverse effect especially during pregnancy and can contribute to cardiovascular disease. Another worry is that from chronic inhalation of toxicants in the vapour to the user could lead to potential cytotoxicity have raised concerns about pregnant women who use electronic cigarettes or are exposed to them.(24) Another worry of the WHO is that the impacts of tobacco-controlled efforts are diminished due to the rapid growth of electronic cigarette use and advertisement. (24)

Electronic cigarette vapour has been found to have some toxic substances however relative to tobacco cigarettes they are lower.(20) The idea of substituting tobacco products with e-cigarettes may substantially reduce exposure to selected tobacco-specific toxicants, however this proposal warrants further study due to the differences in toxins inhaled.(25) With nicotine being observed to be a teratogen when used in pregnancy it is uncertain if delivery through electronic cigarettes will cause a low birth weight, have an influence on gestation, birth defects, stillbirth or premature birth.(26)

From a systematic review on the health effects of electronic cigarettes it was concluded that with many methodological problems, conflicts of interest, very few studies, inconsistencies and contradictions in results, there is no conclusive information that can be collected from studies of electronic cigarettes so far.(27) Lack of regulation and control of studies is an identified issue. With major tobacco companies such as British American Tobacco developing electronic cigarettes and carrying out their own studies give rise to the suspicion of these claims.(28) The World Health Organization’s stance on electronic cigarette use is uncertain as they state that “it is important to identify public health concerns and to consider these concerns when undertaking regulation and surveillance” and that “establishing a scientific basis on which to judge the effects of their use, and for ensuring that adequate research is conducted”.(24) Currently, there are no reported cohort studies conducted on electronic cigarette use in pregnancy.

This prospective cohort protocol aims to explore the perinatal outcomes of electronic cigarette use during pregnancy compared to no exposure. Primarily focusing on examining its use and its association with birth weight. Secondary outcomes of gestational age, birth length, stillbirth, congenital disorders and premature births will also be examined.

Study Aim

The study will follow the PECO format (population, exposure, comparison, and outcome). The population of the study will be pregnant women who are users of electronic cigarettes. The full list of inclusion and exclusion criteria with included rationale can be seen in table 1 and table 2. This population will be recruited from the antenatal clinic of 2 large maternity hospitals (hospital A and hospital B) in Dublin Ireland. Mothers who are users of electronic cigarettes will be recruited over 34 weeks and information regarding their newborn infant will be collected through a questionnaire given by the attending midwife or personnel.

The exposure will be any first-hand electronic cigarette use by the mother during the gestational period. There will also be a recording of the amount of e-liquid consumed per week, brand and strength of e-liquid. This, in turn, will allow for determination of nicotine exposure per week through formulation. Electronic cigarette use will be self-reported by the mother and recorded by a trained midwife or personnel at their antenatal clinic visit.

The comparison will be women who give birth in selected hospital A or hospital B with a full history of antenatal clinic visit information. These women will be selected randomly on the fact that they were not exposed to nicotine-containing products during their pregnancy. A full list of inclusion and exclusion criteria and rationale can be seen in table 3 and table 4. These women will be selected on the factors of the exposed group maternal age at delivery, nulliparous and region of descendants in order to reduce the chance on confounding.

This cohort protocol will be conducted in order to examine the use of electronic cigarettes in pregnancy and its association with birth weight. Other information regarding fetus gestation time, premature birth, stillbirth, and congenital disorders will also be recorded. Descriptive statistics will be applied to describe both groups. Binomial outcomes will be expressed as an odds ratio. Data will be presented in both adjusted and unadjusted formats. Data will be adjusted for maternal age at delivery, nulliparous and region of descendants. Collected information will also be graphed with birth gestation against birth weight for both the exposed values and non-exposed values will be done. A distribution graph of exposed and unexposed will also be created.

