International Open Access Journal of Prevention and Research in Medicine
Director Prof. Francesco Tomei

The Author, in the present research and in the population-based study of 40 eyes affected by various types of glaucoma, examined the correlation with possible iatrogenic side effects as well as the forensic aspects related to a possible progression of glaucoma, which does represent a crucial issue in social medicine as a result of the incidence of visual impairment in adulthood, wherever more specific drugs but with potentially adverse health effects cannot be used during pregnancy due to the magnitude and the  variety of their pharmacological side effects.
In fact, even in the case of a topical therapy with a very low anti-glaucomatous dosage, such as timolol  0.1% gel, a significant amount of its volume up to 80% results in systemic absorption, with all the associated iatrogenic effects, particularly dangerous during the first weeks of pregnancy.
Furthermore, it is also important to consider the particular fetal physiology, which may determine a greater persistence in the circulation of fat-soluble and non-ionized drugs, as the one under review.
It is also obvious that discontinuation of medical therapy during pregnancy, in order to safeguard fetus from possible pharmacological side effects, will only be possible for the patients who, during the time period considered, do not  have excessive increases in intraocular pressure, which cause the specific symptoms of glaucoma.
Indeed, persistent symptoms such as eye pain, a decreased central and / or peripheral vision, the perception of colored halos around unshielded light sources, are particularly annoying and intolerable by patients.

Glaucoma has always been an issue of great social importance, but fortunately it is a disease that rarely occurs in pregnancy.
Currently, there is an increasingly large number of women planning pregnancy at an average age of over 35 years, when the diagnosis of glaucoma has already been made since this is typically a disease of middle and / or advanced age. Thus, at present the association  pregnancy- glaucoma is more detectable.
The choice of therapy for the control of intra-ocular pressure (IOP) in pregnancy is therefore particularly difficult, because of the possible side effects on both the woman and on the product of conception.
However, in the presence of an excessive intraocular pressure , potentially detrimental to the visual function and, as such, requiring  a hypotonic treatment,  the therapeutic choice must be appropriate so as to prevent the detrimental effects of pregnancy and also to safeguard the child’s health.
Given that no medication used for glaucoma appears to be  completely free from side effects for the fetus nor for the infant during the nursing period, in this scientific work we monitored for a period of eighteen months twenty women suffering from glaucoma , with the aim of highlighting the possible side effects of medical therapy proposal:
- On pregnancy;
- On the fetus;
- On the infant during breastfeeding.
Moreover, the ethical and legal aspects are also very important and are likewise worthy of attention.
Fortunately, as concerns the difficulty of choosing a hypotonic drug therapy, during gestation but especially during  the 2nd -3rd month, ocular pressure naturally tends to shrink (about 10%), due to the physiological changes induced by the gestational status in the eyeball.
This condition is probably secondary to both the new hormonal balance and the constant metabolic acidosis that systematically accompanies pregnancy.
Indeed, some authors argue that the flow of aqueous humor remains constant during and after pregnancy; however, intraocular pressure decreases due to the increase of the aqueous humor outflow, which represents the last therapeutic effect sought by the various medical, parasurgical (laser) and surgical treatment options.
These changes are more closely related to increased levels of progesterone and b-HCG, which, acting as an antiglucocorticoid drug, would pharmacologically  increase the  ease in the outflow of aqueous humor.
Several authors claim that high levels of progesterone during pregnancy increase the elasticity of the connective structures present in the trabecular meshwork which is the anatomical pathway of ocular aqueous humor outflow, as well as also blocking the hypertensive effects of the endogenous corticosteroid factors.

