Pharmacokinetics, safety and efficacy of methylphenidate during pregnancy in women with Attention-Deficit (Hyperactivity) Disorder

Although Attention-Deficit Disorder with or without hyperactivity (AD(H)D) is a
neurodevelopmental disorder originally diagnosed during childhood, it persists
into adulthood in 65% of cases. AD(H)D is characterized by two different types
of symptoms: attention-deficit and hyperactivity-impulsivity and the estimated
prevalence among adults in the Netherlands is about 2-5%.

In order to warrant a diagnosis, AD(H)D-symptoms must be severe and cause
clinically significant impairment persistently in at least two domains of an
individual*s life. At the age of 17 and older, five examples of inattentiveness
and five examples of hyperactivity or impulsivity have to be present. Likewise,
symptoms have to be present before the age of 12. The classification of AD(H)D
is based on the occurrence of attention deficit and hyperactivity-impulsivity.
ADD is mainly characterized by attention deficit while ADHD-patients often
suffer from a combination of attention deficit and hyperactivity-impulsivity.
This combination of symptoms often occurs in children, giving them the
diagnosis ADHD. In adulthood, the hyperactivity decreases but inattention,
disorganization and impulsivity leads to difficulties in functioning, both at
home and at work.
AD(H)D-symptoms in adulthood (depression, anxiety, substance misuse, and
impairment across different domains of functioning) are often attributed to
depression, anxiety or personality disorder, which may explain a delayed
diagnoses of AD(H)D. However, both the number of adults diagnosed with AD(H)D
and the number of adults treated with AD(H)D medication are on the rise during
the past years.
The initial treatment of AD(H)D consists of (cognitive) behavior therapy and
coaching. Medication should only be prescribed to patients showing a severe
disorder and who do not respond sufficiently to the non-medical treatment. Next
to this, the risk-benefit balance is of great importance while choosing for
medical treatment. First choice of pharmacological treatment in the Netherlands
is methylphenidate (MPD). MPD is a central nervous system (CNS) stimulant drug
with therapeutic effects of which adults with AD(H)D can benefit with
acceptable side effects.

Methylphenidate during pregnancy
MPD is an amphetamine which influences the sympathetic nerve system.10 During
pregnancy, amphetamines may be associated with an abruptio placentae,
pre-eclampsia and intra uterine growth retardation.3,11 Because there is
insufficient information available on the use of MPD after the first trimester,
MPD is discommended in the 2nd and 3rd trimester until more data on the safety
of the (unborn) child is available. The use of MPD during early pregnancy seems
unlikely to increase the risk of birth defects.3

In practice, pregnant patients are off label treated with benzodiazepines,
haloperidol or antidepressants in order to alleviate symptoms of AD(H)D.
However, this alternative way of symptom reduction is often not satisfactory.
Difficulties in organizing, impulsivity and hyperactivity tend to remain
present. Studies show that these symptoms are associated with depression,
physical strain, less eating, the use of caffeine, smoking and poor vitamin
intake.12,13 AD(H)D symptoms and stress that comes with discontinuing MPD could
therefore place both mother and child at risk.9,13

The assumption is that MPD use is increased during fertile phase of life to
alleviate disruptive symptom in several domains, for example domestic and
professional. Therefore, the number of pregnancies exposed to MPD will
increase.14

Recent studies suggested a possible relationship between the use of
AD(H)D-medication during pregnancy and miscarriage, preterm birth, increased
risk of caesarian delivery and 1 minute APGAR <7. 15,16,17,18 However, these
studies did not distinguish between different types of ADHD-medication, so it
is unclear whether these effects are due to MPD. In addition, most of these
associations can not be confidently attributed to stimulant treatment; in these
cases, the diagnosis ADHD or correlates of it seems to be responsible for the
association. Therefore, confounding by indication must be taken into account.