 Methods

The study will be carried out with pregnant women within antenatal clinics of two large maternity hospitals (hospital A & hospital B) in Dublin, Ireland that roughly 20,000 births per year occur in total. Midwives and personnel will be trained over 12 weeks on how to carry out the study. Participants (pregnant women who are users of electronic cigarettes) will be recruited over 34 weeks with a 10-week contingency period. After consent has been granted a midwife will question the participants with regards to their electronic cigarette use along with their routine obstetrician questions three times over 36 weeks of their gestation. The data will be stored in the participant’s antenatal file. Firstly upon their visit at less than 12 weeks gestation, followed up by their routine antenatal clinic visits at week 28 and at week 36. There will be a follow-up period of 36 weeks at the last day of recruitment for completion of all pregnancies. With recruitment starting when a mother indicates she is pregnant at the antenatal clinic (estimated 5-12 weeks gestation) along with a 36-week birth period this will allow for 41-48 weeks gestation. This will ensure all pregnancies will be completed by the end of the 36 weeks. Records of the infant’s birth details will be gathered and recorded at the end of the birth period by a representative of the study. An appropriate comparison of non-exposed will be recruited from electronic records of hospital A and hospital B and selected randomly by a representative following inclusion and exclusion criteria seen in table 3 and table 4. The total time for training and the study to be carried out is predicted to be 92 weeks. Data collection, selection of unexposed comparison from electronic records, sorting of data, and analysis of data is estimated to take 13 weeks The total estimated time is 105 weeks.

Figure 1: Gantt chart of study period.

Table 1: Inclusion criteria for exposed group (users of electronic cigarettes).

Inclusion Criteria	Rationale
1. Can speak English	This will ensure patients can understand what they are consenting to and understand the questions being asked.
2. Over the age of 18	The participant is an adult.
3. Has an intention to give birth at selected hospital A or hospital B	The collection of birth information can then be conducted quickly and efficiently.
4. Is in the first 12 weeks of gestation	Patients are at the start of their pregnancy and exposure can be recorded more accurately.
5. A user of electronic cigarettes	Study exposure.
6. Gives informed written consent	The participant is happy to share their information with the study.

Table 2: Exclusion criteria for exposed group (users of electronic cigarettes).

Exclusion Criteria	Rationale
1. Women who intend to use nicotine containing products (cigarettes, smokeless tobacco, and NRT)	This will ensure the only exposure of any nicotine-containing product is electronic cigarettes.
2. Women who intend to use an illicit drug or methadone during their pregnancy	The use of illicit drugs and methadone has been related to an increased risk of stillbirth and reduced fetal growth.(29, 30)
3. Women who have any serious underlying conditions that could effect the development of a fetus.	Serious conditions such as HIV have been associated with low birth weight.(31)
4. Women who intend to consume alcohol during their pregnancy	Maternal alcohol consumption has been associated with low birth weight infants.(32)

Of these women eligible for the study, the midwife will carry out an interview at their first antenatal clinic visit at <12 weeks gestation. The study will be discussed and the requirements for participation will be explained. Women will be given a participant information leaflet (see Appendix 1.A) and those who agree to participate will give written consent (see Appendix 1.B).(33)

The women who qualify for the study will then be asked a series of questions following their routine antenatal clinic questions with regards to their electronic cigarette use.

1. Average e-liquid consumption (in ml) per week
2. Brand of e-liquid used
3. Strength of e-liquid used (in mg/ml)

Then in order to classify nicotine exposure from electronic cigarettes, the following formula will be used.

E Liquid consumption per week in ml × E Liquid strength inmgml=Average amount of nicotine inhaled in mg per week

Upon the subsequent visits at week 28 and week 36 thereafter, women will be asked the questions again with regards to their use since the last visit. Their average weekly electronic cigarette use will be calculated as an average over the entire pregnancy. This will be recorded as a continuous variable and then sorted categorically upon statistical analysis upon completion of the study. The mothers will be grouped indicating nicotine exposure from electronic cigarettes with regards to self-reported use (low: 0-14.99mg/week, medium: 15-134.99mg/week and high:

≥135mg/week). Both the continuous and categorical data will be analyzed through statistical methods.

The control group will be selected from the electronic booking delivery records of hospital A and hospital B. Of these records, women will be selected as a comparison based on certain maternal factors of maternal age at delivery, nulliparous and region of descendants in order to minimize the risk of selection bias.

Table 3: Inclusion criteria for non-exposed group (non-users of electronic cigarettes).

Inclusion Criteria	Rationale
1. Singleton birth	Twin and triplet births can have an influence on low birth weight and preterm delivery.(34)
2. Women who have reported zero nicotine exposure (cigarettes, smokeless tobacco, and NRT)	This will ensure there was no exposure to any nicotine-containing product and will allow for appropriate comparison.