Materials and Methods
Based on the above-described physio-pharmacological assumptions, we carried out our research in the Eye Clinic of  Policlinico Umberto I of  Rome on twenty pregnant women with a mean age of 38 years + / -0.9, suffering from overt glaucoma characterized by the specific symptomatologic triad (intraocular hypertension, specific deficits of the visual field and clinically evident deficits of optic disc) or by simple intraocular hypertension, namely:
- 2 women  suffering from pigment dispersion syndrome;
- 18 women suffering from open-angle glaucoma (40 eyes in total).
None of the patients examined had previously undergone surgical and / or parasurgical eye  intervention before the pregnancy in question.
All patients were also widely informed about the risks associated with the present study by means of a valid informed consent they were asked to sign. Hence, at the time of enrollment and for the first three months of gestation , the glaucoma drug therapy in use before pregnancy was discontinued in order to limit the teratogenic effects of the hypotonic eye medications used (1).
Of course, throughout pregnancy, the patients were routinely subjected to periodical oculistic and  obstetric check-ups.
Specialist eye examination included: visual acuity measurement (using Snellen charts), ocular examination, applanation tonometry, fundus oculi examination with assessment of the cup/disc at the level of the optic disc, OCT examination of the optic disc and visual field, according to the Hamphrey 30-2 method and statistical processing of the results of this exam.
The data collected were thereafter broken down and analyzed  by age group, according to the drugs used, based on the type of glaucoma,  the level of intraocular pressure (IOP) prior to and  after enrollment, as well as on  the visual fields obtained before, during and after pregnancy.
The clinical data in question were also used as a reference to detect any worsening of the clinical picture.
As a matter of fact, only the eyes showing a variation of less than 5 mmHg of IOP or with an IOP lower than 20 mmHg in the course of the study, were considered acceptable.
Indeed, during the second and third trimesters of pregnancy , intraocular pressure tends to decrease in women with intra-ocular hypertonia, whereas  high levels of  IOP, requiring  continued medical treatment, still persist in some women (2, 3).
A worsening of the existing visual field defects detected and /or the presence of a new arched defect, or showing the so-called "nasal jump" (typical of glaucoma in evolution), or an increase in the constriction of isopteres was in fact considered significant.
In patients showing a significant rise in IOP and/or associated with a significant reduction in retinal sensitivity compared to the visual fields previously measured, however, a therapy with Timolol  0.1% gel once daily was readily established (4).
We chose the simple Timolol 0.1% as a drug to be introduced in our study  since,  as confirmed by scientific works carried out by other authors, in addition to being the specific beta-blocker at  minimum dosage currently present on the market, this drug  does not induce further weight reduction at birth even if used after the first trimester of pregnancy (5, 6).
Furthermore, the gel solution given once daily, also associated to the subsequent occlusion of the lacrimal grooves in the same patient in order to reduce the systemic absorption of the drug, also enabled to greatly reduce the occurrence of unpleasant side effects likely to affect the product of  conception.
These patients were  also constantly assisted in the Department of Gynecology of our hospital, where all fetal parameters were properly monitored.
Indeed, the international literature referred to above contains many reports of fetal complications from beta-blockers medications, mainly concerning the occurrence of fetal bradycardia and other cardiac arrhythmias (7), however  no pathophysiological alteration of this type has so far been detected with the topical ocular therapies, based on low doses of timolol also administered in gel (8).

Our study focused on  the observation of  IOP  in 20 eyes of 10 women, all pregnant and to which  IOP therapy was discontinued.
The average level of  IOP observed in the 20 eyes was as follows: 17.7 mmHg during the first quarter, 16.8 mmHg in the second quarter and 15.7 mmHg  in the third quarter.
In one eye of a patient with pigment dispersion syndrome, a prompt topical IOP medical therapy (timolol 0.1% gel) was necessary  from the second trimester of pregnancy.
Indeed, in this case  IOP had increased from 21 mmHg during the first 2 months, 24 in the 3rd month and up to 28 mmHg in the second quarter.
The topical therapy used, however, allowed a rapid reduction of intraocular pressure until resetting it to 20mmHg in the first month and then it remained constant at 19mmHg, until the end of pregnancy without fortunately resulting in significant anatomic changes of the optic nerve or the retinal sensitivity.
In 4 eyes of 2 patients with open-angle glaucoma, the topical IOP therapy (timolol 0.1% gel) was instead necessary since the 2nd quarter of pregnancy.