In a recent meta-analysis of Jiang et al., eight cohort studies that estimated
adverse maternal or neonatal outcomes associated with exposure to ADHD
medication during pregnancy were included. No association of MPD was found with
pre*eclampsia, diabetes, post*partum haemorrhage, placental abruption,
spontaneous abortion, preterm birth, small for gestational age (SGA), low birth
weight, low Apgar scores, stillbirth and major congenital malformations.
Exposure to ADHD medication was associated with an increased risk of neonatal
intensive care unit (NICU) admission compared with no exposure at any time (RR
1.88; 95% CI, 1.7-2.08) and compared with women with exposure either before or
after pregnancy (RR 1.38; 95% CI, 1.23-1.54; P < 0.001). However, only two
studies contributed to these pooled estimates and no distinction was made
between type of ADHD-medication.19 Another meta-analysis (Lin Li et al.)
included the same eight studies as Jiang et al. and demonstrated that the
absolute RDs were overall small in magnitude, particularly for studies using
alternative comparisons groups to rule out confounding. Because of the limited
number of studies and control for confounding, Lin Li et al. stated it is
currently unclear whether these small associations are due to a causal effect
of prenatal exposure to ADHD medication or confounding.20
In the meta-analysis of Jiang et al., it was found that methylphenidate is
marginally associated with cardiac malformations in the neonate (RR 1.27; 95%
CI, 0.99*1.63; P = 0.065) compared to no exposure. This correlation was also
found in the meta-analysis of Koren et al. (OR 1.59; 95% CI, 1.02-2.49), which
focused on congenital malformations including only MPD-exposed infants. This
study also yielded an OR of 1.26 (95% CI, 1.05-1.51) for major malformations.21
More research on the possible association between MPD use during pregnancy and
(cardiac) malformations in the neonate needs to be conducted.

Pharmacokinetics of MPD during pregnancy
In general, during pregnancy the aim is to determine the lowest but effective
dose of psychotropic drugs. MPD is a short-acting stimulant with a duration of
action of 1 to 4 hours and a pharmacokinetic half-life value of 2 to 3 hours,
and with a maximum exposure at two hours. It is an indirect acting epinephrine
like drug, which does not influence the epinephrine receptors directly, but
inhibits the reuptake of dopamine and norepinephrine. MPD is quickly and
completely absorbed by the intestines. The blood brain barrier is passed easy
as a result of high lipophilicity and low protein binding. MPD are 50-90 %
excreted in urine as ritalinic acid. Only 1.5-3.3 % is excreted by faeces. A
marked individual variability in the dose-response is observed, dosage has to
be titrated for optimal therapeutic effect with minimal toxicity.
Carboxylesterase 1 (CES1A1) is the major enzyme responsible for the first pass,
stereoselective metabolism of MPD.22,23 Several physiological changes occur in
the pregnant state, affecting the pharmacokinetics of many drugs, especially
psychotropics.24 It is not clear yet how and if CES1A1 enzymes change during
pregnancy. Therefore, it is not clear if MPD serum levels change during
pregnancy. This possible change in MPD serum levels may be relevant in the
treatment of pregnant women.

Primary objective is assessment of the pharmacokinetic profile of MPD in
pregnancy. Secondary objectives are the safety and efficacy of any use of MPD
during pregnancy.

This study compromises a prospective cohort study in a level II and III
obstetrical setting in a pregnant population with AD(H)D and their offspring.
We will measure drug concentration levels in the mother during pregnancy and
after birth in both the mother and the neonate to assess the pharmacokinetic
profile of MPD in pregnancy. Furthermore, we will look at the effect of
(dis)continuing MPD during pregnancy on birth weight, miscarriages, APGAR
score, Finnegan score, major congenital malformations and maternal AD(H)D
symptom severity. We will follow AD(H)D-patients included in the Isala
Psychiatry-Gynaecology-Pediatrics (PGP) protocol during their pregnancy by
taking blood samples and conducting WFIRS-S at different moments in pregnancy.
The exact number of blood samples and WFIRS-S assessments will depend on the
stage of pregnancy the patient is in when she is included in the study. All
other parameters will be determined after birth.

The risks of participation in this study compromises extra blood sampling for
patients and the newborn attending the study programme. Blood sampling can
cause infections in exceptional cases. Only qualified personnel will draw blood
samples according to standard procedures in the Isala Klinieken. APGAR score,
birth weight and major congenital malformations are part of the regular control
performed after giving birth. The Finnegan score is validated for
opiate-exposed infants. Because there is no scoring system for the measurement
of withdrawal symptoms in MPD-exposed infants, this score list is used. The
WFIRS-S is the only measure of functional impairment that looks at 7 specific
domains and has been psychometrically validated in the AD(H)D population. This
rating scale is already part of the regular care of AD(H)D-patients. The blood
sampling and WFIRS-S administrations will be combined with visits to the
psychiatrist already planned. In this way, the burden for the patients will be
minimal. The patients decide for themselves whether they want to continue,
adjust or stop using AD(H)D-medication during their pregnancy. All medical
treatment decisions will be made between the participant and her treating
provider, independent of study participation. By assessing the different
endpoints in women during pregnancy with or without the use of MPD, the effect
of MPD on both mother and child can be determined. This information is valuable
for AD(H)D-treatment in pregnant women in the future.