Table 4: Exclusion criteria for non-exposed group (non-users of electronic cigarettes).

Exclusion Criteria	Rationale
1. Did not book into antenatal care	This will ensure participant’s information and exposures are accurate.
2. Consumed alcohol during their pregnancy	Maternal alcohol consumption has been associated with low birth weight infants.(32)
3. Had taken any illicit drug or methadone during their pregnancy	The use of illicit drugs and methadone has been related to an increased risk of stillbirth and reduced fetal growth.(29, 30)

The primary outcome that will be measured will be birth weight in grams. Secondary outcomes will be the gestational time in weeks, premature birth, the occurrence of a stillbirth and any congenital defects present.

Birth weight will be recorded on a previously calibrated weighing scale to the nearest gram. The attending midwife or obstetrician will determine birth gestation time and classification of malformation.

Table 5: Other potential confounders that will be analyzed.

Potential Confounders	Rationale
Maternal age at delivery (<20, 20-24, 25-29, 30-34 or   ≥35 years old)	Mothers younger than 20 have been reported to have a higher incidence of low birth weight.(35)
Nulliparous (No/Yes)	Parity was found to be significant influence on the incidence of low birth weight.(35)
Maternal descendants (Europe, Asia, Middle East, South America, North America, Africa, Australia & NZ)	Infants of European decent have been reported to weigh more that of infants of Asian decent.(36)

Electronic cigarette use will be self-reported by the exposed group and recorded by the midwife or trained personnel. E-liquid consumption will be recorded in milliliters per week, the brand of e-liquid used and nicotine concentration of e-liquid will be recorded in milligram per milliliter (indicated on the packaging of e-liquid). The total concentration of nicotine inhaled through electronic cigarettes per week will then be calculated in milligrams.

Application for ethical approval to carry out the study will be done at the start of the study. There will be an application for individual informed consent for the unexposed group from electronic records to be waived for this study. No intervention in care is planned and data for unexposed will be retrospectively gathered. Upon completion of all births in the exposed group electronic records of hospital A and hospital B data for the unexposed group will be gathered. Application of inclusion and exclusion criteria will be applied. Unexposed will be selected with similar maternal traits of maternal age at delivery, nulliparous and region of descendants in order to reduce the chance of confounding. The records will then be randomly selected and used as a comparison to the exposed group.

To carry out this cohort study there are key responsibilities in which we must undertake to ensure data rules are applied to. For obtaining and process of information fairly, the exposed group they will be in the knowledge of their information being shared with the study. This will be explained clearly in the participant information sheet in Appendix 1.A and written consent is given in Appendix 1.B.  Data from electronic records for non-exposed will be pseudonymised, the key of a persons identity will be retained by the data controller only and will not be revealed to third parties.

The specified purpose of the collection and storage of the data will be only to carry out the prospective cohort study of the association of electronic cigarette use in pregnancy with birth weight. Registration with the Data Protection Commissioner will be applied for and collected data will only be used for this study.

Data will be ensured to have been fairly processed and will not be further processed in any manner incompatible with the purpose of the study.

Appropriate security measures will be applied to the storage of data. Paper records and files will be handled in such a way that only approved personnel can access them. They will be stored in a secure location and locked away when not required. Upon completion and gathering of all data, shredding and incineration will be carried out by trained personnel and will securely disposed of. Approved members of staff can only access electronic records under a username and password security system over selected networks. Data will be wiped from the network upon completion of the study.

Only data needed for this study will be gathered from participants. Data of their routine antenatal clinic visits will also be collected. This study will not interrupt the antenatal clinic process, supplemental questions will be asked at the end of the routine questions.

If the participant requests a copy of her gathered data they are entitled to for a small handling fee, provided she makes a request before completion of the study.

There are many factors that may result in bias, therefore, it is important to identify and attempt them to prevent it from occurring.

The biggest concern is response bias. As this is a self-reporting study of electronic cigarette use participants may purposely misreport their behavior or give an incorrect response due to the participant “forgetting”.(37) Explanation that their honesty can help understand the effects of electronic cigarettes in pregnancy and can help society in the future. Encouragement of participants to keep a diary of their use of electronic cigarette use may help reduce this source of bias.