Indeed, we observed an increase in IOP in the first 2 months of the second quarter, till an average of 25.25 mmHg. However, by administering the drops we were able to keep  IOP under control  below 20 mmHg until the end of  pregnancy.
No change was recorded during specialist fetal controls.
In these patients, timolol was then discontinued seven days before giving birth, in order to avoid complications in the infant at the beginning of the labor and replaced with topical prostaglandins during lactation (9), which are found to be compatible with this maternal physiological function also by the American Academy of Pediatrics.
However, the subsequent monitoring of infants and mothers did not fall within the scope of our study.
Medico-legal and ethical considerations
In the light of the results of this scientific work and of the experience gained over time by our school (Scuderi and Balacco Gabrieli), as well as in the light of the considerations by modern and contemporary literature on the subject of iatrogenic effects and side effects of specific antiglaucomatous drugs , even from the medico-legal point of view (10, 11), also taking into account  the current case law on the subject, the pathophysiology of different clinical types of glaucoma, the current etiopathological guidelines  expressed by many authors and of course mentioned in the bibliography (12), which seem to consider the glaucomatous disease more like an optic nerve degeneration genetically conditioning (13, 14), rather than  as an expression of degeneration induced only by mechanical factors associated with the intraocular hypertonia (but that always characterizes the clinical course of this disease), the young age of the mothers, as well as the need not to induce  fetal anatomical and physiological iatrogenic changes of a permanent nature, we can consider as appropriate, to our best knowledge and belief, the systematic replacement of antiglaucomatous molecules topically used  and more likely to have systemic side effects with those presenting fewer side effects and more largely studied, even because they have long and more extensively been used in ophthalmological clinical practice. As an alternative we also envisage the possibility of discontinuing medical therapy in these patients for a certain period of time, especially with respect to the periods of pregnancy considered as more  susceptible to iatrogenic effects in the unborn child. Indeed, the above described considerations remain valid only for a relatively short period of time, if compared to the time required for the clinical evolution of glaucoma, which is usually measured in years, decades and often includes lifetime, as it is also clear from the scientific literature and medico-legal references (10, 15). 

In conclusion, after topical application of the eye drops in question (Timolol 0.1% gel), roughly 80% of its volume drains through the lacrimal grooves and is  then absorbed into the blood of the organism, thus circumventing the hepatic metabolism that specifically applies to all ß-blocker drugs (2).
This can explain all the possible side effects of these  topical ophthalmic drugs, despite the low dosage.
Moreover, since these drugs are fat soluble, non-ionized and with a low molecular weight, they readily cross the placenta and enter the fetal circulation where they can be excreted via the kidneys into the amniotic fluid, via  the skin or the lungs. The half-life of an administered drug can therefore be much longer in the fetus than in adults, due to a recirculation through swallowing, respiration and fetal excretion (3). Furthermore, the blood volume and the immature structures of the metabolic system of the fetus, are frequently associated with these mechanisms.
Consequently, plasma levels of topical ophthalmic drugs in the mother can certainly exceed the therapeutic dose range in the fetus, which can lead to an increased risk of systemic adverse effects on the latter (5).
Obviously this study was conducted on patients in a state of pregnancy for  most of whom it  was possible to discontinue the antiglaucomatous therapy  in place until the time of labor, whereas for some of them  it was necessary to reintroduce  a specific topical therapy during the study.
We also believe that the gel formulation and single dose administration of these drugs represent  valid therapies for the treatment of glaucoma in pregnancy, necessarily associated with digital occlusion of the lacrimal grooves by the patient herself.
Obviously, this administration cannot be deprived of a strict specialist  control of the ocular conditions of the patient throughout pregnancy.
In fact,  the above-referred  international  literature  (16)  confirms the possibility of using low-dose timolol during the gestational state without complications for the unborn child, but the cases studied so far are  relatively few yet.
In the light of the experience published  herein, we believe that in the case of women who obviously do not intend to undergo parasurgical or surgical interventions for glaucoma, it is nevertheless necessary to discontinue  all antiglaucoma drugs used in the first quarter, if possible, even throughout pregnancy, if the rise of intraocular pressure does not reach levels incompatible with a good eye coenaesthesia, with specific symptoms represented by eye pain, decreased visual acuity, presence of colored halos around light sources unshielded, etc.
Our study has highlighted that  IOP fluctuations during pregnancy are limited and lower than the values prior to that state, while this situation appears to be maintained throughout pregnancy (17).