Another source of bias will be selection bias. If the exposed group was not truly comparable with non-exposed with regards to certain confounders (such as maternal age, nulliparous, region of descendants) it would not be representative of the population of interest. Therefore the use of electronic records of maternity hospitals will be applied appropriately in order to minimize the chance of confounders leading to bias. This will provide a larger selection of women to pick from to have more of a true comparison of the association of electronic cigarette use during pregnancy and birth weight.

Attrition bias is also a concern due to women who can be lost to follow up as they may have given birth in another hospital or lost contact. In the interview process, the midwife will ask the mother if she intends to give birth in another hospital or move house by the end of her pregnancy. This will be one of the exclusion criteria. With the participant’s consent upon their first clinic visit, women who gave birth in another hospital unexpectedly, there will be an attempt to make contact with her and their birth information collected from the hospital they gave birth in. To prevent this bias from having a major effect an excess of participants will be recruited, contact details will be taken and consent to contact participant will be acquired.

Withdrawal bias can occur also if certain participants decide to discontinue the study. This could be for many reasons such as embarrassment, too time consuming, privacy issues etc. This can distort the results in follow up, therefore midwives and personnel should have appropriate training to make it clear to the patient the potential benefits to society and possibly the patient themselves if they continue with the study. However not to put the patient in an uncomfortable/ pressured position. If the woman still wants to withdraw it will be recorded.

Inappropriate measurement of the birth weight or gestation time may be a concern and can lead to measurement bias. Ensuring correct training of personnel and that the measurements are completed on a previously calibrated scale will lower the chance of this bias from occurring.

Interview bias may give rise to skewed results. The interviewer may have an inconsistency in questioning, use leading questions and poor body language, which can lead to the bias of recording of data. To prevent this from occurring midwives and personnel will receive correct training to ensure that they do not influence the questions asked. They will be trained to not use leading questions or anything else that can influence the response.

According to The Lancet’s global reference for fetal-weight and birthweight percentiles during 2004 and 2008, the mean birth weight of an infant at 41 weeks is 3428g.(38) In the 95th percentile, the weight of a child would be 4090g. Therefore a single standard deviation can be calculated by (4090g-3428g)/2. The standard deviation is 331g and the mean is 3428g. These will be our values for group 1.

Classification of reduced birth weight will be a reduced weight of 129g from the average mass of a newborn infant.(7) This value was sourced from the influence of active maternal smoking of cigarettes during pregnancy on birth weights. From this study of 34,928 singleton births, it was reported that the average birth weight of a baby born to maternal cigarette use was lower by 129g (95% CI -170, -87) for all babies.(7) Therefore the calculation to find the mean for this group is 3428-129=3299g. This value will be our group 2.

With group 1 having a mean of 3428g and a standard deviation of 331g and group 2 have a mean of 3299g the study size can be calculated. The enrollment ratio will be 1:1, with an alpha value of 0.05 and a power of 90%

Δ = |μ2-μ1| = absolute difference between two means

σ1, σ2 = variance of mean #1 and #2

n1 = sample size for group #1

n2 = sample size for group #2

α = probability of type I error (0.05)

β = probability of type II error (0.1)

z = critical Z value for a given α or β

k = ratio of sample size for group #2 to group #1

k=n2n1=1

n1= (σ12+ σ22/K)(z1-a/2+ z1-β)2∆2

n1= (3312+ 3312/1)(1.96+ 1.28)21292

n1=138

n2=K*n1= 138

n2+n1=276

The sample size suggested is 276 women separated into one group of 138 exposed (users of electronic cigarettes) and another group of 138 unexposed (non-users of electronic cigarettes). This will have an alpha error of 0.05 and a power of 90%.

Birth weight will be classified according to the World Health Organization, a birth weight of below 2500g will be categorized as low birth weight.(39) Preterm births (premature birth) will be classified as less than 37 weeks gestation (less than 259 completed days).(39) Stillbirth will be classified as all pregnancy losses after 22 weeks of gestation for the fetus.(40) Any congenital disorder will follow the World Health Organization definition as any congenital malformations, deformations, and chromosomal abnormalities.(41)

Descriptive statistics will be used in order to describe both groups. Variables that are normally distributed will be summarized in terms of mean and standard deviation. Skewed data will be described in terms of mean and interquartile range. Baseline comparability of groups before analysis will be tested by clinical judgment and formally, using appropriate statistical tests such as t-tests and Mann–Whitney U test. Statistical significance at all tests will be taken to be a p-value of less than 0.05.

Potential confounders that will be taken into account are the maternal age at delivery, nulliparous, maternal descendants (Europe, Asia, Middle East, South America, North America, Africa, Australia & NZ). Continuous outcomes will be expressed as a ratio of the exposed group versus the unexposed group. Binomial outcomes will be expressed as an odds ratio. Data will be presented in both adjusted and unadjusted formats.

Missing data is an issue that can arise during this study. Assuming that the missing data will be at random, the values will be imputed using multiple imputations by chained equations by using a program such as the MICE package. (42) However if this is not applicable, information regarding the participant’s electronic cigarette use will be calculated as an average use over the entire duration of the study (one, two or three visits).

Determination of the loss of follow up rate will be completed at the end of the study. The denominator will be the number of participant’s in the exposed group (electronic cigarette users) and the numerator will be the number within this group lost to follow up. Percentage then will be calculated for the loss of follow up. If the loss to follow up value is less than 5% this indicates little bias, greater than 20% loss can lead to serious threats to validity. However, even if there is <20% loss can have a threat to validity. (43)

If there is a high drop out rate or low follow up, it is possible that this can lead to bias within the results. Therefore sensitivity analysis will be carried out. It will be assumed that the proportion of the women that continued with the study applied to the group as a whole.

Analysis

Within hospital A and hospital B, there are at least 20,000 births per year this would give (34/52) x 20,000 = 13,076 births over a 34 weeks recruitment phase with 10-week contingency. From similar studies within Ireland there are ~7% of women who would not have been booked into antenatal care and of this, ~1.3% would have no antenatal booking interview completed, therefore, there would be ~12,003 left.(44) Also, it has been previously recorded that ~0.9% would have taken an illicit drug or methadone, therefore, they will be removed from the study leaving with a predicted  ~11,895 women.(44) Illicit drug use can have an impact on the development of a child, therefore, these women have been excluded from the study.

Assuming there is a 50% consent rate to participate in the study there will be ~5,947 women. Women may not consent if they are embarrassed by their electronic cigarette use, privacy, or unexplainable. According to the Office for National Statistics in Great Britain, 4.9% of women over the age of 16 are current electronic cigarette users leaving with a predicted number of ~291 women.(45) It has been reported within the Coombe Women’s hospital that 50% of women try to quit smoking when they find out they are pregnant.(46)

Assuming this is equivalent for electronic cigarette use 50% of the women using electronic cigarettes will leave us with ~146 women that will be eligible to be included in the electronic cigarette user group. The occurrence of an ectopic molar or hydatidiform mole pregnancy is ~0.3%, they will be excluded from this study.(47) With 3.45% of births being a twin, triplet or higher and 1% being stillbirths this will then leave the study with ~140 infants. (48, 49) However, stillbirths will be taken into account with statistical analysis.

Women who are not users of electronic cigarettes (n=~5,656)

Women who gave up electronic cigarettes during pregnancy (n=~146)

Women who gave birth to twins, triplets or higher (n=~5)

Women who had an ectopic molar or hydatidiform pregnancy (n=~1)

Women who had a stillbirth (n=~1)

Figure 2: Flow chart of recruitment of exposed pregnant women.

Table 6: Maternal factors associated with birth weight template

Women who only attended one or two of the antenatal clinic interviews will have their electronic cigarette use calculated as an average of those visits. If they have been lost to follow up due to dropping out or giving birth in a different hospital, an attempt to gather this information from the other hospital will be done. If access is not possible it will be noted, their information excluded from the study and study will be completed.

Once the birth information of patients is collected there will be no follow up period for this study.

Table 7: Template for electronic cigarette use among the cohort.

Table 8: Crude and Adjusted OR and 95% CI for low birth weight with the categorized use of electronic cigarettes during pregnancy.

*Adjusted for maternal age, parity and region of descendants.

Table 9: Crude and Adjusted OR and 95% CI for premature births with the use of electronic cigarettes during pregnancy.

* Adjusted for maternal age, parity and region of descendants.

Table 10: Crude and Adjusted OR and 95% CI for still births with the use of electronic cigarettes during pregnancy

* Adjusted for maternal age, parity and region of descendants.

Table 11: Crude and Adjusted OR and 95% CI for congenital defects with the use of electronic cigarettes during pregnancy

* Adjusted for maternal age, parity and region of descendants.

Graphing of the data of birth gestation (in weeks) on the x-axis and birth weight on the y-axis from both the exposed values and non-exposed values will be done. This will visualize the data to see if there is an association between maternal electronic cigarette use and lower gestational time/birth weight.

Analysis of users of subgroups of nicotine strength used and amount of e-liquid consumed per week will be done. This will give a greater view of the relation of exposure to the association if there is any.

A distribution graph of birth weights of both the exposed and unexposed group will be constructed. A predicted bell curve shape is predicted for both groups. The x-axis will be birth weight, and the y-axis will be the number of infants. Both the exposed and unexposed will be placed on the graph with different colour lines to differentiate from one another.

 

 

 

 

 

 

Discussion

This prospective cohort study protocol proposes a method to filling the gap in knowledge of electronic cigarette use in pregnancy and its association with birth weight.

With electronic cigarette use growing rapidly recreationally and as a proposed cessation technique its effect on the unborn fetus is unknown. As tobacco cigarettes have been seen to reduce birth weight could electronic cigarettes be a viable alternative, they have a greater patient acceptability and seen to have no greater adverse effects than that of NRT. Proposal of their use will have to be further examined in order to determine their effectiveness and safety. However, due to lack of studies in the area, vital information about their negative effects has not yet been determined.

Further studies of electronic cigarette use in pregnancy and its long-term effect on infants will also have to be explored in the future. As seen with Bupropion an increased risk of ADHD proposed from its use during pregnancy compared to that of non-users.(16) There is a need for electronic cigarette cohorts to be carried out in the short term and long term effects it has on an infant with its use during pregnancy. This could be positive or negative in the population. It could, in fact, be a better alternative to NRT for patients to quit or it could have negative unknown effects in the future.

Ideas of stricter control of production and sale may be beneficial to general public gave been generated. Refining the production process, reduction of harmful excipients or modifications to devices to reduce nicotine exposure could help reduce the harm of nicotine-containing products such as smoking and smokeless tobacco.

Since the participant’s use of electronic cigarettes is self-reported this may give rise to skewed results if the patient is not honest about their use. Embarrassment, forgetfulness or misremembering can influence this. It could be considered in future studies to measure saliva cotinine levels to examine their nicotine exposure alongside a questionnaire. However, this may be expensive.

Indicating exposure of vapour/nicotine to the patient is hard to indicate. With certain users using modified devices with higher wattage that can give them a “bigger hit” of nicotine leaving them to greater exposure. Also, there is an assumption that the user has the correct inhalation technique. Poor technique may lead to lower levels than predicted. There is a concern also over the use of unregulated e-liquids. Certain liquids have been sold with no indication of its concentration and some have been tested to show that it contained in excess of 100mg/ml concentration of nicotine in solution (5 times over the maximum nicotine concentration allowed by the EU).(50) Currently, with the vast amount of devices, modifications, and liquid brands, there are potentially many influences on nicotine exposure to the user. Studies in the future could potentially focus on the use of selected devices, modifications used or brands.

There is also a concern about women who may have smoked cigarettes or consumed alcohol during their first few weeks of pregnancy not knowing they were pregnant, this could have an influence on the birth weight later in the study. It has been seen that embryos can be 2-6 days behind in growth if exposed to maternal cigarette smoking than that of non-smokers and maternal alcohol use can lead to spontaneous abortion.(51)

This study will give an insight into the effects of electronic cigarette use and its influence on birth weight. However, results from this study will not be conclusive. Repeating of this prospective cohort will give a greater indication of how great electronic cigarette use in pregnancy associated with birth weight. Due to lack of similar studies being carried out in this area, it is hard to predict the results. With the vast amount of confounders that can influence birth weight this study or forms of it will have to be carried out several times. As mentioned by the WHO determination of their safety is key and could potentially be a safer alternative to tobacco cigarettes, NRT, Bupropion or Varenicline. However, this should not let electronic cigarettes be ignored, with the rapid movement to them from tobacco cigarettes it is not appropriate to assume they are entirely safe.

As this study includes wide inclusion criteria, the participants recruited will be generable to the users of electronic cigarettes within the population. With ~13,000 women being questioned within hospital A and hospital B a valid sample will be selected as an appropriate model for the general public within Ireland.

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